Thames Valley SACT Regimens · Thames Valley CAV SACT regimens – Lung Cancer 8 Indication: First line treatment for SCLC in patients not able to tolerate platinum and etoposide

Thames Valley

Thames Valley SACT Regimens

Lung Cancer

Thames Valley

Network SACT Regimens – Lung Cancer 2

Notes from the editor All SACT regimens, and associated guidelines eg antiemetics and dose bands are available on the Network website www.tvscn.nhs.uk/networks/cancer-topics/chemotherapy/ Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] Acknowledgements These regimens have been compiled by the Network Pharmacy Group in collaboration with the Lung CAG with key contributions from Dr Nick Bates, Consultant Oncologist, BHT Dr Paul Rogers, Consultant Oncologist, RBFT Dr Joss Adams, Consultant Oncologist, RBFT Prof Denis Talbot, Consultant Oncologist, OUH

© Thames Valley Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner.

http://www.tvscn.nhs.uk/networks/cancer-topics/chemotherapy/

Thames Valley

SACT regimens – Lung Cancer 3

Thames Valley SACT Regimens Lung Cancer Network SACT regimens used in the management of Lung Cancer Date published: November 2019 Date of review: November 2021

SACT Regimens Name of regimen Indication Page

List of amendments to this version 5

ACE Small Cell lung 6

CAV Small Cell lung 8

Carboplatin Etoposide Small cell lung 10

Cisplatin (75) Etoposide (100) with concurrent RT Small cell lung 12

Cisplatin (60) Etoposide (120) Small cell lung 14

Topotecan oral Small cell lung 16

Afatinib Non small cell lung 18

Alectinib Non small cell lung 20

Atezolizumab Non small cell lung 23

Brigatinib Non small cell lung 28

Carboplatin Pembrolizumab Pemetrexed Non small cell lung 33

Ceritinib Non small cell lung 37

Cisplatin (50) Etoposide (50) with concurrent RT Non small cell lung 40

Cisplatin Pembrolizumab Pemetrexed Non small cell lung 42

Cisplatin Vinorelbine with concurrent RT Non small cell lung 46

Gemcitabine Cisplatin Non small cell lung 48

Cisplatin 40 RT Non small cell lung 50

Crizotinib Non small cell lung cancer 52

Dacomitinib Non small cell lung 54

Docetaxel 75 Non small cell lung 57

Docetaxel (75) Cisplatin (75) Non small cell lung 59

Docetaxel (75) Carboplatin Non small cell lung 61

Durvalumab Non small cell lung 63

Erlotinib Non small cell lung 67

Gefitinib Non small cell lung 69

Thames Valley


Name of regimen Indication Page

Gemcitabine (1200) Carboplatin Non small cell lung and small cell lung 71

Gemcitabine Non small cell lung 73

Nintedanib Docetaxel Non small cell lung 75

Nivolumab Non-small cell lung 78

Osimertinib Non small cell lung 82

Paclitaxel 80mg (days 1, 8 and 15) Non small cell lung 84

Pembrolizumab Non small cell lung 86

Vinorelbine (25) Carboplatin Non small cell lung 89

Vinorelbine (25) Cisplatin (80) Non small cell lung 91

Vinorelbine Non small cell lung 93

Vinorelbine (oral) Non small cell lung 94

Vinorelbine elderly (oral) Non small cell lung 96

Vinorelbine (oral) Cisplatin Non small cell lung 98

Vinorelbine (oral) Carboplatin Non small cell lung 101

Carboplatin Pemetrexed Non small cell lung, Mesothelioma 103

Cisplatin Pemetrexed Non small cell lung, Mesothelioma 105

Pemetrexed maintenance Non small cell lung 107

Pre and post hydration regimens 109

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List of amendments in this version Regimen type: Lung Tumours Date due for review: November 2021 Previous Version number: 4.1 This version number: 4.2 Table 1 Amendments

Page Amendment Made/ asked by

Table 2 New regimens to be approved and checked by CAG included in this version

Name of regimen Indication Reason / Proposer

Carboplatin Pembrolizumab Pemetrexed

Non small cell lung CDF

Cisplatin Pembrolizumab Pemetrexed

Non small cell lung CDF

Brigatinib Non small cell lung CDF

Dacomitinib Non small cell lung CDF

Durvalumab Non small cell lung CDF

For anti-emetic guidelines: http://tvscn.nhs.uk/networks/cancer/cancer-topics/chemotherapy/

For dose banded chemotherapy standardized product specifications: www.england.nhs.uk/commissioning/spec-services/npc-crg/group-b/b02/dose-banded-chemotherapy-standardised-product-specifications/

Thames Valley


ACE Indication: Has been used as first line treatment for SCLC but platinum/etoposide is preferred People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 DOXORUBICIN 40mg/2

IV bolus CYCLOPHOSPHAMIDE 600mg/m2

IV bolus ETOPOSIDE 100mg/m2

infusion in 1000ml* sodium chloride 0.9% over 60 minutes Day 2 ETOPOSIDE 100mg/m2

infusion in 1000ml* sodium chloride 0.9% over 60 minutes Day 3 ETOPOSIDE 100mg/m2 infusion in 1000ml* sodium chloride 0.9% over 60 minutes *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% NB Day 2 and 3 etoposide can be given orally ETOPOSIDE 200mg/m2

PO but is not recommended as oral absorption is variable (it may cause reduced efficacy or severe toxicity in patients), the intravenous route is preferred, however for logistical reasons the oral route may be necessary.

Cycle Frequency: Every 21 days Number of cycles: Usually 6 (subject to tolerance and response)

DOSE MODIFICATIONS Doxorubicin: Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit If AST is 2-3 x ULN give 75% dose If AST is >3 x ULN give 50% dose Maximum cumulative dose = 450 mg/m2

(in normal cardiac function) = 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation)

Etoposide: CrCl >50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision

ACE Lung CAG Chair Authorisation: Date:

Page 1 of 2 Published: November 2019 Review: November 2021

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Cyclophosphamide: GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration

Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFT) Serum Creatinine

2) Non urgent blood tests Tests relating to disease response/progression ECG (possibly ECHO) required if patient has preexisting cardiac disease (Doxorubicin)

CONCURRENT MEDICATION

ANTIEMETIC POLICY High emetic risk day 1 Low emetic risk days 2 and 3

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cyclophosphamide may irritate bladder, drink copious volumes of water. Cardiotoxicity – Monitor cardiac function to minimise the risk of anthracycline induced cardiac failure. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue.

REFERENCES 1. Aisner J et al. Cancer Treat Rep 1982; 66: 221 230 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic

impairment. 2009, The North London Cancer Network.

ACE Lung CAG Chair Authorisation: Date:


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CAV Indication: First line treatment for SCLC in patients not able to tolerate platinum and etoposide (e.g. performance status of 3). Can also be used as second line treatment after relapse. People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 VINCRISTINE 1.3mg/m2

(max. 2 mg) in 50ml sodium chloride 0.9% IV over 10 mins DOXORUBICIN 40mg/m2

IV bolus CYCLOPHOSPHAMIDE 750 mg/m2

IV bolus Cycle Frequency: Every 21 days Number of cycles: Usually 6 (subject to tolerance and response)

DOSE MODIFICATIONS Vincristine: If patient complains of tingling of fingers and/or toes, discuss. Bilirubin 25-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L and normal AST give 50% dose Bilirubin >51micromol/L and AST >180u/L omit Doxorubicin: Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit If AST is 2-3 x ULN give 75% dose If AST is >3 x ULN give 50% dose Maximum cumulative dose = 450 mg/m2

(in normal cardiac function) = 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation)

Cyclophosphamide: GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose

CAV Lung CAG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

Liver function tests (LFT) Serum Creatinine 2) Non urgent blood tests Tests relating to disease response/progression ECG (possibly ECHO) required if patients has pre-existing cardiac disease (Doxorubicin)


ANTIEMETIC POLICY High emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity – Monitor cardiac function to minimise the risk of anthracycline induced cardiac failure. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cyclophosphamide may irritate bladder, drink copious volumes of water.

REFERENCES 1. Greco FA et al. Am J Med 1979; 66: 625 630. 2. Roth BJ et al. J Clin Oncol 1992; 10: 282291 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


CAV Lung CAG Chair Authorisation: Date:


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CARBOPLATIN ETOPOSIDE Indication: Standard first line treatment for SCLC People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 CARBOPLATIN AUC 5 infusion in 500ml glucose 5% infusion over 30 minutes

Dose (mg) = AUC x (GFR+25) ETOPOSIDE 100mg/m2



infusion in 1000ml* sodium chloride 0.9% over 60 minutes *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% NB Day 2 and 3 can be given orally ETOPOSIDE 100mg/bd

PO but is not recommended as oral absorption is variable (it may cause reduced efficacy or severe toxicity in patients), the intravenous route is preferred, however for logistical reasons the oral route may be necessary. If days 2 and 3 are given orally the day 1 IV dose should be increased to 120mg/m2.

Ideally EDTA GFR should be used, Cycle Frequency: Every 21 days Number of cycles: Usually 6 (subject to tolerance and response)

DOSE MODIFICATIONS Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If GFR / calculated CrCl = or < 20ml/min contraindicated. Etoposide: CrCl >50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision

Carboplatin/ etoposide

Lung CAG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL ≥10 < 10


Ideally EDTA GFR should be used (Carboplatin) Creatinine clearance (GFR) calculated, at the Consultants discretion Liver function tests (LFT) 2) Non urgent blood tests. Tests relating to disease response/progression

CONCURRENT MEDICATION FOR PREVENTION Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours.

ANTIEMETIC POLICY Moderate emetic risk day 1 Low emetic risk days 2 and 3

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity – monitor. REFERENCES 1. Skarlos DV et al. Ann Oncol 1994; 5: 601 607 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic

impairment. 2009, The North London Cancer Network. 3. Study 12/14

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CISPLATIN (75) ETOPOSIDE (100) Indication: Standard first line treatment for SCLC with concurrent radiotherapy People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 Pre-hydration

ETOPOSIDE 100mg/m2

infusion in 1000ml* sodium chloride 0.9% over 60 minutes CISPLATIN 75mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post hydration

Day 2 ETOPOSIDE 100mg/m2


infusion in 1000ml* sodium chloride 0.9% over 60 minutes *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% NB Day 2 and 3 etoposide can be given orally ETOPOSIDE 200mg/m2/day but is not

recommended as oral absorption is variable (it may cause reduced efficacy or severe toxicity in patients), the intravenous route is preferred, however for logistical reasons the oral route may be necessary.


DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min omit dose If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration. Etoposide: CrCl >50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision

Cisplatin 75 / etoposide 100



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Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) calculated, or EDTA at the Consultants discretion (Cisplatin) Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre and post hydration prescribed as per day case schedule at the end of TVCN regimens. If urine output is <100 ml/hour or if patient gains >2kg in weight during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities.

REFERENCES 1. Evans WK et al. J Clin Oncol 1985; 3: 1471 1477. Roth BJ et al. J Clin Oncol 1992; 10: 282291 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Cisplatin 75 / etoposide 100



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CISPLATIN (60) with ETOPOSIDE (120) Indication: Standard first line treatment for SCLC at RBH and HWP People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 Pre-hydration ETOPOSIDE 120mg/m2

infusion in 1000ml* sodium chloride 0.9% over 60 minutes CISPLATIN 60mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post-hydration Day 2 ETOPOSIDE 120mg/m2


infusion in 1000ml* sodium chloride 0.9% over 60 minutes *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% NB Day 2 and 3 etoposide can be given orally ETOPOSIDE 240mg/m2/day but is not

recommended as oral absorption is variable (it may cause reduced efficacy or severe toxicity in patients), the intravenous route is preferred, however for logistical reasons the oral route may be necessary.


DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration Etoposide: CrCl >50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision

Cisplatin 60 /etoposide 120



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INVESTIGATIONS 1) Blood results required before SACT administration

Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100

Neutrophils x 109/L ≥1.5 < 1.5

Creatinine clearance (GFR) calculated, or EDTA at the Consultants discretion (Cisplatin) Liver function tests (LFT) 2) Non urgent blood tests: tests relating to disease response/progression



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS

Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities.

REFERENCES 1. Evans WK et al. J Clin Oncol 1985; 3: 1471 1477. 2. Roth BJ et al. J Clin Oncol 1992; 10: 282291 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Cisplatin 60 /etoposide 120 in



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TOPOTECAN (Hycamtin) (oral) Indication: Relapsed small cell lung cancer (second line) People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE) NICE: Oral topotecan is recommended as an option only for people with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen is not considered appropriate and the combination of cyclophosphamide, doxorubicin and vincristine (CAV) is contraindicated (for details of the contraindications to CAV see the summary of product characteristics for each of the component drugs). DRUG REGIMEN Days 1 to 5 Topotecan 2.3mg/m2 orally daily Cycle Frequency: Every 3 weeks until progression DOSE MODIFICATIONS Topotecan: Renal impairment CrCl >40ml/min give 100% dose CrCl 20-39ml/min give 50% dose CrCl <20ml/min contraindicated Hepatic impairment Bilirubin <170micromol/L give 100% dose Bilirubin >170micromol/L Clinical decision Neutropenia Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts. In this clinical situation, dose reduction is usually appropriate If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m2/day to 1.9 mg/m2/day (or subsequently down to 1.5 mg/m2/day if necessary).

Topotecan oral



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INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration

Give Discuss

Hb x g/dL 9 < 9

Plt x 109/L 100 < 100 Neutrophils x 109/L 1.5 < 1.5 1st treatment, <1.0 for subsequent treatment Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION ANTIEMETIC POLICY Low emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Febrile neutropenia Interstitial lung disease Diarrhoea - may be severe and on occasion associated with neutropenic colitis. It should be managed aggressively with anti-diarrhoeals, antibiotics, maintenance of hydration and admission if required. REFERENCES 1. NICE TA 184 November 2009 2. SPC November 2010

Topotecan oral



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AFATINIB (Giotrif) Indication: Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation-positive locally advanced or metastatic Non Small Cell Lung Cancer where the person has not previously had an EGFR-TK inhibitor

NICE TA310 Afatinib is recommended as a possible treatment for adults with locally advanced or metastatic non-small-cell lung cancer if: their cancer tests positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and they have not had a type of drug called an EGFR-TK inhibitor before

DRUG REGIMEN Day 1 Afatinib 40mg orally daily (may be escalated to 50mg/daily) Cycle Frequency: Until disease progression or unacceptable toxicity. Review every 2 months by CT scan

DOSE MODIFICATIONS If dose reduction required reduce dose by 10mg increments to 20mg Afatinib: Renal impairment Severe renal impairment (CrCl <30ml/min) not recommended. Hepatic impairment Exposure to afatinib is not significantly changed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Adjustments to the starting dose are not necessary in patients with mild or moderate hepatic impairment. This medicinal product has not been studied in patients with severe (Child Pugh C) hepatic impairment. Treatment in this population is not recommended

Afatinib Lung CAG Chair Authorisation: Date:


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https://www.nice.org.uk/guidance/ta310/ifp/chapter/the-condition-and-the-treatment





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Give Discuss

Hb x g/dL ≥10 < 10


Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Take one hour before or two hours after meals. Some of the following may be required for treatment of the skin rash: E45 / Diprobase, Hydrocortisone 1%/2.5%, Clindamycin gel 1%, Oxytetracycline 500mg po bd (for 2 weeks) Prednisolone 25mg po od for 7 days then reducing by 5mg per day to stop.

ANTIEMETIC POLICY Minimal emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin rash – initial rash may be severe. Diarrhoea –Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal medicinal products especially within the first 6 weeks of the treatment is important and should start at first signs of diarrhoea. REFERENCES Afatinib Named Patient Use (1200.52) Information Pack Sept 2011 SPC June 2014

Afatinib Lung CAG Chair Authorisation: Date:


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ALECTINIB (Alecensa) Alectinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer where the following criteria are met: 2. The patient has a histologically or cytologically confirmed diagnosis of stage IIIB or IV non small cell lung cancer that carries an anaplastic lymphoma kinase (ALK) rearrangement 3. The patient has received no previous ALK-targeted therapy 4. The patient has received no previous cytotoxic chemotherapy for locally advanced or metastatic non small cell lung cancer ie no previous systemic treatment except when this has been given as neoadjuvant or adjuvant therapy or concurrently with radiotherapy 5. Alectinib will be used only as single-agent therapy 6. The patient has an ECOG performance status of 0 or 1 or 2 7. The patient either has no brain metastases or, if the patient has brain metastases, the patient is symptomatically stable prior to starting alectinib 8. The patient will be treated until loss of clinical benefit or excessive toxicity or patient choice to discontinue treatment, whichever is the sooner 9. Treatment breaks of up to 6 weeks are allowed but solely to allow toxicities to settle 10. Alectinib will be otherwise used as set out in its Summary of Product Characteristics 11. In cases of intolerance to alectinib, either ceritinib or crizotinib is to be used only if the patient has not had progressive disease whilst on alectinib. Neither ceritinib nor crizotinib are to be used following disease progression on alectinib as there is no current clear evidence to support treatment with ceritinib or crizotinib after disease progression on alectinib. Alectinib cannot be used in any line other than 1st line as the manufacturer chose not to make a submission to NICE for its licensed indication for use after crizotinib

DRUG REGIMEN Day 1 Alectinib 600mg orally twice daily Cycle Frequency: Until disease progression or unacceptable toxicity. Review every 2 months by CT scan

DOSE MODIFICATIONS If dose reduction required reduce dose by 10mg increments to 20mg Alectinib: Dose reduction schedule Dose level Starting dose 600 mg twice daily First dose reduction 450 mg twice daily Second dose reduction 300 mg twice daily

Alectinib Lung CAG Chair Authorisation: Date:


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Dose modification advice for specified Adverse Drug Reactions CTCAE grade Alecetinib treatment ILD/pneumonitis of any severity grade Immediately interrupt and permanently discontinue Alecetinib if no other potential causes of ILD/pneumonitis have been identified.

ALT or AST elevation of Grade ≥ 3 Temporarily withhold until recovery to baseline (> 5 times ULN) with total or ≤ Grade 1 (≤ 3 times ULN), then resume at bilirubin ≤ 2 times ULN reduced dose

ALT or AST elevation of Grade ≥ 2 Permanently discontinue Alecetinib (> 3 times ULN) with total bilirubin elevation > 2 times ULN in the absence of cholestasis or haemolysis

Bradycardia Grade 2 or Grade 3 Temporarily withhold until recovery to ≤ Grade 1 (symptomatic, may be severe and (asymptomatic) bradycardia or to a heart rate of medically significant, medical ≥ 60 bpm. Evaluate concomitant medicinal products intervention indicated) known to cause bradycardia, as well as anti-hypertensive medicinal products. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60bpm. If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dose upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60bpm.

Bradycardia Grade 4 (life-threatening Permanently discontinue if no contributing concomitant consequences, urgent intervention medicinal product is identified. If a contributing indicated) medicinal product is identified and discontinued, or its dose is adjusted, resume at reduced dose upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm, with frequent monitoring as clinically indicated. Permanently discontinue in case of recurrence.

CPK elevation > 5 times ULN Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at the same dose.

CPK elevation > 10 times Temporarily withhold until recovery to baseline or to ULN or second occurrence of ≤ 2.5 times ULN, then resume at reduced dose CPK elevation of > 5 times ULN



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Hepatic impairment No dose adjustment is required in patients with mild hepatic impairment. Alecensa has not been studied in patients with moderate to severe hepatic impairment. Therefore, Alecensa is not recommended in patients with moderate to severe hepatic impairment (see section 5.2). Also see SPC Renal impairment No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not been studied in patients with severe renal impairment. However, since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see section 5.2).

INVESTIGATIONS Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically, Blood tests should initially be performed as clinically indicated. FBC Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Interstitial lung disease / pneumonitis Hepatotoxicity Bradycardia Severe myalgia GI effects REFERENCES EAMS letter 1/9/17 SPC July 2017 NICE TA310 April 2014 SPC 20.Jan. 2014 CDF 28/6/18



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ATEZOLIZUMAB (Tecentriq) Indications: Atezolizumab for treating previously platinum-treated locally advanced/ metastatic non squamous or squamous non-small cell lung cancer which has been prospectively determined before this application to be PD-L1 positive or PD-L1 negative or PD-L1 unquantifiable at PD-L1 assay or one in which PD-L1 status cannot be determined on account of insufficient lung cancer tissue being available for PD-L1 assay 2. The prescribing clinician is fully aware of the management of and the treatment modifications that may be required for immune-related adverse reactions due to anti-PD-L1 treatments including pneumonitis, colitis, nephritis, endocrinopathies and hepatitis. 3. The patient has a histologically- or cytologically-confirmed diagnosis of stage IIIB or IV non-small cell lung cancer and is either non-squamous or squamous in type. 4. The patient has either progressed after previously receiving at least 2 cycles of platinum-containing chemotherapy for stage IIIB or IV non-small cell lung cancer and also a targeted treatment if the tumour is EGFR positive or ALK positive or progressed within 6 months of completing platinum-based chemotherapy given as adjuvant or neoadjuvant therapy or concurrent with radiotherapy 5. PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score (TPS) has been attempted prior to this application. Either:- The TPS score will be documented- The TPS score cannot be documented as the TPS result was unquantifiable - PD-L1 testing was not possible as the pathologist has documented that there is insufficient tissue for PD-L1 analysis 6. The patient has a performance status (PS) of 0 or 1 and would otherwise be potentially fit for docetaxel-based 2nd line chemotherapy 7. The patient has no symptomatically active brain metastases or leptomeningeal metastases. 8. Atezolizumab will be administered as monotherapy 9. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 10. Atezolizumab will be stopped at 2 years of treatment or on loss of clinical benefit or unacceptable toxicity, whichever occurs first. 11. A formal medical review as to whether treatment with atezolizumab should continue or not will be scheduled to occur at least by the end of the first 9 weeks of treatment 12. Treatment breaks of up to 12 weeks beyond the expected cycle length of atezolizumab are allowed solely to allow immune toxicities to settle 13. Atezolizumab will otherwise be used as set out in SPC with the exception of criteria 10

DRUG REGIMEN Day 1 Atezolizumab 1200mg in 250ml sodium chloride 0.9% IV infusion

Cycle Frequency: every 3 weeks until disease progression to a maximum 2 years

Atezolizumab Lung CAG Chair Authorisation: Date:


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DOSE MODIFICATIONS Dose modification advice for specified adverse drug reactions Pneumonitis Grade 2 Withhold Atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day ≤Grade 3 or 4 Permanently discontinue Atezolizumab Hepatitis Grade 2: Withhold Atezolizumab (ALT or AST > 3 to Treatment may be resumed when the event improves to Grade 0 or 5 x [ULN]x x ULN Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ or blood or bilirubin > 1.5 10 mg prednisone or equivalent per day to 3 x ULN) Grade 3 or 4: Permanently discontinue Atezolizumab (ALT or AST > 5 x ULN or blood bilirubin > 3 x ULN) Colitis Grade 2 or 3 Diarrhoea Withhold Atezolizumab (increase of ≥ 4 Treatment may be resumed when the event improves to Grade 0 or stools/day over baseline) Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ or Symptomatic Colitis 10 mg prednisone equivalent per day Grade 4 Diarrhoea or Permanently discontinue Atezolizumab Colitis (life threatening; urgent intervention indicated) Hypothyroidism or hyperthyroidism Symptomatic Withhold Atezolizumab Hypothyroidism: Treatment may be resumed when symptoms are controlled by thyroid replacement therapy and TSH levels are decreasing Hyperthyroidism: Treatment may be resumed when symptoms are controlled by antithyroid medicinal product and thyroid function is improving



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SACT Regimens– Urological Cancer 25

Adrenal insufficiency Symptomatic Withhold Atezolizumab Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Hypophysitis Grade 2 or 3 Withhold Atezolizumab Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Grade 4 Permanently discontinue Atezolizumab Type 1 diabetes mellitus Grade 3 or 4 Withhold Atezolizumab hyperglycaemia (fasting Treatment may be resumed when metabolic control is achieved on glucose > 250 mg/dL insulin replacement therapy or 13.9 mmol/L) Infusion-related reactions Grade 1 or 2 Reduce infusion rate or interrupt. Treatment may be resumed when the event is resolved Grade 3 or 4 Permanently discontinue Atezolizumab Rash Grade 3 Withhold Atezolizumab Treatment may be resumed when rash is resolved and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 4 Permanently discontinue Atezolizumab Myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome and Meningoencephalitis All Grades Permanently discontinue Atezolizumab



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Pancreatitis Grade 3 or 4 serum Withhold Atezolizumab amylase or lipase levels Treatment may be resumed when serum amylase and lipase levels increased (> 2 x ULN) improve to Grade 0 or Grade 1 within 12 weeks, or symptoms of or Grade 2 or 3 pancreatitis have resolved, and corticosteroids have been reduced pancreatitis to ≤ 10 mg prednisone or equivalent per day Grade 4 or any grade Permanently discontinue Atezolizumab of recurrent pancreatitis Atezolizumab should be permanently discontinued: • For Grade 4 toxicities except for endocrinopathies that are controlled with replacement hormones • For any recurrent event at Grade ≥ 3 severity • If a treatment-related toxicity does not resolve to Grade 0 or Grade 1 within 12 weeks after adverse reaction onset date • If a corticosteroid dose of > 10 mg prednisone or equivalent per day is required for treatment-related toxicity beyond 12 weeks after adverse reaction onset date.


Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests Tests relating to disease response/progression

CONCURRENT MEDICATION None required

ANTI-EMETIC POLICY Low emetic risk



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS inflammation of the lung (pneumonitis): symptoms may include new or worsening cough, shortness of breath, and chest pain • inflammation of the liver (hepatitis): symptoms may include yellowing of skin or eyes, nausea, vomiting, bleeding or bruising, dark urine, and stomach pain • inflammation of the intestines (colitis): symptoms may include diarrhoea (watery, loose or soft stools), blood in stools, and stomach pain • inflammation of the thyroid and adrenal glands (hypo-thyroidism, hyper-thyroidism, or adrenal insufficiency): symptoms may include tiredness, weight loss, weight gain, change in mood, hair loss, constipation, and dizziness • type 1 diabetes mellitus, including acid in the blood produced from diabetes (diabetic ketoacidosis): symptoms may include feeling more hungry or thirsty than usual, need to urinate more often, weight loss, and feeling tired • inflammation of the brain (encephalitis) or inflammation of the membrane around the spinal cord and brain (meningitis): symptoms may include neck stiffness, headache, fever, chills, vomiting, eye sensitivity to light, confusion and sleepiness • inflammation or problems of the nerves (neuropathy): symptoms may include muscle weakness and numbness, tingling in hands and feet • inflammation of the pancreas (pancreatitis): symptoms may include abdominal pain, nausea and vomiting • severe reactions associated with infusion (events occurring during or within one day of having the infusion) may include fever, chills, shortness of breath and flushing. REFERENCES SPC



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BRIGATINIB (Alunbrig) Indication: Brigatinib for anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer previously treated with crizotinib where all the following criteria have been met: 2. The patient has a histologically or cytologically confirmed diagnosis of stage IIIB or IV non small cell lung cancer that carries an anaplastic lymphoma kinase (ALK) rearrangement. 3. The only TKI treatment that the patient has progressed on is 1st line crizotinib or 2nd line crizotinib after 1st line chemotherapy and that the patient has not been treated with either 1st line alectinib or 1st line ceritinib. Brigatinib is only licensed, NICE-approved and funded in patients who have been treated with and progressed on crizotinib as their sole TKI treatment. 4. The patient has not been treated with 2nd line ceritinib after 1st line crizotinib unless the ceritinib had to be stopped within 3 months of its start solely as a consequence of dose-limiting toxicity and in the clear absence of disease progression. 5. The patient has not been previously treated with brigatinib unless brigatinib has been received as part of any compassionate use scheme and the patient meets all the other criteria set out here. 6. Brigatinib will be used only as monotherapy. 7. The patient has an ECOG performance status of 0 or 1 or 2. 8. The patient either has no brain metastases or, if the patient has brain metastases, the patient is symptomatically stable prior to starting brigatinib 9. The patient will be treated with brigatinib until loss of clinical benefit or excessive toxicity or patient choice to discontinue treatment, whichever is the sooner. 10. Treatment breaks of up to 6 weeks are allowed but solely to allow toxicities to settle. 11. Brigatinib will be otherwise used as set out in its Summary of Product Characteristics

DRUG REGIMEN Day 1 Brigatinib 90mg po daily for the first 7 days then 180mg po daily If Brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should be resumed at 90mg once daily for 7 days before increasing to previously tolerated dose Cycle Frequency: Until disease progression or unacceptable toxicity.

DOSE MODIFICATIONS If dose reduction required reduce dose by 10mg increments to 20mg Brigatinib: Renal impairment No dose adjustment of Brigatinib is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). A reduced starting dose of 60 mg once daily for the first 7 days, then 90 mg once daily is recommended for patients with severe renal impairment (eGFR < 30 mL/min). Patients with severe renal impairment should be closely monitored for new or worsening respiratory symptoms that may indicate ILD/pneumonitis (e.g., dyspnoea, cough, etc.) particularly in the first week

Brigatinib Lung CAG Chair Authorisation: Date:


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Hepatic impairment No dose adjustment of Brigatinib is required for patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). A reduced starting dose of 60 mg once daily for the first 7 days, then 120 mg once daily is recommended for patients with severe hepatic impairment (Child-Pugh class C)

Dose 1st dose reduction 2nd dose reduction 3rd dose reduction

90mg once daily (first 7 days)

reduce to 60mg once daily

permanently discontinue

NA

180mg once daily reduce to 120mg once daily



Recommended Brigatinib dose modifications for adverse reactions

Adverse reaction

Severity* Dose modification

Interstitial lung disease (ILD) /pneumonitis

Grade 1 • If event occurs during the first 7 days of treatment, Brigatinib should be withheld until recovery to baseline, then resumed at same dose level and not escalated to 180 mg once daily. • If ILD/pneumonitis occurs after the first 7 days of treatment, Brigatinib should be withheld until recovery to baseline, then resumed at same dose level. • If ILD/pneumonitis recurs, Brigatinib should be permanently discontinued.

Grade 2 • If ILD/pneumonitis occurs during the first 7 days of treatment, Brigatinib should be withheld until recovery to baseline, then resumed at next lower dose level as described in Table 1 and not escalated to 180 mg once daily. • If ILD/pneumonitis occurs after the first 7 days of treatment, Brigatinib should be withheld until recovery to baseline. Brigatinib should be resumed at next lower dose level as described in Table 1. • If ILD/pneumonitis recurs, Brigatinib should be permanently discontinued.

Grade 3 or 4 • Brigatinib should be permanently discontinued.

Hypertension Grade 3 hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, medical intervention indicated, more than one anti-hypertensive medicinal product, or more intensive therapy than previously used indicated)

• Brigatinib should be withheld until hypertension has recovered to Grade ≤ 1 (SBP < 140 mmHg and DBP < 90 mmHg), then resumed at same dose. • If Grade 3 hypertension recurs, Brigatinib should be withheld until hypertension has recovered to Grade ≤ 1 then resumed at the next lower dose level per Table 1 or permanently discontinued

Grade 4 hypertension (life threatening consequences, urgent intervention indicated)

• Brigatinib should be withheld until hypertension has recovered to Grade ≤ 1 (SBP < 140 mmHg and DBP < 90 mmHg), then resumed at the next lower dose level per Table 1 or permanently discontinued. • If Grade 4 hypertension recurs, Brigatinib should be permanently discontinued.



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Bradycardia (HR less than 60 bpm)

Symptomatic bradycardia • Brigatinib should be withheld until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. • If a concomitant medicinal product known to cause bradycardia is identified and discontinued, or its dose is adjusted, Brigatinib should be resumed at same dose upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. • If no concomitant medicinal product known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose modified, Brigatinib should be resumed at the next lower dose level per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.

Bradycardia with life-threatening consequences, urgent intervention indicated

• If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, Brigatinib should be resumed at the next lower dose level per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. • Brigatinib should be permanently discontinued if no contributing concomitant medicinal product is identified. • Brigatinib should be permanently discontinued in case of recurrence.

Elevation of CPK

Grade 3 elevation of CPK (> 5.0 × ULN)

• Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 2.5 × ULN) or to baseline, then resumed at the same dose. • If Grade 3 elevation of CPK recurs, Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 2.5 × ULN) or to baseline, then resumed at the next lower dose level per Table 1.

Grade 4 elevation of CPK (> 10.0 × ULN)

• Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 2.5 × ULN) or to baseline, then resumed at the next lower dose level per Table 1.

Elevation of lipase or amylase

Grade 3 elevation of lipase or amylase (> 2.0 × ULN)

• Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, then resumed at same dose. • If Grade 3 elevation of lipase or amylase recurs, Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, then resumed at the next lower dose level per Table 1.

Grade 4 elevation of lipase or amylase (> 5.0 x ULN)

• Brigatinib should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN), then resumed at the next lower dose level per Table 1.

Hepatotoxicity Grade ≥ 3 elevation (> 5.0 × ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with bilirubin ≤ 2 × ULN

• Brigatinib should be withheld until recovery to baseline or less than or equal to 3 × ULN, then resumed at next lower dose per Table 1.

Grade ≥ 2 elevation (> 3 × ULN) of ALT or AST with concurrent total bilirubin elevation > 2 × ULN in the absence of cholestasis or haemolysis

• Brigatinib should be permanently discontinued.

Hyperglycaemia For Grade 3 (greater than 250 mg/dL or 13.9 mmol/L) or greater

• If adequate hyperglycaemic control cannot be achieved with optimal medical management, Brigatinib should be withheld until adequate hyperglycaemic control is achieved. Upon recovery, Brigatinib may either be resumed at the next lower dose or permanently discontinued.



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Visual Disturbance

Grade 2 or 3 • Brigatinib should be withheld until recovery to Grade 1 or baseline, then resumed at the next lower dose level per Table 1.

Grade 4 • Brigatinib should be permanently discontinued.

Other adverse reactions

Grade 3 • Brigatinib should be withheld until recovery to baseline, then resumed at the same dose level. • If the Grade 3 event recurs, Brigatinib should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1 or permanently discontinued.

Grade 4 • Brigatinib should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1. • If the Grade 4 event recurs, Brigatinib should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1 or permanently discontinued.


Give Discuss

Hb x g/dL ≥10 < 10




ANTIEMETIC POLICY Low emetic risk



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary adverse reactions Hypertension Bradycardia Visual disturbance REFERENCES Sullivan I, Planchard D. Editorial on the article entitled “Brigatinib efficacy and safety in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer in a phase I/II trial”. J Thorac Dis 2016;8(10):E1287- E1292. doi: 10.21037/jtd.2016.10.57 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107501/pdf/jtd-08-10-E1287.pdf NIHR Innovation Observatory Evidence Briefing: August 2017 http://www.io.nihr.ac.uk/wp-content/uploads/migrated_new/8348-Brigatinib-for-ALK-positive-non-small-cell-lung-cancer.pdf Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial. Tiseo M.; Ahn M.-J.; Reckamp K.L.; Hansen K.H.; Kim S.-W et al. JCO. 2017; 35 (22) p 2490-2498. (abstract only)



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CARBOPLATIN PEMBROLIZUMAB (Keytruda) PEMETREXED Indications: Pembrolizumab in combination with pemetrexed-based combination chemotherapy for treating untreated PD-L1-positive or negative locally advanced or metastatic non-squamous non-small-cell lung cancer where the following criteria are met: 3. The patient has a histologically- or cytologically-confirmed diagnosis of stage IIIB or IV non-squamous non-small cell lung cancer. 4. EGFR and ALK mutation testing have been done and both are negative. 5. PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score (TPS) has been attempted prior to this application and the result is set out below.Note: for fully informed patient consent of all the potential 1st line treatment options, PD-L1 testing must still be attempted and recorded here. Please document the actual TPS below (if negative, record ’0’) OR indicate below the reason that the actual TPS cannot be documented:- Please enter 'yes' if the TPS result was unquantifiable OR- Please enter 'yes' if PD-L1 testing was not possible as the pathologist has documented that there is insufficient tissue for PD-L1 analysis 6. The patient has not received previous systemic therapy for advanced /metastatic disease. Completion of treatment with CT and/or RT as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease 7. The patient will be treated with a maximum of 4 cycles of pembrolizumab plus pemetrexed-based combination chemotherapy with either cisplatin or carboplatin (AUC 5). 8. On completion of 4 cycles of pembrolizumab plus pemetrexed-based chemotherapy in combination with cisplatin or carboplatin and in the absence of disease progression, treatment with pembrolizumab in combination with ‘maintenance’ pemetrexed will continue for a total treatment duration of 2 years (or a maximum of 35 3-weekly cycles) or until disease progression or unacceptable toxicity or withdrawal of patient consent, whichever occurs first. 9. The patient has a performance status (PS) of 0 or 1 and is potentially fit for pemetrexed- and platinum-based chemotherapy in combination with pembrolizumab. 10. Patient has no symptomatically active brain metastases or leptomeningeal metastases. 11. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. 12. A formal medical review as to whether treatment with pembrolizumab in combination with pemetrexed plus cisplatin/carboplatin should continue or not will be scheduled to occur at least by the end of the first 6 weeks of treatment 13. Treatment breaks of up to 12 weeks beyond the expected 3-weekly cycle length are allowed but solely to allow any immune toxicities to settle. 14. The licensed dose and frequency of pembrolizumab will be used with the exception of a maximum treatment duration of 2 years (or 35 cycles of 3-weekly treatment)




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DRUG REGIMEN Day 1 PEMBROLIZUMAB 200mg IV infusion in 100ml sodium chloride over 30 minutes

Pre-medication Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Folic acid 400mcg/day orally starting 1 to 3 weeks before chemotherapy continuing until 21 days after the last dose of pemetrexed. Hydroxycobalamin 1000mcg IM every 9 weeks starting 1 to 3 weeks before chemotherapy (give with every 3rd cycle of chemotherapy) PEMETREXED 500mg/m2 IV infusion in 100ml (Alimta brand use sodium chloride 0.9% but all generic brands use glucose 5%) over 10 minutes CARBOPLATIN AUC 5 IV infusion in 500ml glucose 5% over 30 minutes

(30 minutes after completing Pemetrexed)

Cycle frequency: Every 21 days Number of cycles: Carboplatin cycles 1 to 4 only, pemetrexed and pembrolizumab up to

maximum 2 years (maximum 35 cycles).

DOSE MODIFICATIONS Pemetrexed: Delay treatment until resolution then treat with appropriate dose modification. Nadir neutrophils <0.5 and nadir platelets >50 75% of previous dose

Nadir platelets 50 regardless of nadir neutrophils 50% of previous dose Any Grade 3 or 4 non-haematological toxicities except mucositis 75% of previous dose Any diarrhoea requiring hospitalisation (irrespective of grade) 75% of previous dose or Grade 3 or 4 diarrhoea Grade 3 or 4 mucositis 50% of previous dose Neurotoxicity grade 3 or 4 Discontinue therapy Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Creatinine clearance (GFR) should be 45ml/min (calculated or EDTA) otherwise clinical decision Liver function tests (LFTs)

Total bilirubin should be 1.5 x upper limit of normal.

Alk phos, AST and ALT 3 x upper limit of normal. (Alk phos, AST, and ALT 5 x normal is acceptable if liver has tumour involvement). Clinical decision

Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If GFR/ calculated CrCl = or < 20ml/min contraindicated




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Pembrolizumab: Pembrolizumab should be withheld for a drug-related non-hematological toxicity > Grade 2 (excluding fatigue). Once the patient has recovered to Grade 0-1 consider increasing the dosing interval in subsequent cycles by 1 week (e.g., to 4 weeks). The use of corticosteroids should be considered for management of immune-related adverse events (irAEs). Additional information is available in the Event of Clinical Interest and Immune-Related Adverse Event Guidance Document. If the drug-related toxicity does not resolve to Grade 0-1 within 12 weeks after onset of toxicity, discontinuation is recommended Immune-related adverse reactions Severity Treatment modification Pneumonitis Grade 2 pneumonitis Withhold* Grade 3 or 4, or recurrent Grade 2 pneumonitis Permanently discontinue Colitis Grade 2 or 3 colitis Withhold* Grade 4 colitis Permanently discontinue Nephritis Grade 2 nephritis with creatinine > 1.5 to 3 times upper limit of normal (ULN) Withhold* Grade ≥ 3 nephritis with creatinine ≥ 3 times ULN Permanently discontinue Endocrinopathies Symptomatic hypophysitis Type 1 diabetes associated with Grade > 3 hyperglycemia (glucose > 250 mg/dL or > 13.9 mmol/L) or associated with ketoacidosis Hyperthyroidism Grade ≥ 3 Withhold* For patients with Grade 3 or Grade 4 endocrinopathy that improved to Grade 2 or lower and is controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued. Hypothyroidism may be managed with replacement therapy without treatment interruption. Hepatitis Hepatitis with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times ULN or total bilirubin > 1.5 to 3 times ULN (Grade 2) Withhold* Hepatitis with AST or ALT > 5 times ULN or total bilirubin > 3 times ULN (Grade ≥ 3) Permanently discontinue In case of liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT increases ≥ 50% and lasts ≥ 1 week Permanently discontinue Infusion-related reactions Grade 3 or 4 infusion-related reactions Permanently discontinue * until adverse reactions recover to Grade 0-1. Pembrolizumab should be permanently discontinued: • For Grade 4 toxicity except for endocrinopathies that are controlled with replacement hormones • If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks • If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose




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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression Ideally EDTA GFR should be used (Carboplatin) Creatinine clearance (GFR) calculated, at the Consultants discretion Liver function tests (LFT)

CONCURRENT MEDICATION Avoid use of high dose NSAIDs with CrCl > 80ml/min. Avoid all NSAIDS with CrCl between 45 and 79ml/min for at least 5 days prior to and 2 days after pemetrexed dose.

ANTI-EMETIC POLICY High emetic risk





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CERITINIB (Zykadia) Indication: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The first line treatment of anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer 2. The patient has a histologically or cytologically confirmed diagnosis of stage IIIB or IV non small cell lung cancer that carries an anaplastic lymphoma kinase (ALK) rearrangement 3. The patient has received no previous ALK-targeted therapy 4. The patient has received no previous cytotoxic chemotherapy for locally advanced or metastatic non small cell lung cancer ie no previous systemic treatment except when this has been given as neoadjuvant or adjuvant therapy or concurrently with radiotherapy 5. Ceritinib will be used only as single-agent therapy 6. The patient has an ECOG performance status of 0 or 1 or 2 7. The patient either has no brain metastases or, if the patient has brain metastases, the patient is symptomatically stable prior to starting ceritinib 8. The patient will be treated until loss of clinical benefit or excessive toxicity or patient choice to discontinue treatment, whichever is the sooner 9. Treatment breaks of up to 6 weeks are allowed but solely to allow toxicities to settle 10. Ceritinib will be otherwise used as set out in its Summary of Product Characteristics 11. Crizotinib is to be used only if the patient cannot tolerate ceritinib and has not had progressive disease whilst on ceritinib. Crizotinib is not to be used following disease progression on ceritinib as there is no current clear evidence to support treatment with crizotinib after disease progression on ceritinib

NICE TA395 Ceritinib is recommended, within its marketing authorisation, as an option for treating advanced anaplastic lymphoma kinase positive non-small-cell lung cancer in adults who have previously had crizotinib. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.

DRUG REGIMEN Day 1 Ceritinib 450mg orally daily (with or after food) Cycle Frequency: Until disease progression or unacceptable toxicity. Review every 2 months by CT scan

Ceritinib Lung CAG Chair Authorisation: Date:


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DOSE MODIFICATIONS Dose Interruption, Reduction, or Discontinuation Recommendations ALT or AST elevation greater than 5 times ULN with total bilirubin elevation less than or equal to 2 times ULN Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume ceritinib with a 150mg dose reduction. ALT or AST elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Permanently discontinue ceritinib. Any Grade treatment-related ILD/pneumonitis Permanently discontinue ceritinib. QTc interval greater than 500 msec on at least 2 separate ECGs Withhold until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume ceritinib with a 150mg dose reduction. QTc interval prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue ceritinib. Severe or intolerable nausea, vomiting or diarrhea despite optimal anti-emetic or anti-diarrheal therapy Withhold until improved, then resume ceritinib. with a 150mg dose reduction. Persistent hyperglycemia greater than 250 mg/dL despite optimal anti-hyperglycemic therapy Withhold until hyperglycemia is adequately controlled, then resume ceritinib with a 150mg dose reduction. If adequate hyperglycemic control cannot be achieved with optimal medical management, discontinue ceritinib. Symptomatic bradycardia that is not life-threatening Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate concomitant medications known to cause bradycardia, and adjust the dose of ceritinib. Clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking a concomitant medication also known to cause bradycardia or a medication known to cause hypotension Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If the concomitant medication can be adjusted or discontinued, resume ceritinib. with a 150mg dose reduction, with frequent monitoring. Life-threatening bradycardia in patients who are not taking a concomitant medication also known to cause bradycardia or known to cause hypotension Permanently discontinue ceritinib..

Dose Modification for Strong CYP3A4 Inhibitors Avoid concurrent use of strong CYP3A inhibitors during treatment with ceritinib If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the ceritinib dose by a pproximately one-third, rounded to the nearest 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib dose that was taken prior to initiating the strong CYP3A4 inhibitor.



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INVESTIGATIONS Pre assessment CT- chest abdomen pelvis FBC U and E's LFT's ECG Creatinine Blood tests should initially be performed monthly FBC Creatinine Liver function tests (LFT)



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS REFERENCES SPC September 2015



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CISPLATIN (50) ETOPOSIDE (50) with RT Indication: Superior sulcus non-small cell carcinoma

DRUG REGIMEN Day 1, 8, 29 & 36 Pre-hydration

CISPLATIN 50mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post hydration

Days 1 to 5 ETOPOSIDE 50mg/m2

infusion in 500ml* sodium chloride 0.9% over 60 minutes Days 29 to 33 ETOPOSIDE 50mg/m2

infusion in 500ml* sodium chloride 0.9% over 60 minutes *doses 48mg to 88mg in 250ml, 96mg to 180mg in 500ml, 200mg to 360mg in 1000ml sodium chloride 0.9% This regimen is given concurrently with radiotherapy. Radiation and chemotherapy to start within 24 hours of each other. Number of cycles: 1 cycle

DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration. Etoposide: CrCl >50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST 60-180u/L give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision

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Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression


ANTIEMETIC POLICY High emetic risk days 1, 8, 29 and 36 Low emetic risk days 2 to 5 and days 30 to 33


REFERENCES 1. Rusch VW, Giroux KJ, Kraut JC et al. Induction Chemoradiation and Surgical Resection for

Superior Sulcus Non-Small Cell Lung Carcinomas: Long-Term Results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25: 313-318, 2007.

Cisplatin / etoposide sulcus



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CISPLATIN PEMBROLIZUMAB (Keytruda) PEMETREXED Indications: Pembrolizumab in combination with pemetrexed-based combination chemotherapy for treating untreated PD-L1-positive or negative locally advanced or metastatic non-squamous non-small-cell lung cancer where the following criteria are met: 2. The prescribing clinician is fully aware of the management of and the treatment modifications that may be required for immune-related adverse reactions due to anti-PD-L1 treatments including pneumonitis, colitis, nephritis, endocrinopathies and hepatitis. 3. The patient has a histologically- or cytologically-confirmed diagnosis of stage IIIB or IV non-squamous non-small cell lung cancer. 4. EGFR and ALK mutation testing have been done and both are negative. 5. PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score (TPS) has been attempted prior to this application and the result is set out below.Note: for fully informed patient consent of all the potential 1st line treatment options, PD-L1 testing must still be attempted and recorded here. Please document the actual TPS below (if negative, record ’0’) OR indicate below the reason that the actual TPS cannot be documented:- Please enter 'yes' if the TPS result was unquantifiable OR- Please enter 'yes' if PD-L1 testing was not possible as the pathologist has documented that there is insufficient tissue for PD-L1 analysis 6. The patient has not received previous systemic therapy for advanced /metastatic disease. Completion of treatment with CT and/or RT as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease 7. The patient will be treated with a maximum of 4 cycles of pembrolizumab plus pemetrexed-based combination chemotherapy with either cisplatin or carboplatin (AUC 5). 8. On completion of 4 cycles of pembrolizumab plus pemetrexed-based chemotherapy in combination with cisplatin or carboplatin and in the absence of disease progression, treatment with pembrolizumab in combination with ‘maintenance’ pemetrexed will continue for a total treatment duration of 2 years (or a maximum of 35 3-weekly cycles) or until disease progression or unacceptable toxicity or withdrawal of patient consent, whichever occurs first. 9. The patient has a performance status (PS) of 0 or 1 and is potentially fit for pemetrexed- and platinum-based chemotherapy in combination with pembrolizumab. 10. The patient has no symptomatically active brain or leptomeningeal metastases. 11. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. 12. A formal medical review as to whether treatment with pembrolizumab in combination with pemetrexed plus cisplatin/carboplatin should continue or not will be scheduled to occur at least by the end of the first 6 weeks of treatment 13. Treatment breaks of up to 12 weeks beyond the expected 3-weekly cycle length are allowed but solely to allow any immune toxicities to settle. 14. The licensed dose and frequency of pembrolizumab will be used with the exception of a maximum treatment duration of 2 years (or 35 cycles of 3-weekly treatment)




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DRUG REGIMEN Day 1 PEMBROLIZUMAB 200mg IV infusion in 100ml over 30 minutes

Pre-medication Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Folic acid 400mcg/day orally starting 1 to 3 weeks before chemotherapy continuing until 21 days after the last dose of pemetrexed. Hydroxycobalamin 1000mcg IM every 9 weeks starting 1 to 3 weeks before chemotherapy (give with every 3rd cycle of chemotherapy)

Pre-hydration PEMETREXED 500mg/m2 IV infusion in 100ml (Alimta brand use sodium chloride 0.9% but all generic brands use glucose 5%) over 10 minutes CISPLATIN 75mg/m2 IV infusion in 1000ml sodium chloride 0.9% over 2 hours (30 minutes

after completing Pemetrexed) Post-hydration

Cycle frequency: Every 21 days Number of cycles: Cisplatin cycles 1 to 4 only, pemetrexed and pembrolizumab up to

maximum 2 years (maximum 35 cycles)


Nadir platelets 50 regardless of nadir neutrophils 50% of previous dose Any Grade 3 or 4 non-haematological toxicities except mucositis 75% of previous dose Any diarrhoea requiring hospitalisation (irrespective of grade) 75% of previous dose or Grade 3 or 4 diarrhoea Grade 3 or 4 mucositis 50% of previous dose Neurotoxicity grade 3 or 4 Discontinue therapy

Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Creatinine clearance (GFR) should be 45ml/min (calculated or EDTA). Clinical decision Liver function tests (LFTs)


Alk phos, AST and ALT 3 x upper limit of normal. (Alk phos, AST, and ALT 5 x normal is acceptable if liver has tumour involvement). Clinicial decision

Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.




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Pembrolizumab: Pembrolizumab should be withheld for a drug-related non-hematological toxicity > Grade 2 (excluding fatigue). Once the patient has recovered to Grade 0-1 consider increasing the dosing interval in subsequent cycles by 1 week (e.g., to 4 weeks). The use of corticosteroids should be considered for management of immune-related adverse events (irAEs). Additional information is available in the Event of Clinical Interest and Immune-Related Adverse Event Guidance Document. If the drug-related toxicity does not resolve to Grade 0-1 within 12 weeks after onset of toxicity, discontinuation is recommended Immune-related adverse reactions Severity Treatment modification Pneumonitis Grade 2 pneumonitis Withhold* Grade 3 or 4, or recurrent Grade 2 pneumonitis Permanently discontinue Colitis Grade 2 or 3 colitis Withhold* Grade 4 colitis Permanently discontinue Nephritis Grade 2 nephritis with creatinine > 1.5 to 3 times upper limit of normal (ULN) Withhold* Grade ≥ 3 nephritis with creatinine ≥ 3 times ULN Permanently discontinue Endocrinopathies Symptomatic hypophysitis Type 1 diabetes associated with Grade > 3 hyperglycemia (glucose > 250 mg/dL or > 13.9 mmol/L) or associated with ketoacidosis Hyperthyroidism Grade ≥ 3 Withhold* For patients with Grade 3 or Grade 4 endocrinopathy that improved to Grade 2 or lower and is controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued. Hypothyroidism may be managed with replacement therapy without treatment interruption. Hepatitis Hepatitis with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times ULN or total bilirubin > 1.5 to 3 times ULN (Grade 2) Withhold* Hepatitis with AST or ALT > 5 times ULN or total bilirubin > 3 times ULN (Grade ≥ 3) Permanently discontinue In case of liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT increases ≥ 50% and lasts ≥ 1 week Permanently discontinue Infusion-related reactions Grade 3 or 4 infusion-related reactions Permanently discontinue * until adverse reactions recover to Grade 0-1. Pembrolizumab should be permanently discontinued: • For Grade 4 toxicity except for endocrinopathies that are controlled with replacement hormones • If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks • If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration 2) Non urgent blood tests Tests relating to disease response/progression




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CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN regimens. If fluid balance is > 2L positive after 8 hours post hydration OR if patient gains >2kg in weight or urine output <100ml/hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV. Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Avoid use of high dose NSAIDs with CrCl > 80ml/min. Avoid all NSAIDS with CrCl between 45 and 79ml/min for at least 5 days prior to and 2 days after pemetrexed dose.



REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic





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CISPLATIN VINORELBINE with concurrent RT Indication: Non-small cell lung cancer suitable for chemoradiotherapy

DRUG REGIMEN Days 1 to 4 & 22 to 25 Pre-hydration

CISPLATIN 20mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours (with fractions 1-4 and 16-19 of radiotherapy) Post hydration

Days 1, 8, 19 & 26 VINORELBINE 15mg/m2

infusion in 50ml sodium chloride 0.9% over 10 minutes prior to radiotherapy on fractions 1, 6, 15, and 20

Radiotherapy should be given no more than 6 hours after starting the cisplatin Number of cycles: 1 cycle of 42 days

DOSE MODIFICATIONS Haematological ANC X109/L PLATELETS X109/L VINORELBINE CISPLATIN >1.5 and >100 100% 100% 1.0-1.5 or 60-100 omit 100% <1.0 or <60 omit omit Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration. Vinorelbine: If bilirubin > 2 x ULN or AST/ALT > 5 x ULN reduce to 66.6%

Cisplatin / vinorelbine RT



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Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre and post hydration prescribed as per day case schedule at the end of TVCN regimens. If urine output is <100 ml/hour or if patient gains >2kg in weight during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV. Ciprofloxacin 500mg po BD days 8 to 20 and 29 to 41

ANTIEMETIC POLICY Highly emetogenic day 1-4 and 22-25 Minimal emetogenic risk days 8, 19 and 26


REFERENCES SOCCAR trial

Cisplatin / vinorelbine RT


Page 2of 2 Published: November 2019 Review: November 2021

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GEMCITABINE CISPLATIN Indication: Standard combination for palliative treatment of NSCLC Unknown primary if appropriate

NICE guidance – www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.

DRUG REGIMEN Day 1 PRE-HYDRATION

GEMCITABINE 1250mg/m2

infusion in 250ml sodium chloride 0.9% (or licensed dose volume) over 30 minutes CISPLATIN 80mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours POST-HYDRATION Day 8 GEMCITABINE 1250mg/m2

infusion in 250ml sodium chloride 0.9% (or licensed dose volume) over 30 minutes

Cycle Frequency: Every 21 days Number of cycles: up to 4 (subject to tolerance and response)

DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.

Gemcitabine: CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2

Neutrophils >1.5x10x9/L and platelets >100x10x9/L give 100% dose (Day 1 and 8) Neutrophils 0.5-1.5x10x9/L or platelets 50-100x10x9/L give 75% dose (Day 8 only) or delay based on clinical assessment (Day 1 and 8) Neutrophils <0.5x10x9/L or platelets <50x10x9/L delay treatment (Day 1) or omit treatment (Day 8).

Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose

Omit if treatment is delayed for more than 4 weeks but continue with Cisplatin

Cisplatin / Gemcitabine



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Give Discuss

Hb x g/dL ≥10 < 10


Liver function tests (LFT)

Creatinine clearance (GFR) calculated OR EDTA at the Consultants discretion (Cisplatin). 2) Non urgent blood tests Tests relating to disease response/progression


ANTIEMETIC POLICY High emetic risk day 1 Low emetic risk day 8


Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. Diarrhoea – see dose modifications treat with loperamide or codeine. Mucositis – see dose modifications use routine mouth care. REFERENCES 1. Giaccone G et al. Seminars in Oncology 2002; 29 (3) Supp 9: 47 49 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Cisplatin / Gemcitabine



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CISPLATIN (40) concurrent radiotherapy Indication: Unresectable stage IIIA/IIIB Non small cell lung cancer concurrently with radical radiotherapy after neoadjuvant chemotherapy with 2 cycles of cisplatin/vinorelbine.


CISPLATIN 40mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post-hydration Cycle Frequency: Every week for 4 weeks. Start early in Radiotherapy.

DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration


Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) calculated, or EDTA at the Consultants discretion. (Cisplatin) Consider transfusions to keep Hb > 12 x g/dL 2) Non urgent blood tests Tests relating to disease response/progression


Cisplatin + radiotherapy



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ANTIEMETIC POLICY Moderately emetic risk.

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. SchaakeKoning C et al. N Eng J Med 1992; 326: 524 530 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Cisplatin + radiotherapy



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CRIZOTINIB (Xalkori) Indications: Crizotinib for untreated anaplastic lymphoma kinase-positive advanced NSCLC 2. The patient has a histologically or cytologically conformed diagnosis of stage IIIB or IV non smallcell lung cancer that carries an anaplastic lymphoma kinase (ALK) rearrangement 3. The patient has had no previous 1st line systemic therapy (chemotherapy or other ALK inhibitors) for advanced or metastatic non-small cell lung cancer unless any NICE-approved 1st line ALK inhibitor therapy has had to be discontinued on account of unacceptable toxicity AND there is no evidence of disease progression 4. The patient will receive the licensed dose and frequency of crizotinib. Crizotinib for previously treated anaplastic lymphoma kinase-positive advanced NSCLC 2. The patient has a histologically or cytologically conformed diagnosis of stage IIIB or IV nonsmallcell lung cancer that carries an anaplastic lymphoma kinase (ALK) rearrangement 3. This is a 2nd or subsequent line treatment post 1st line platinum based combination chemotherapy and the patient has not previously been treated with another ALK inhibitor 3. The patient will receive crizotinib as set out in its SPC First or subsequent line systemic therapy for ROS1-positive inoperable locally advanced/metastatic non squamous NSCLC Histologically or cytologically non-squamous NSCLC (stage IIIB or stage IV) with a confirmed ROS1 gene rearrangement as demonstrated by an accurate and validated assay. The patient has received no previous ROS1-targeted therapy. EITHER the patient has received no previous cytotoxic chemotherapy for locally advanced or metastatic non-small cell lung cancer OR has been previously treated with cytotoxic chemotherapy for locally advanced or metastatic disease Note: NHS England has a strong preference for ROS1-positive patients to be treated with crizotinib as 1st line therapy for locally advanced/metastatic NSCLC, though recognises that some patients have had to be treated with chemotherapy for urgent clinical reasons before the ROS1 result was known No brain metastases or, if the patient has brain metastases, the patient is symptomatically stable prior to starting crizotinib. ECOG performance status of 0 or 1 or 2. Crizotinib will be otherwise used as set out in its SPC

DRUG REGIMEN Day 1 Crizotinib 250mg orally twice daily Cycle Frequency: Continuously until disease progression

DOSE MODIFICATIONS Renal impairment No starting dose adjustment is recommended for patients with mild (creatinine clearance 60 to 90 mL/min) and moderate renal impairment (CLcr 30 to 60 mL/min). No data are available in patients with severe and end-stage renal disease and, no formal dosing recommendation could be made.

Crizotinib Lung CAG Chair Authorisation: Date:


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Hepatic impairment Clinical studies that were conducted excluded patients with AST or ALT >2.5 x upper limit of normal (ULN), or if due to underlying malignancy, >5.0 x ULN or with total bilirubin >1.5 x ULN. Treatment with Crizotinib should be used with caution in patients with mild and moderate hepatic impairment and should not be used in patients with severe hepatic impairment, CTCAE grade Treatment

Grade 3 or 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation with Grade ≤1 total bilirubin

Withhold until recovery to Grade ≤1 or baseline, then resume at 200 mg twice dailyb

Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or hemolysis)

Permanently discontinue

Any Grade pneumonitisc Permanently discontinue

Grade 3 QTc prolongation Withhold until recovery to Grade ≤1, then resume at 200 mg twice dailyb

Grade 4 QTc prolongation Permanently discontinue


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS REFERENCES

Crizotinib Lung CAG Chair Authorisation: Date:


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DACOMITINIB (Vizimpro) Indication: The treatment of untreated EGFR mutation-positive non-small-cell lung cancer where all the following criteria have been met: 2. The patient has a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is either stage IIIB or stage IV NSCLC 3. This patient’s NSCLC has been shown to express an EGFR-activating mutation as demonstrated by an accurate and validated assay 4. The patient has received no previous EGFR-targeted therapy unless this has had had to be stopped within 3 months of its start solely as a consequence of dose-limiting toxicity and in the clear absence of disease progression. 5. The patient has received no previous cytotoxic chemotherapy for locally advanced or metastatic non-small cell lung cancer 6. Dacomitinib will be used only as monotherapy 7. The patient has an ECOG performance status of 0 or 1 8. The prescribing clinician is aware of the potential drug interactions associated with dacomitinib therapy and the dose reductions or discontinuations required for the management of interstitial lung toxicity, diarrhoea and cutaneous toxicity. 9. The patient will be treated until loss of clinical benefit or excessive toxicity or patient choice to discontinue treatment, whichever is the sooner 10. Treatment breaks of up to 6 weeks are allowed but solely to allow toxicities to settle 11. Dacomitinib will be otherwise used as set out in its Summary of Product Characteristics

DRUG REGIMEN Day 1 DACOMITINIB 45mg orally daily

Cycle Frequency: until loss of clinical benefit or excessive toxicity or patient choice to discontinue treatment, whichever is the sooner

DOSE MODIFICATIONS Recommended dose modifications for Dacomitinib adverse reactions Recommended starting dose 45 mg First dose reduction 30 mg Second dose reduction 15 mg Dose modification and management for Dacomitinib adverse reactions Interstitial lung disease (ILD/Pneumonitis) • Withhold dacomitinib during ILD/Pneumonitis diagnostic evaluation. • Permanently discontinue dacomitinib if ILD/Pneumonitis is confirmed.

Dacomitinib Lung CAG Chair Authorisation: Date:


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Diarrhoea • For Grade 1 diarrhoea, no dose modification is required. Initiate treatment with anti-diarrhoeal medicinal products (e.g., loperamide) at first onset of diarrhoea. Encourage adequate oral fluid intake during diarrhoea. • For Grade 2 diarrhoea, if not improved to Grade ≤ 1 within 24 hours while using anti-diarrhoeal medicinal products (e.g., loperamide) and adequate oral fluid intake, withhold dacomitinib. Upon recovery to Grade ≤ 1, resume dacomitinib at the same dose level or consider a reduction of 1 dose level. • For Grade ≥ 3 diarrhoea, withhold dacomitinib. Treat with anti-diarrhoeal medicinal products (e.g., loperamide), and adequate oral fluid intake or intravenous fluids or electrolytes as appropriate. Upon recovery to Grade ≤ 1, resume dacomitinib with a reduction of 1 dose level. Skin-related adverse reactions • For Grade 1 rash or erythematous skin conditions, no dose modification is required. Initiate treatment (e.g., antibiotics, topical steroids, and emollients). • For Grade 1 exfoliative skin conditions, no dose modification is required. Initiate treatment (e.g., oral antibiotics and topical steroids). • For Grade 2 rash, erythematous or exfoliative skin conditions, no dose modification is required. Initiate treatment or provide additional treatment (e.g., oral antibiotics and topical steroids). • If Grade 2 rash, erythematous or exfoliative skin conditions persist for 72 hours despite treatment, withhold dacomitinib. Upon recovery to Grade ≤ 1, resume dacomitinib at the same dose level or consider a reduction of 1 dose level. • For Grade ≥ 3 rash, erythematous or exfoliative skin conditions, withhold dacomitinib. Initiate or continue treatment and/or provide additional treatment (e.g., broad spectrum oral or intravenous antibiotics and topical steroids). Upon recovery to Grade ≤ 1, resume dacomitinib with a reduction of 1 dose level. Other • For Grade 1 or 2 toxicity, no dose modification is required. • For Grade ≥ 3 toxicity, withhold dacomitinib until symptoms resolve to Grade ≤ 2. Upon recovery, resume dacomitinib with a reduction of 1 dose level Renal impairment No starting dose adjustments are required when administering Dacomitinib to patients with mild or moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min). Limited data are available in patients with severe renal impairment (CrCl < 30 mL/min). No data are available in patients requiring haemodialysis. Thus no dosing recommendations can be made for either patient population Hepatic impairment No starting dose adjustments are required when administering Dacomitinib to patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Dacomitinib has not been studied in patients with severe (Child-Pugh class C) hepatic impairment. Treatment in this population is not recommended



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INVESTIGATIONS Routine Blood test Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. 2) Non-urgent tests Tests relating to disease response/progression Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Some of the following may be required for treatment of the skin rash: E45 / Diprobase, Hydrocortisone 1%/2.5%, Clindamycin gel 1%, Oxytetracycline 500mg po bd (for 2 weeks) Prednisolone 25mg po od for 7 days then reducing by 5mg per day to stop

ANTI-EMETIC POLICY Minimal emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin rash – initial rash may be severe. Diarrhoea – dose reduction may be required. Moderate or severe diarrhoea may require loperamide REFERENCES CDF 8/7/19 SPC June 2019



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DOCETAXEL (75) Indication: Second line therapy for NSCLC after failure of platinum containing chemotherapy NICE guidance www.nice.org.uk Docetaxel monotherapy should be considered where second line treatment is appropriate for patients with locally advanced or metastatic NSCLC when relapse has occurred after prior chemotherapy.

DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8 mg BD starting 24 hours before chemotherapy

(or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m2

infusion in 250ml sodium chloride 0.9% over 60 minutes Cycle Frequency: Every 21 days Number of cycles: Individualised but not usually more than 6 (subject to tolerance and response)

DOSE MODIFICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated.


Give Discuss

Hb x g/dL ≥10 < 10


2) Non urgent blood tests Tests relating to disease response/progression

Docetaxel Lung CAG Chair Authorisation: Date:


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CONCURRENT MEDICATION Ensure pre-medication is given. This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions



Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. REFERENCES 1. Shepherd F et al. J Clin Oncol 2000; 18: 2095 2103. Fossella F et al. J Clin Oncol 2000; 18:

2354 2362 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Docetaxel Lung CAG Chair Authorisation: Date:


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DOCETAXEL (75) CISPLATIN (75) Indication: First line therapy for NSCLC NICE guidance www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.

DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy

(or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) Pre-hydration DOCETAXEL 75mg/m2 in 250ml sodium chloride 0.9% over 60 minutes CISPLATIN 75mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours

Post-hydration Cycle Frequency: Every 21 days Number of cycles: 4 to 6 cycles

DOSE MODIFICATIONS Docetaxel: Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.

Docetaxel + cisplatin



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Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) calculated OR EDTA at the Consultants discretion.


CONCURRENT MEDICATION Docetaxel - Ensure pre-medication is given. This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions Cisplatin - Ensure adequate pre and post hydration prescribed as per day case schedule at the end of TVCN regimens. If urine output is <100 ml/hour or if patient gains >2kg in weight during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV.

ANTIEMETIC POLICY High emetic risk


Docetaxel - Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Shepherd F et al. J Clin Oncol 2000; 18: 2095 2103. 2. Fossella F et al. J Clin Oncol 2000; 18: 2354 2362 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Docetaxel + cisplatin



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DOCETAXEL (75) CARBOPLATIN Indication: First line therapy for NSCLC NICE guidance www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.


(or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m2 in 250ml sodium chloride 0.9% over 60 minutes CARBOPLATIN AUC5 in 500ml glucose 5% infusion over 30 minutes

Cycle Frequency: Every 21 days Number of cycles: 4 to 6 cycles

DOSE MODIFICATIONS Docetaxel: Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If EDTA GFR = or < 20ml/min contraindicated

Docetaxel + carboplatin



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Give Discuss

Hb x g/dL ≥10 < 10


Creatinine clearance (GFR) EDTA at the Consultants discretion.


CONCURRENT MEDICATION Docetaxel - Ensure pre-medication is given. This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions Ototoxicity - monitor Neurotoxicity – monitor.

ANTIEMETIC POLICY Moderate emetic risk


Docetaxel - Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Shepherd F et al. J Clin Oncol 2000; 18: 2095 2103. 2. Fossella F et al. J Clin Oncol 2000; 18: 2354 2362 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Docetaxel + carboplatin



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DURVALUMAB Indications: Durvalumab for treating PD-L1 >=1% positive locally advanced and unresectable non-small-cell lung cancer which has not progressed following concurrent platinum-based chemoradiotherapy. 3. Histologically- or cytologically-confirmed diagnosis of non-small cell lung cancer. 4. PD-L1 testing with an approved and validated test to determine the PD-L1 Tumour Proportion Score (TPS) has been done prior application and the result either demonstrates a PD-L1 score of >=1% and the result is set out below or the PD-L1 TPS cannot be ascertained despite a clear intent and a reasonable attempt to do so. Note: durvalumab is not approved for use if the PD-L1 result is <1% or negative. 5. Locally advanced and unresectable non small cell lung cancer which is either stage IIIA or stage IIIB or stage IIIC at the time of commencing concurrent chemoradiotherapy. 6. Patient has recently completed treatment with 2 or more cycles (defined according to local practice) of platinum-based combination chemotherapy given concurrently with definitive radical radiotherapy which must have been at a dose of 54-66Gy (or a biologically equivalent dose of 54-66Gy). Note: durvalumab is not approved by NICE for use after sequential chemotherapy and radiotherapy. 7. The patient has been re-staged since chemoradiotherapy was completed and does not have any evidence of disease progression or metastatic spread. 8. The patient will start first treatment with durvalumab within 42 days of the last active treatment date of the concurrent chemoradiotherapy treatment program. 9. The patient has an ECOG performance status (PS) of 0 or 1. 10. The maximum treatment duration with durvalumab will be 12 months, this being measured from the date of first durvalumab treatment. Note: the total active treatment period is a maximum of 12 months ie in those patients who have toxicity and thus have dose interruptions, the maximum number of treatment cycles is 26 2-weekly cycles. 11. Treatment with durvalumab will continue until loss of clinical benefit or excessive toxicity or the patient decision to stop therapy or the treatment duration of 12 months has been completed, whichever is the sooner. Note: no re-treatment with durvalumab is allowed. 12. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody unless durvalumab has been received as part of AstraZeneca’s early access program for durvalumab after concurrent chemoradiotherapy. Note: patients treated in the AZ early access program with sequential chemotherapy and radiotherapy or any patient with PD-L1 TPS <1% or PD-L1 negative disease are not eligible for durvalumab from the CDF. For such patients who have already started durvalumab, AstraZeneca will continue to supply durvalumab as a consequence of its commitment in its expanded access program. 13. Aformal medical review as to whether treatment with durvalumab should continue or not will be scheduled to occur at least by the end of the first 6 weeks of treatment. 14. Treatment breaks of up to 12 weeks beyond the expected 2-weekly cycle length are allowed but solely to allow any immune toxicities to settle. 15. Licensed dose and frequency of durvalumab will be used.

Durvalumab Lung CAG Chair Authorisation: Date:


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DRUG REGIMEN Day 1 DURVALUMAB 10mg/kg in 250ml sodium chloride 0.9% IV infusion over 60 minutes

Cycle Frequency: every 2 weeks for maximum 12 months

DOSE MODIFICATIONS

Adverse reactions Severitya Durvalumab treatment modification

Corticosteroid treatment unless otherwise specified

Immune-mediated pneumonitis/interstitial lung disease

Grade 2 Withhold dose Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Grade 3 or 4 Permanently discontinue 1 to 4 mg/kg/day prednisone or equivalent followed by a taper

Immune-mediated hepatitis

Grade 2 with ALT or AST > 3-5 x ULN and/or total bilirubin > 1.5-3 x ULN

Withhold dose

Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Grade 3 with AST or ALT > 5-≤ 8 x ULN or total bilirubin > 3-≤ 5x ULN

Grade 3 with AST or ALT > 8 x ULN or total bilirubin > 5 x ULN

Permanently discontinue Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULN with no other cause

Immune-mediated colitis or diarrhoea

Grade 2 Withhold dose Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper Grade 3 or 4 Permanently discontinue

Immune-mediated hyperthyroidism

Grade 2-4 Withhold dose until clinically stable

Symptomatic treatment, see section 4.8

Immune-mediated hypothyroidism Grade 2-4 No changes Initiate thyroid hormone replacement as clinically indicated

Immune-mediated adrenal insufficiency or hypophysitis/hypopituitarism

Grade 2-4 Withhold dose until clinically stable

Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated

Immune-mediated type 1 diabetes mellitus

Grade 2-4 No changes Initiate treatment with insulin as clinically indicated



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Immune-mediated nephritis

Grade 2 with serum creatinine > 1.5-3 x (ULN or baseline)

Withhold dose

Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Grade 3 with serum creatinine > 3 x baseline or > 3-6 x ULN; Grade 4 with serum creatinine > 6 x ULN


Immune-mediated rash or dermatitis

Grade 2 for > 1 week Withhold dose Initiate 1 to 2 mg/kg/day

prednisone or equivalent followed by a taper

Grade 3

Grade 4 Permanently discontinue

Immune-mediated myocarditis

Grade 2 Withold doseb Initiate 2 to 4 mg/kg/day prednisone or equivalent followed by a taper

Grade 3 or 4, or any Grade with positive biopsy


Immune-mediated myositis/polymyositis

Grade 2 or 3 Withhold dose Initiate 1 to 4 mg/kg/day prednisone or equivalent followed by a taper Grade 4 Permanently discontinuec

Infusion-related reactions Grade 1 or 2

Interrupt or slow the rate of infusion

May consider pre-medications for prophylaxis of subsequent infusion reactions

Grade 3 or 4 Permanently discontinue

Infection Grade 3 or 4 Withold dose until clinically stable

Other immune-mediated adverse reactions

Grade 3 Withhold dose Consider initial dose of 1 mg/kg/day to 4 mg/kg/day prednisone or equivalent followed by taper

Grade 4 Permanently discontinue

INVESTIGATIONS Blood results required before chemotherapy administration FBC,U&E,Cr,LFTs every cycle TFT Every other cycle CT every 12 weeks while on treatment ECG Non urgent blood tests – tests relating to disease response/progression.

CONCURRENT MEDICATION None required



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ANTI-EMETIC POLICY Minimal

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Immune mediated pneumonitis Immune mediated hepatitis Immune mediated colitis Immune mediated endocrinopathies REFERENCES SPC CDF list



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ERLOTINIB (Tarceva) Indication: Locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Factors associated with prolonged survival should be taken into account when prescribing erlotinib. NICE TA162 Erlotinib is recommended as an alternative to docetaxel for patients with non-small-cell lung cancer (NSCLC) who have already tried one chemotherapy regimen but it has not worked. Erlotinib should be used only when the manufacturer provides the drug at the same overall treatment cost as docetaxel. This cost includes the cost of giving the drug, treatments for any side effects and the cost of monitoring patients to check that treatment is working. NICE recommends erlotinib as a possible first-line treatment (that is, if you have not had drug treatment before) for some people with locally advanced or metastatic non-small-cell lung cancer.

DRUG REGIMEN Day 1 Erlotinib 150mg orally daily Cycle Frequency: Initial review after 1 or 2 weeks of treatment then review every month until stable then review every 2 months

DOSE MODIFICATIONS If dose reduction required reduce dose to 100mg daily Erlotinib: Renal impairment Severe renal impairment - erlotinib not recommended. Hepatic impairment Mild – moderate hepatic impairment – dose reduction or interruption of erlotinib should be considered if severe adverse reactions occur. Severe hepatic impairment – erlotinib not recommended

Erlotinib Lung CAG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL ≥10 < 10





ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin rash – initial rash may be severe. Diarrhoea – dose reduction may be required. Moderate or severe diarrhoea may require loperamide REFERENCES 1. Erlotinib in previously treated non-small cell lung cancer. Shepherd FA, Pereira JR, Ciuleanu, T

et al. N Engl J Med 2005;353; 123-132

Erlotinib Lung CAG Chair Authorisation: Date:


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GEFITINIB (NSCLC) Indication: Locally advanced or metastatic non-small cell lung cancer, first line NICE: Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if: they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation.

DRUG REGIMEN Day 1 Gefitinib 250mg orally daily Cycle Frequency: Continuous treatment

DOSE MODIFICATIONS Gefitinib: Renal imparment CrCl ≤20ml/min caution is advised Hepatic impairment Patients with moderate to severe hepatic impairment due to cirrhosis have increased plasma concentrations of gefitinib. These patients should be closely monitored for adverse events. Plasma concentrations were not increased in patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases.


Give Discuss

Hb x g/dL 10 < 10

Plt x 109/L 100 < 100 Neutrophils x 109/L 1.5 < 1.5 Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

Gefitinib Lung CAG Chair Authorisation: Date:


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CONCURRENT MEDICATION Take at the same time each day. Swallow whole or disperse tablets in half a glass of water (noncarbonated) without crushing it. The glass should be swirled occasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should be drunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsed with half a glass of water, which should also be drunk.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin rash Diarrhoea Elevation in ALT REFERENCES 1. Gefitinib SPC July 2009 2. NICE TA 192 July 2010

Gefitinib Lung CAG Chair Authorisation: Date:


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GEMCITABINE (1200) CARBOPLATIN Indication: Standard combination for palliative treatment of NSCLC / SCLC Unknown primary if appropriate

NICE guidance www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine should each be considered, with a platinum drug, as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.

People with small-cell lung cancer should have treatment initiated within 2 weeks of the pathological diagnosis. (NICE)

DRUG REGIMEN Day 1 GEMCITABINE 1200mg/m2

infusion in 250ml sodium chloride 0.9% (or licensed dose volume) over 30 minutes CARBOPLATIN AUC 5* infusion in 500ml glucose 5% over 30-60 minutes Dose = (25 + GFR) x AUC

Day 8 GEMCITABINE 1200mg/m2


Cycle Frequency: Every 21 days Number of cycles: Up to 4 for NSCLC and up to 6 for SCLC (subject to tolerance and response)

NB * EDTA GFR should be used, If GFR is measured or EDTA then: AUC = 5 If calculated from serum creatinine the result is less accurate

DOSE MODIFICATIONS Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If GFR/ calculated CrCl = or < 20ml/min contraindicated

Gemcitabine: CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2 Neutrophils >1.5x10x9/L and platelets >100x10x9/L give 100% dose (Day 1 and 8) Neutrophils 0.5-1.5x10x9/L or platelets 50-100x10x9/L give 75% dose (Day 8 only) or delay based on clinical assessment (Day 1 and 8) Neutrophils <0.5x10x9/L or platelets <50x10x9/L delay treatment (Day 1) or omit treatment (Day 8).


Omit if treatment is delayed for more than 4 weeks but continue with Carboplatin

Gemcitabine /carboplatin



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Give Discuss

Hb x g/dL ≥10 < 10


Liver function tests (LFTs)

GFR should be measured using EDTA clearance. Estimating creatinine clearance from the serum creatinine, weight and age is less accurate. 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours.

ANTIEMETIC POLICY Moderate emetic risk day 1 Low emetic risk day 8


Diarrhoea – see dose modifications treat with loperamide or codeine. Mucositis – see dose modifications use routine mouth care. Ototoxicity - monitor Neurotoxicity – monitor REFERENCES 1. Danson S et al. Cancer 2003; 98: 542 553 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Gemcitabine /carboplatin



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GEMCITABINE Indication: Palliative treatment of NSCLC when patient not fit enough to tolerate platinum (e.g. performance status 2)

NICE guidance – www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.

DRUG REGIMEN Day 1 GEMCITABINE 1g/m2


Day 8 GEMCITABINE 1g/m2


Day 15 GEMCITABINE 1g/m2


Cycle Frequency: Every 28 days Number of cycles: Up to 4 (subject to tolerance and response)

DOSE MODIFICATIONS CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2

Neutrophils >1.5x10x9/L and platelets >100x10x9/L give 100% dose (Day 1 and 8) Neutrophils 0.5-1.5x10x9/L or platelets 50-100x10x9/L give 75% dose (Day 8 only) or delay based on clinical assessment (Day 1 and 8) Neutrophils <0.5x10x9/L or platelets <50x10x9/L delay treatment (Day 1) or omit treatment (Day 8).



Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests. Tests relating to disease response/progression

Gemcitabine Lung CAG Chair Authorisation: Date:


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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Diarrhoea – see dose modifications treat with loperamide or codeine. Mucositis – see dose modifications use routine mouth care. REFERENCES 1. Gridelli C et al. Journal of the National Cancer Institute 2003; 95: 363 372 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Gemcitabine Lung CAG Chair Authorisation: Date:


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NINTEDANIB (Vargatef) DOCETAXEL

Indication: Previously treated locally advanced, metastatic, or locally recurrent NSCLC

NICE guidance www.nice.org.uk TA347 for treating locally advanced, metastatic or locally recurrent non-small-cell lung cancer of adenocarcinoma histology that has progressed after first-line chemotherapy.


or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m2

infusion in 250ml sodium chloride 0.9% over 60 minutes Days 2-21NINTEDANIB 200mg bd PO

Cycle Frequency: Every 21 days. Following completion of at least 4 cycles (up to 6 cycles) of docetaxel and nintedanib combination, nintedanib may continue as monotherapy until disease progression

DOSE MODIFICATIONS Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated.

Nintedanib As initial measure for the management of adverse reactions treatment with nintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). Nintedanib treatment may be resumed at a reduced dose. Dose adjustments in 100mg steps per day (ie a 50mg reduction per dosing) based on individual safety and tolerability are recommended as below. In case of further persistence of the adverse reaction(s), ie if a patient does not tolerate 100mg twice daily, treatment with nintedanib should be permanently discontinued. In case of specific elevations of aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) values to >3xULN in conjunction with an increase of total bilirubin to ≥ 2 x ULN and alkaline phosphatase (ALKP) <2xULN; (see below) treatment with nintedanib should be interrupted. Unless there is an alternative cause established, nintedanib should be permanently discontinued. Recommended dose adjustments for nintedanib in case of diarrhoea, vomiting and other nonhaematological or haematological adverse reactions

Docetaxel nintedanib



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CTCAE* Adverse reaction Dose adjustment Diarrhoea ≥ grade 2 for more than 7 consecutive After treatment interruption and recovery days despite anti-diarrhoeal treatment grade 1 or baseline, dose reduction OR from 200mg twice daily to 150mg Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment twice daily and - if a 2nd dose reduction is considered Vomiting ≥ grade 2 daily. necessary - from 150mg twice AND/OR daily to 100mg twice daily Nausea ≥ grade 3 despite anti-emetic treatment Other non-haematological or haematological adverse reaction of ≥ grade 3

Recommended dose adjustments for nintedanib in case of AST and/or ALT and bilirubin elevations AST / ALT and bilirubin elevations Dose adjustment Elevation of AST and/or ALT values to > 2.5 x ULN in After treatment interruption and recovery conjunction with total bilirubin elevation to ≥ 1.5 x ULN of transaminase-values to ≤ 2.5x ULN OR in conjunction with bilirubin to normal, Elevation of AST and/or ALT values to > 5x ULN dose reduction from 200mg twice daily to 150mg twice daily and - if a 2nd dose reduction is considered necessary - from 150mg twice daily to 100mg twice daily. Elevation of AST and/or ALT values to > 3 x ULN in Unless there is an alternative cause conjunction with an increase of total bilirubin to ≥ 2 x established, nintedanib should be ULN and ALKP < 2 x ULN permanently discontinued

The docetaxel dose can be reduced, only once, as follows: • from 75mg/m2 to 60mg/m2 • patients that require a second docetaxel reduction and have not completed a minimum of 4 cycles of combination therapy should be discontinued. Those that have completed 4 cycles may continue to receive nintedanib monotherapy. In some cases treatment should be temporarily interrupted, to allow for the adverse event to recover to CTCAE Grade: = <1 or baseline before re-starting at a reduced dose.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression




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CONCURRENT MEDICATION Ensure pre-medication is given. This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions Loperamide may be required.



Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Diarrhoea, nausea and vomiting Venous thromboembolic events REFERENCES 1. Shepherd F et al. J Clin Oncol 2000; 18: 2095 2103. Fossella F et al. J Clin Oncol 2000; 18:

2354 2362 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic





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NIVOLUMAB (Opdivo)

Indications: The treatment of previously treated locally advanced or metastatic non-squamous non-small-cell lung cancer 2. The patient has a confirmed diagnosis of stage IIIB or IV non-squamous non-small cell lung cancer 3. The patient has progressed after previously receiving at least 2 cycles of platinum-containing chemotherapy for stage IIIB or IV non-small cell lung cancer and also a targeted treatment if the tumour is EGFR positive or ALK positive 4. The patient has an ECOG performance status of 0 or 1 5. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody unless it was received as part of the nivolumab EAMS programme for this indication and the patient meets all other criteria listed here 6. The patient has had PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score. 7. The patient’s tumour expresses PD-L1 (that is, with a tumour proportion score (TPS) ≥ 1%) by an approved and validated test. 8. The patient’s tumour proportion score* is: * Note: the patient’s TPS score must be provided, otherwise the application will not be authorised. 9. Nivolumab will be administered as monotherapy. 10. The patient has no symptomatically active brain metastases or leptomeningeal metastases. 11. Nivolumab will be stopped at 2 years of treatment or on disease progression* or unacceptable toxicity, whichever occurs first.*Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until further disease progression is confirmed. 12. Nivolumab will otherwise be used as set out in its SPC with the exception of criterion 11. The treatment of previously treated locally advanced or metastatic squamous non-small-cell lung cancer 3. The patient has a histologically or cytologically confirmed diagnosis of stage IIIB or IV squamous non-small cell lung cancer. 4. The patient has progressed after previously receiving at least 2 cycles of platinum-containing chemotherapy for stage IIIB or IV non-small cell lung cancer and also a targeted treatment if the tumour is EGFR positive or ALK positive. 5. The patient has an ECOG performance status of 0 or 1 and would otherwise be potentially fit for docetaxel-based 2nd line chemotherapy.

6. The patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody unless it was received as part of the nivolumab EAMS programme for this indication and the patient meets all other criteria listed here.

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7. Every effort has been made for the patient to have PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score (TPS). Please document the TPS results below:- TPS (if negative enter zero): OR- Please enter ‘yes’, if the TPS cannot be quantified OR- Please enter ‘yes’, if PD-L1 testing was not possible as the pathologist has documented that these was insufficient tissue 8. Nivolumab will be administered as monotherapy. 9. The patient has no symptomatically active brain metastases or leptomeningeal metastases. 10. Nivolumab will be stopped at 2 years of treatment or on disease progression* or unacceptable toxicity, whichever occurs first.*Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until further disease progression is confirmed. 11. Nivolumab will otherwise be used as set out in its SPC with the exception of criterion 11. Blueteq form needs to be completed for all patients for all funding streams

DRUG REGIMEN Day 1 NIVOLUMAB 240mgin 100ml* sodium chloride 0.9% infusion over 30 minutes

Cycle Frequency: Every 14 days until progression or intolerance (maximum 2 years)

DOSE MODIFICATIONS

Nivolumab: Renal impairment Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment Based on the population PK results, no dose adjustment is required in patients with mild hepatic impairment. Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. Nivolumab must be administered with caution in patients with moderate (total bilirubin > 1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.



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Immune-related adverse reaction Severity Treatment modification

Immune-related pneumonitis Grade 2 pneumonitis Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete

Grade 3 or 4 pneumonitis Permanently discontinue treatment

Immune-related colitis Grade 2 diarrhoea or colitis Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete

Grade 3 diarrhoea or colitis - Nivolumab monotherapy

Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

Grade 4 diarrhoea or colitis Permanently discontinue treatment

Immune-related hepatitis Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Permanently discontinue treatment

Immune-related nephritis and renal dysfunction

Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation Permanently discontinue treatment

Immune-related endocrinopathies Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis, Grade 2 adrenal insufficiency Grade 3 diabetes

Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete. Treatment should be continued in the presence of hormone replacement therapy

a as long as no

symptoms are present

Grade 4 hypothyroidism Grade 4 hyperthyroidism Grade 4 hypophysitis Grade 3 or 4 adrenal insufficiency Grade 4 diabetes


Grade 4 rash Permanently discontinue treatment

Other adverse reactions Grade 3 (first occurrence) Withhold dose(s)

Grade 4 or recurrent Grade 3 ; persistent Grade 2 or 3 despite treatment modification ; inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day




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INVESTIGATIONS

Routine Blood test 1) Blood results required before drug administration

Give Discuss

Hb x g/dL ≥10 < 10


2) Non urgent tests Tests relating to disease response/progression


ANTIEMETIC POLICY None required

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Management of and the treatment modifications that may be required for immune-related adverse reactions due to anti-PD-L1 treatments including pneumonitis, colitis, nephritis, endocrinopathies and hepatitis. Immune-mediated adverse reactions: Administer corticosteroids based on the severity of the reaction. - Immune-mediated pneumonitis: Withhold for moderate and permanently iscontinue for severe or life-threatening pneumonitis. - Immune-mediated colitis: Withhold for moderate or severe and permanently discontinue for life-threatening colitis. - Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or lifethreatening transaminase or total bilirubin elevation. - Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate and permanently discontinue for severe or life-threatening serum creatinine elevation. - Immune-mediated hypothyroidism and hyperthyroidism: Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. - Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. REFERENCES 1. SPC Nivolumab SPC Ref 3677021 June 2015 2. CDF October 2017



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OSIMERTINIB (Tagrisso) Indication: The treatment of locally advanced or metastatic epidermal growth factor receptor and T790M mutation-positive non-small-cell lung cancer (NSCLC) where all the following criteria are met: -Histologically or cytologically documented NSCLC that carries an EGFR and a T790M mutation -Locally advanced or metastatic NSCLC. -Radiological documentation of disease progression following 1st line EGFR TKI treatment with only one TKI and without any further systemic anticancer treatment. -Treatment with no more than one prior line of treatment for advanced NSCLC. -No prior chemotherapy unless any prior neoadjuvant or adjuvant chemotherapy had been completed at least 6 months prior to starting 1st line EGFR treatment. -PS 0 or 1 -At time of starting osimertinib, the patient must be fit enough to have potentially started platinum-based doublet chemotherapy

DRUG REGIMEN Day 1 Osimertinib 80mg orally daily Cycle Frequency: continuously until disease progression or unacceptable toxicity

DOSE MODIFICATIONS Osimertinib: Renal impairment No recommended dose in severe renal impairment (CrCl<30ml/min) or end stage renal disease. Hepatic impairment No recommended dose in moderate /severe hepatic impairment. PULMONARY - Interstitial lung disease /pneumonitis - discontinue permanently CARDIAC QTc interval >500msec on at least 2 separate occasions- withold until interval <481 or recovery to baseline if baseline > 481 msec then resume at 40mg QTC prolongation with signs/symptoms of life threatening arrhythmia - discontinue permanently Asymptomatic, absolute decrease in LVEF of 10% from baseline and below 50% - withhold for up to 4 weeks- if improved to baseline LVEF , resume. If not improved to baseline - discontinue permanently. Symptomatic congestive heart failure- discontinue permanently

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OTHER Grade 3 or higher adverse reaction – withhold for up to 3 weeks If improvement to grade 0-2 within 3 weeks - Resume at 80 or 40mg daily If no improvement within 3 weeks- discontinue permanently

INVESTIGATIONS PRE - ASSESSMENT lung function tests, FBC, full biochemistry, chest xray ECG (repeat ECG after 2 weeks of treatment) MONTHLY FBC, full biochemistry, Creatinine, Liver function tests (LFT) (ECG for patients with ongoing risk of other QT prolonging medication or cardiac failure) Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Some of the following may be required for treatment of the skin rash: E45 / Diprobase, Hydrocortisone 1%/2.5%, Clindamycin gel 1%, Oxytetracycline 500mg po bd (for 2 weeks) Prednisolone 25mg po od for 7 days then reducing by 5mg per day to stop


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin rash – initial rash may be severe. Diarrhoea – dose reduction may be required. Moderate or severe diarrhoea may require loperamide Interstitial lung disease/pneumonitis Cardiomyopathy QTc interval prolongation REFERENCES New England Journal Of Medicine Pasi A et all Vol 372 No 18 pages 1689-1699

Osmertinib Lung CAG Chair Authorisation: Date:


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PACLITAXEL 80mg (days 1, 8 and 15) Indication: NSCLC

DRUG REGIMEN Day 1 PREMEDICATION 30mins prior to infusion:

DEXAMETHASONE 8mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2

in 250ml* sodium chloride 0.9% infusion over 1 hour *doses 162mg to 600mg in 500ml sodium chloride 0.9% Cycle Frequency: Days 1, 8 and 15 every 28 days up to 3 cycles subject to tolerance and response

DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment


Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure pre-medication is given.

Paclitaxel 80mg weekly q28d



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ANTIEMETIC POLICY

Low emetogenic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS (2% risk of severe hypersensitivity) Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10 minutes), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment.

Paclitaxel 80mg weekly q28d



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PEMBROLIZUMAB (Keytruda)

Indication: The treatment of untreated PD-L1 positive metastatic non-small-cell lung cancer where all the following criteria are met: 2. The prescribing clinician is fully aware of the management of and the treatment modifications that may be required for immune-related adverse reactions due to anti-PD-L1 treatments including pneumonitis, colitis, nephritis, endocrinopathies and hepatitis. 3. The patient has a histologically- or cytologically-confirmed diagnosis of stage IIIB or IV non-small cell lung cancer (squamous or non-squamous) 4. The patient’s tumour expresses PD-L1 (that is, with a tumour proportion score [TPS] ≥50%) by an approved and validated test 5. The patient either does not have an adenocarcinoma/non-squamous histology OR does have an adenocarcinoma/non-squamous histology but does not have an EGFR or ALK-positive tumour. 6. The patient has not received previous systemic therapy for advanced /metastatic disease. Completion of treatment with CT and/or RT as part of neoadj/adj therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease 7. The patient has a performance status (PS) of 0 or 1 and is potentially fit for platinum-based chemotherapy 8. The patient has no active brain metastases or leptomeningeal metastases 9. Pembrolizumab will be administered as monotherapy 10. The patient has not received prior treatment with an anti-PD-1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody unless received as part of the pembrolizumab EAMS programme for this indication and meeting all other criteria listed. 11. Pembrolizumab will be stopped at 2 years of treatment or on disease progression* or unacceptable toxicity, whichever occurs first. *Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until further disease progression is confirmed. 12. Pembrolizumab will be used as outlined in the SPC with the exception of criteria 11 Indication: The treatment of PD-L1-positive non small-cell lung cancer after chemotherapy where all the following criteria are met: The prescribing clinician is fully aware of the management of and the treatment modifications that may be required for immune-related adverse reactions due to anti-PD-L1 treatments including pneumonitis, colitis, nephritis, endocrinopathies and hepatitis. The patient has a histologically- or cytologically-confirmed diagnosis of stage IIIB or IV non-small cell lung cancer (squamous or non-squamous). The patient's tumour expresses PD-L1 (that is, with a tumour proportion score [TPS] ≥1%) by an approved and validated test. The patient has progressed after treatment with at least two cycles of platinum-containing

Pembrolizumab Lung CAG Chair Authorisation: Date


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doublet chemotherapy for stage IIIB/IV disease AND a targeted treatment if they have an EGFR or ALK-positive tumour. The patient has an ECOG performance status of 0 or 1. The patient has no active brain metastases or leptomeningeal metastases. The patient has not received prior treatment with an anti-PD-1, anti-PDL2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. Pembrolizumab will be stopped at 2 years of treatment or on disease progression* or unacceptable toxicity, whichever occurs first. *Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until further disease progression is confirmed.

DRUG REGIMEN Day 1 PEMBROLIZUMAB 200mg in 100ml sodium chloride 0.9% infusion over 30 minutes

Cycle Frequency: Every 21 days until disease progression for a maximum of 2 years uninterrupted treatment

May switch to 6 weekly dosing after 4 doses of 200mg 3 weekly dosing Day 1 PEMBROLIZUMAB 400mg in sodium chloride 0.9% infusion over 30 minutes

Cycle Frequency: Every 42 days until disease progression total maximum of 24 months ie 4 cycles 3 weekly then 16 cycles of 6 weekly dosing

DOSE MODIFICATIONS Pembrolizumab See Immuno-oncology adverse event management guidelines

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration FBC,U&Es including magnesium, ,Cr, LFTs Every cycle TFT Every other cycle ECG Non urgent blood tests - Tests relating to disease response/progression

CONCURRENT MEDICATION None required.

ANTIEMETIC POLICY Low emetogenic risk



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Immune-mediated pneumonitis Immune-mediated colitis Immune-mediated hepatitis Immune-mediated endocrinopathies

REFERENCES SPC July 2015 CDF May 2017



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VINORELBINE (25) CARBOPLATIN Indication: Palliative treatment of NSCLC. NICE guidance www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients.

DRUG REGIMEN Day 1 VINORELBINE 25mg/m2

in 50ml sodium chloride 0.9% IV infusion over 10 mins CARBOPLATIN AUC = 5* in 500ml glucose 5% over 30 minutes Dose = (25 + GFR) x AUC

Day 8 VINORELBINE 25mg/m2

in 50ml sodium chloride 0.9% IV infusion over 10 mins Cycle Frequency: Every 21 days Number of cycles: 2 or 3 if given in neoadjuvant and adjuvant setting, up to 4 in palliative setting (subject to tolerance and response) NB *Ideally EDTA GFR should be used, If GFR is measured or EDTA then: AUC = 5 If calculated from serum creatinine the result is less accurate

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Vinorelbine: If there is significant hepatic impairment the dose should be reduced If bilirubin > 2 x ULN and AST/ALT >5 x ULN give 66.6% dose Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If GFR/ calculated CrCl = or < 20ml/min contraindicated

Vinorelbine/ carboplatin



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Give Discuss

Hb x g/dL ≥10 < 10


GFR should be measured using EDTA clearance. Estimating creatinine clearance from the serum creatinine, weight and age is less accurate. Liver function tests (LFTs) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours.

ANTIEMETIC POLICY

Moderate emetic risk day 1 Minimal emetic risk day 8


Ototoxicity - monitor Neurotoxicity – monitor

REFERENCES 1. Baldini E et al. Br J Cancer 1998; 77: 2367 2370. 2. Cremonesi M et al. Oncology 2003; 64 : 97-101 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Vinorelbine/ carboplatin



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VINORELBINE (25) CISPLATIN (80) Indication: Palliative treatment of unresectable NCSLC. Also used as neoadjuvant treatment prior to radical chemoradiotherapy and adjuvant treatment of patients following complete resection of non-small cell lung cancer NICE guidance www.nice.org.uk. Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients. 4 cycles of vinorelbine plus cisplatin are indicated for adjuvant treatment of patients following complete resection of non small cell lung cancer


VINORELBINE 25mg/m2

in 50ml sodium chloride 0.9% IV infusion over 10 mins CISPLATIN 80mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post-hydration Day 8 VINORELBINE 25mg/m2

in 50ml sodium chloride 0.9% IV infusion over 10 mins Cycle Frequency: Every 21 days Number of cycles: 2 or 3 if given in neoadjuvant and adjuvant setting, up to 4 in palliative setting (subject to tolerance and response)

DOSE MODIFICATIONS Vinorelbine: If there is significant hepatic impairment the dose should be reduced If bilirubin > 2 x ULN and AST/ALT >5 x ULN give 66.6% dose Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.

Vinorelbine / cisplatin



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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) calculated OR EDTA at the Consultants discretion (Cisplatin). Liver function tests (LFTs) 2) Non urgent blood tests. Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre and post hydration prescribed as per day case schedule at the end of TVCN regimens. If urine output is <100 ml/hour or if patient gains >2kg in weight during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV. .

ANTIEMETIC POLICY High emetic risk day 1 Minimal emetic risk day 8


Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Wozniak AJ et al. J Clin Oncol 1998; 16: 2459 2465 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic


Vinorelbine / cisplatin



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VINORELBINE

NICE guidance – www.nice.org.uk Docetaxel, gemcitabine, paclitaxel and vinorelbine should each be considered as part of first-line chemotherapy options for advanced (stage III and IV) NSCLC patients.

Indication: Palliative treatment of NSCLC when patient not fit enough to tolerate platinum (e.g. performance status 2)


in 50ml sodium chloride 0.9% IV infusion over 10 mins Day 8 VINORELBINE 30mg/m2

in 50ml sodium chloride 0.9% IV infusion over 10 mins

Administration should always be followed by a 250ml sodium chloride 0.9% infusion to flush the vein. Cycle Frequency: Every 21 days Number of cycles: Individualised but rarely more than 4

DOSE MODIFICATIONS If there is significant hepatic impairment the dose should be reduced If bilirubin > 2 x ULN and AST/ALT >5 x ULN give 66.6% dose


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests - Tests relating to disease response/progression


ANTIEMETIC POLICY Minimal emetic risk.


REFERENCES 1. Gridelli C et al. Oncologist 2001; 6: Supp 1: 4 7

Vinorelbine Lung CAG Chair Authorisation: Date:


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VINORELBINE (oral) Indication: Palliative treatment of stage III or IV NSCLC or patients not fit enough to tolerate platinum NICE guidance Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients. 4 cycles of vinorelbine plus cisplatin are indicated for adjuvant treatment of patients following complete resection of non-small cell lung cancer

DRUG REGIMEN Cycle 1 Day 1, 8 and 15 VINORELBINE 60mg/m2

orally once a week. (Maximum dose 160 mg/week) Cycle 2 onwards - dose escalation at the Consultant’s discretion if cycle 1 tolerated Day 1, 8 and 15 VINORELBINE 80mg/m2

orally once a week (see dose modifications) (Maximum dose 160 mg/week)

NB capsules should be swallowed with food and water without chewing or sucking the capsule at least 30 minutes after antiemetic. Available as 20, 30, 40 and 80mg capsules NB Based on clinical studies, the oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the iv form and 60 mg/m2 to 25 mg/m2

Cycle Frequency: every 21 days

DOSE MODIFICATIONS AND DELAYS Dose escalation from cycle 2 onwards to 80mg/m2

except in patients for whom the neutrophil count has dropped once below 0.5 x109/L OR more than once between 0.5-1.0 x109/L during the first cycle doses, in these patients continue at 60mg/m2

For doses planned to be given at 80mg/m², if the neutrophil count is below 0.5 x109/L OR more than once between 0.5-1.0 x109/L administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the following cycles. If the neutrophil count is below 1.5 x109/L AND/OR the platelet count is between 75-100 x109/L then the treatment should be delayed until recovery

Vinorelbine PO



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Hepatic impairment No prospective study is available in order to establish guidelines for the dose reduction of vinorelbine capsules. If there is significant hepatic impairment the dose of Vinorelbine soft capsules should be reduced. In patients with massive liver metastases (i.e.> 75% of liver volume replaced by the tumour) it is empirically suggested that a 75% dose be given and the haematological parameters closely monitored.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFTs) 2) Non urgent blood tests- Tests relating to disease response/progression

CONCURRENT MEDICATION Cytochrome P450 is likely to be mainly involved in the metabolism of vinorelbine, combination with inducers or inhibitors of this isoenzyme may alter its pharmacokinetics. Omeprazole and fluoxetine (norfluoxetine), inhibitors for CYP3A4, were both found to moderately inhibit the metabolism of vinorelbine, although the clinical relevance of this inhibition is not known

ANTIEMETIC POLICY Moderate emetic risk days 1 and 8


Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver. REFERENCES 1. NAVELBINE soft capsules http://emc.medicines.org.uk [accessed 25/03/08]

Vinorelbine PO



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VINORELBINE elderly (oral) Indication: Palliative treatment of stage III or IV NSCLC or patients not fit enough to tolerate platinum NICE guidance Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients. 4 cycles of vinorelbine plus cisplatin are indicated for adjuvant treatment of patients following complete resection of non-small cell lung cancer

DRUG REGIMEN Cycle 1 Day 1 and 8 VINORELBINE 60mg/m2

orally. (Maximum dose 160 mg/week) Cycle 2 onwards - dose escalation at the Consultant’s discretion if cycle 1 tolerated Day 1 and 8 VINORELBINE 80mg/m2

(see dose modifications, (Maximum dose 160 mg/week)

NB capsules should be swallowed with food and water without chewing or sucking the capsule at least 30 minutes after antiemetic. Available as 20, 30, 40 and 80mg capsules NB Based on clinical studies, the oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the iv form and 60 mg/m2 to 25 mg/m2

Cycle Frequency: every 21 days



For doses planned to be given at 80mg/m², if the neutrophil count is below 0.5 x109/L OR more than once between 0.5-1.0 x109/L administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the following cycles. If the neutrophil count is below 1.5 x109/L AND/OR the platelet count is between 75-100 x109/L then the treatment should be delayed until recovery

Vinorelbine elderly PO



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Hepatic impairment No prospective study is available in order to establish guidelines for the dose reduction of Vinorelbine capsules. If there is significant hepatic impairment the dose of Vinorelbine soft capsules should be reduced. In patients with massive liver metastases (i.e.> 75% of liver volume replaced by the tumour) it is empirically suggested that a 75% dose be given and the haematological parameters closely monitored.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFTs) 2) Non urgent blood tests.- Tests relating to disease response/progression

CONCURRENT MEDICATION Cytochrome P450 is likely to be mainly involved in the metabolism of vinorelbine, combination with inducers or inhibitors of this isoenzyme may alter its pharmacokinetics. Omeprazole and fluoxetine (norfluoxetine), inhibitors for CYP3A4, were both found to moderately inhibit the metabolism of vinorelbine, although the clinical relevance of this inhibition is not known

ANTIEMETIC POLICY Moderate emetic risk days 1 and 8


Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver. REFERENCES 1. NAVELBINE soft capsules http://emc.medicines.org.uk [accessed 25/03/08]

Vinorelbine elderly PO



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VINORELBINE (oral) CISPLATIN Indication: Palliative treatment of unresectable NCSLC. Adjuvant treatment following complete resection of NSCLC. Also used as neoadjuvant treatment prior to radical chemoradiotherapy NICE guidance Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients. 4 cycles of vinorelbine plus cisplatin are indicated for adjuvant treatment of patients following complete resection of non small cell lung cancer

DRUG REGIMEN Cycle 1 Day 1 Pre-hydration

VINORELBINE 60mg/m2

orally (Maximum dose 160mg/week) CISPLATIN 80mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours Post-hydration Day 8 VINORELBINE 60mg/m2

orally (Maximum dose 160mg/week) Cycle 2 onwards - dose escalation at the Consultant’s discretion if cycle 1 tolerated Day 1 Pre-hydration

VINORELBINE 80mg/m2

orally (Maximum dose 160mg/week) CISPLATIN 80mg/m2

infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient)

Post-hydration Day 8 VINORELBINE 80mg/m2

orally (Maximum dose 160mg/week) NB capsules should be swallowed with food and water without chewing or sucking the capsule at least 30 minutes after antiemetic. Available as 20, 30, 40 and 80mg capsules NB Based on clinical studies, the oral dose of 60mg/m2 was demonstrated to correspond to 25mg/m2 of the iv form and 80mg/m2 to 30mg/m2, Vinorelbine dose may be increased to 80mg/m2 Cycle Frequency: Every 21 days Number of cycles: 2 or 3 if given in neoadjuvant setting, up to 4 in palliative setting, 4 cycles for adjuvant treatment following complete resection (subject to tolerance and response)

Vinorelbine PO/ cisplatin



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For doses planned to be given at 80mg/m², if the neutrophil count is below 0.5 x109/L OR more than once between 0.5-1.0 x109/L administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the following cycles. I If the neutrophil count is below 1.5 x109/L AND/OR the platelet count is between 75-100 x109/L then the treatment should be delayed until recovery Hepatic impairment No prospective study is available in order to establish guidelines for the dose reduction of Vinorelbine capsules.

If there is significant hepatic impairment the dose of Vinorelbine soft capsules should be reduced. In patients with massive liver metastases (i.e.> 75% of liver volume replaced by the tumour) it is empirically suggested that the dose be reduced by 25 % and the haematological parameters closely monitored.

Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 40ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) calculated OR EDTA at the Consultants discretion (Cisplatin). Liver function tests (LFTs) 2) Non urgent blood tests- Tests relating to disease response/progression




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CONCURRENT MEDICATION Cisplatin - Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN regimens. If fluid balance is > 2L positive after 8 hours post hydration OR if patient gains >2kg in weight or urine output <100ml/hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV. Vinorelbine- Cytochrome P450 is likely to be mainly involved in the metabolism of vinorelbine, combination with inducers or inhibitors of this isoenzyme may alter its pharmacokinetics. Omeprazole and fluoxetine (norfluoxetine), inhibitors for CYP3A4, were both found to moderately inhibit the metabolism of vinorelbine, although the clinical relevance of this inhibition is not known

ANTIEMETIC POLICY High emetic risk day 1 Moderate emetic risk day 8


Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver. REFERENCES 1. Wozniak AJ et al. J Clin Oncol 1998; 16: 2459 2465 2. NAVELBINE soft capsules http://emc.medicines.org.uk [accessed 25/03/08] 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic





Version 4.2


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VINORELBINE (oral) CARBOPLATIN Indication: Palliative treatment of unresectable NCSLC. Also used as neoadjuvant treatment prior to radical chemoradiotherapy NICE guidance Docetaxel, gemcitabine, paclitaxel and vinorelbine, with a platinum drug, should each be considered as part of first line chemotherapy options for advanced (stage III and IV) NSCLC patients. 4 cycles of vinorelbine plus cisplatin are indicated for adjuvant treatment of patients following complete resection of non-small cell lung cancer


orally (maximum dose 160mg/week) CARBOPLATIN AUC5 in 500ml glucose 5% infusion over 30 minutes

Day 8 VINORELBINE 60mg/m2

orally (maximum dose 160mg/week) NB capsules should be swallowed with food and water without chewing or sucking the capsule at least 30 minutes after antiemetic. Available as 20, 30, 40 and 80mg capsules NB Based on clinical studies, the oral dose of 60mg/m2 was demonstrated to correspond to 25mg/m2 of the iv form and 80mg/m2 to 30mg/m2, Vinorelbine dose may be increased to 80mg/m2 Cycle Frequency: Every 21 days Number of cycles: 2 or 3 if given in neoadjuvant setting, up to 4 in palliative setting (subject to tolerance and response)

DOSE MODIFICATIONS AND DELAYS Hepatic impairment No prospective study is available in order to establish guidelines for the dose reduction of Vinorelbine capsules. If there is significant hepatic impairment the dose of Vinorelbine soft capsules should be reduced. In patients with massive liver metastases (i.e.> 75% of liver volume replaced by the tumour) it is empirically suggested that the dose be reduced by 25 % and the haematological parameters closely monitored. Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If EDTA GFR = or < 20ml/min contraindicated

Vinorelbine PO/ carboplatin



Version 4.2

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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) calculated OR EDTA at the Consultants discretion (Carboplatin). Liver function tests (LFTs) 2) Non urgent blood tests- Tests relating to disease response/progression

CONCURRENT MEDICATION Vinorelbine- Cytochrome P450 is likely to be mainly involved in the metabolism of vinorelbine, combination with inducers or inhibitors of this isoenzyme may alter its pharmacokinetics. Omeprazole and fluoxetine (norfluoxetine), inhibitors for CYP3A4, were both found to moderately inhibit the metabolism of vinorelbine, although the clinical relevance of this inhibition is not known

ANTIEMETIC POLICY High emetic risk day 1 Moderate emetic risk day 8


Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver. REFERENCES 1. Wozniak AJ et al. J Clin Oncol 1998; 16: 2459 2465 2. NAVELBINE soft capsules http://emc.medicines.org.uk [accessed 25/03/08] 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic

impairment. 2009, The North London Cancer Network

Vinorelbine PO/ carboplatin



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CARBOPLATIN PEMETREXED

Indications: Palliative treatment of non-resectable malignant mesothelioma in patient with an ECOG performance status of 0-1. First line treatment of Non-small cell lung cancer. NICE: Pemetrexed is recommended as a possible treatment for malignant pleural mesothelioma in people: with advanced disease whose cancer is not suitable for surgical resection (removal) and who have a WHO performance status of 0 or 1 Pemetrexed is recommended as 1st line treatment of NSCLC adenocarcinoma and large cell undifferentiated carcinoma.

DRUG REGIMEN Day 1 Pre-medication

Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Folic acid 400mcg/day orally starting 1 to 3 weeks before chemotherapy continuing until 21 days after the last dose of pemetrexed. Hydroxycobalamin 1000mcg IM every 9 weeks starting 1 to 3 weeks before chemotherapy (give with every 3rd cycle of chemotherapy) PEMETREXED 500mg/m2 IV infusion in 100ml (Alimta brand use sodium chloride 0.9% but all generic brands use glucose 5%) over 10 minutes CARBOPLATIN AUC 5 IV infusion in 500ml glucose 5% over 30 minutes

(30 minutes after completing Pemetrexed)

Cycle frequency: Every 21 days Number of cycles: Plan for 3 cycles and repeat cross sectional imaging and full

assessment. Maximum 6 cycles depending on tolerance and response.



Carboplatin / Pemetrexed



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Creatinine clearance (GFR) should be 45ml/min (calculated or EDTA) otherwise clinical decision Liver function tests (LFTs)


Alk phos, AST and ALT 3 x upper limit of normal. (Alk phos, AST, and ALT 5 x normal is acceptable if liver has tumour involvement). Clinical decision

Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/L If GFR/ calculated CrCl = or < 20ml/min contraindicated


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression Ideally EDTA GFR should be used (Carboplatin) Creatinine clearance (GFR) calculated, at the Consultants discretion Liver function tests (LFT)

CONCURRENT MEDICATION Avoid use of high dose NSAIDs with CrCl > 80ml/min. Avoid all NSAIDS with CrCl between 45 and 79ml/min for at least 5 days prior to and 2 days after pemetrexed dose.





Carboplatin / Pemetrexed



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CISPLATIN PEMETREXED

Indications: Palliative treatment of non-resectable malignant mesothelioma in patient with an ECOG performance status of 0-1. Pemetrexed is recommended as a possible treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) if: •the cancer is a particular type (adenocarcinoma or large-cell carcinoma) and •the person has not had any treatment for NSCLC before. NICE TA181 NICE: Pemetrexed is recommended as a possible treatment for malignant pleural mesothelioma in people: with advanced disease whose cancer is not suitable for surgical resection (removal) and who have a WHO performance status of 0 or 1 Pemetrexed is recommended as 1st line treatment of NSCLC adenocarcinoma and large cell undifferentiated carcinoma.


Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Folic acid 400mcg/day orally starting 1 to 3 weeks before chemotherapy continuing until 21 days after the last dose of pemetrexed. Hydroxycobalamin 1000mcg IM every 9 weeks starting 1 to 3 weeks before chemotherapy (give with every 3rd cycle of chemotherapy)

Pre-hydration PEMETREXED 500mg/m2 IV infusion in 100ml (Alimta brand use sodium chloride 0.9% but all generic brands use glucose 5%) over 10 minutes CISPLATIN 75mg/m2 IV infusion in 1000ml sodium chloride 0.9% over 2 hours (30 minutes

after completing Pemetrexed) Post-hydration

Cycle frequency: Every 21 days Number of cycles: Plan for 3 cycles and repeat cross sectional imaging and full

assessment. Maximum 6 cycles depending on tolerance and response.



Cisplatin / Pemetrexed



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Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss with SpR or Consultant before administration.

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN regimens. If fluid balance is > 2L positive after 8 hours post hydration OR if patient gains >2kg in weight or urine output <100ml/hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV. Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Avoid use of high dose NSAIDs with CrCl > 80ml/min. Avoid all NSAIDS with CrCl between 45 and 79ml/min for at least 5 days prior to and 2 days after pemetrexed dose.





Cisplatin / Pemetrexed



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PEMETREXED maintenance

Indication: Locally advanced or metastatic non-small cell lung cancer following treatment with pemetrexed and cisplatin.

NICE: Pemetrexed is recommended as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.

For the maintenance treatment of locally advanced or metastatic non-squamous non-small-cell lung cancer in adults when their disease has not progressed immediately after 4 cycles of pemetrexed and cisplatin induction therapy


Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Folic acid 400mcg/day orally starting 1 to 3 weeks before chemotherapy continuing until 21 days after the last dose of pemetrexed. Hydroxycobalamin 1000mcg IM every 9 weeks starting 1 to 3 weeks before chemotherapy (give with every 3rd cycle of chemotherapy) PEMETREXED 500mg/m2 IV infusion in 100ml (Alimta brand use sodium chloride 0.9% but all generic brands use glucose 5%) over 10 minutes

Cycle frequency: Every 21 days Number of cycles: Maintenance


Nadir platelets 50 regardless of nadir neutrophils 50% of previous dose Any Grade 3 or 4 non-haematological toxicities except mucositis 75% of previous dose Any diarrhoea requiring hospitalisation (irrespective of grade) 75% of previous dose or Grade 3 or 4 diarrhoea Grade 3 or 4 mucositis 50% of previous dose Neurotoxicity grade 3 or 4 Discontinue therapy Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.




Pemetrexed maintenance



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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Dexamethasone 4mg bd for 3 days (starting the day before chemotherapy) Avoid use of high dose NSAIDs with CrCl > 80ml/min. Avoid all NSAIDS with CrCl between 45 and 79ml/min for at least 5 days prior to and 2 days after pemetrexed dose.

ANTI-EMETIC POLICY Low emetic risk




Pemetrexed maintenance



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Pre-hydration and post-hydration regimens

Ensure adequate diuresis is obtained prior to administration and maintained during and after administration. 1. Inpatient

Pre 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours Give cisplatin in 1000ml volume over 4 hours Post 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours

NB 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 6 hours if oral intake is inadequate

2. Day case Pre 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours 200ml mannitol 10% infusion over 30 minutes (immediately before cisplatin) Give cisplatin in 1000ml volume over 2 hours Post 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours

NB Furosemide 40mg may be added if required

Hydration Lung CAG Chair Authorisation: Date


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Documents

Thames Valley SACT Regimens · Thames Valley CAV SACT regimens – Lung Cancer 8 Indication: First line treatment for SCLC in patients not able to tolerate platinum and etoposide