Advanced NSCLC: Treatment algorithms 2014 Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg

Advanced NSCLC: Treatment algorithms 2014

Prof. Christian ManegoldProf. Christian ManegoldMedical Faculty Mannheim

University of Heidelberg

NSCLC: Incidence of single driver mutations

Mutation found in 54% (280/516) oftumours completely tested (CI 50-59%)

Kris et al. J Clin Oncol 29 (suppl 15) 477 (abstr 7506); 2011

1st-line

Platinum-Doublets

(Pem!) plus Bev

Non-Squamous

Advanced NSCLC: Current Treatment algorithm

EGFR-TKIEGFR-TKI Platinum-Doublets

(No Pem, no Bev)

Maintenance

Switch:Pemetrexed

ErlotinibContinuous:Pemetrexed

Switch:Erlotinib

2nd-line

ALK-Inhibitor

Single agentNon-cross resistant


Squamous

Mutant tumors

Oligo progression:Cont. TKI + Local

therapy

Diffuse progression

Cont. TKI + ChemoChemo TKI re-expo

2nd generation TKI

Treatment until

progression

Wild type tumors

Advanced NSCLC: Treatment for non-mutant tumors

First-line – (induction) – therapy-Selection by histo-typeMaintenance therapy-Switch / continuationSecond-line / subsequent-line therapy

NSCLC: International treatment recommendations for advanced disease

• Chemotherapy prolongs survival and is most appropriate for individuals with good performance status (PS 0 or 1, and possibly 2).

• Chemotherapy should be a platinum-based two-drug combination regimen.

• Non-platinum containing regimens may be used as alternatives to platinum-based regimens. For elderly patients, or patients with PS 2, available data support the use of single-agent chemotherapy.

• Chemotherapy should be stopped at 4 cycles in patients who are not responding to treatment, and should be administered for no more than six cycles.

• If chemotherapy is to be given it should be initiated while the patient still has good PS.

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

Advanced NSCLC: Medical management – practical aspects

Feasibility / tolerability: Cis-platin vs carbo-platin-Hotta et al. J Clin Oncol 22, 3852-3859, 2004, Rudd et al. J Clin Oncol 23, 142-153, 2005-Artizoni et al. J Natl Cancer Inst 99, 847-857, 2007

Co-morbidity / regimen: Platin based / free-D‘Addario et al. J Clin Oncol 23, 2926-2936, 2005-Laack et al. J Clin Oncol 22, 2348-2356, 2004,

Age ≥ 70 years: Single agent / combination-Gridelli et al. J Clin Oncol 23, 3125-3137, 2005; Gridelli et al. J Natl Cancer Inst 95, 362-372, 2003-Gridelli et al. J Natl Cancer Inst 91, 66-72, 1999; Sederholm et al. J Clin Oncol 23, 8380-8388, 2005

Performance status ≥ 2: Single agent / combination- Gridelli et al. Ann Oncol 15, 419-426, 2004,

Patient’s expectations: Active therapy / BSC-Gridelli et al. J Clin Oncol 23, 3125-3137, 2005

Selection by histo-type according to efficacy (non-squamous vs squamous)

Pemetrexed+CisplatinMedian OS: 11.0 mos

Gemcitabine+CisplatinMedian OS: 10.1 mos

HR=0.844(95% CI: 0.74–0.96) p=0.011

Pemetrexed+CisplatinMedian OS: 9.4 mos

Gemcitabine+CisplatinMedian OS: 10.8 mos

HR=1.229(95% CI: 1.00–1.51)p=0.051

Nonsquamous* (n=1252) Squamous (n=473)

Survival Time (months) Survival Time (months)

Su

rviv

al

Pro

bab

ilit

y

Su

rviv

al

Pro

bab

ilit

y

Advanced NSCLC: Treatment by histologyCisplatin plus Pemetrexed or Gemcitabine

Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008

Efficacy by Histology in Pemetrexed Studies

NSCLCHistologic Group

Second-linePem vs. Docetaxel

First-linePem/Cis

vs. Gem/CisMaintenance

Pem vs. Placebo

Pem Doc Cis/Pem Cis/Gem Pem Placebo

Non-squamous n=205 n=194 n=618 n=634 n=325 n=156

Median OS, months 9.3 8.0 11.0 10.1 15.5 10.3

Adjusted HR (95% CI)

P value0.78 (0.61–1.00)

0.0480.84 (0.74–0.96)

0.0110.70 (0.56–0.88)

0.002

Squamous n=78 n=94 n=244 n=229 n=116 n=66

Median OS, months 6.2 7.4 9.4 10.8 9.9 10.8

Adjusted HR (95% CI)P value

1.56 (1.08–2.26)0.018

1.23 (1.00–1.51)0.050

1.07 (0.77–1.50)0.678Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology

Scagliotti et al. J Thorac Oncol 6, 64-70, 2011

Ifosfamide in NSCLC: MIC Regimen

Mitomycin C 6 mg/m² i.v. Bolusday 1

Ifosfamide 3.000 mg/m² i.v./3 hday 1

Cisplatin 50 mg/m² i.v./1 hday 1Cycle repeated q3w

Cullen et al, Br J Cancer 58, 359-361, 1988

MESNA-Uroprotection

20 % (IFO) i.v. fractionated (0 hours) 4 h + 8 h

100 % (IFO) i.v. continuous (0 hours) during IFO

+ for additional 12 q 24 h

MIC `s Efficacy is not inferior to other Platinum Doublets

n RR TTP MST 1-y-sRef.

NVB / CIS 206 30 % n.r. 9.5 mo* 37 %Le Chevalier

VDS / CIS 200 19 % n.r. 7.6 mo 28 %(1994)

PAC 135 / CIS Total 27 %* 4.5 mo* 9.6 mo* 37 %Bonomi

PAC 250 / CIS 560 32 %* 5.3 mo* 10 mo* 39 %(1996)

ETO / CIS 12 % 3.0 mo 7.7 mo 32 %

GEM / CIS 154 40 % 4.8 mo 8.6 mo 33 %Crino

MIC 152 28 % 5.0 mo 9.5 mo 34 %(1998)

GEM / CIS 69 41 %* 6.9 mo* 8,7 mo 32 %Cardenal

ETO / CIS 66 22 % 4.3 mo 7.2 mo 26 %(1999)

PAC / CARBO 190 23 %* 4.0 mo 7.7 mo 32 %Belani

ETO / CIS 179 14 % 3.3 mo 8.2 mo 37 %(1998)

*p<.05

Phase IIStage IIIb/IV

PAC 250 mg/m² (3h), d 1

IFO 1600 mg/m² , d 1-3 q3w x 6

NAV 30 mg/m², d 1-3

IFO 1600 mg/m², d 1-3 q3w x 6

Perry et al, Lung Cancer 48,63-68, 2000

RR MS 1ySA: 38% 9mo 35%B: 31% 8mo 38%

Arm An=48

Arm Bn=45

Platinum-free, Ifosfamide based doublets have been developed

Phase IIIStage IIIb/IVPS 0-2

Cis 100 mg/m², d 1 x 6 (n=166)Gem 1250 mg/m² , d 1, 8

Cis 100 mg/m², d 1 x 6 (n=176)Gem 1000 mg/m², d 1, 8Vin 25 mg/m², d 1, 8

Gem 1000 mg/m², d 1, 8 x 3 (n=175)Vin 30 mg/m², d 1, 8

Ifo 3000 mg/m², d 1 x 3Vin 30 mg/m², d 1, 8

Alberola et al, J Clin Oncol, 21:3207-3213, 2003

RR: 41% 40% 24%MS: 10m 8m 11mNtp3/4: 26% 30% 18%Tbp3/4: 18% 23% 7%0

Platinum-free, Ifosfamide based doublets have been developed

Selection by toxicity profile(non-squamous vs squamous)

Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints

12.3 m

Time Months

10.3 m

6.7 m

6.1 m

6.5 m

6.1 m

Sandler et al N Engl J Med 355, 2542-2550, 2006Reck et al, Ann Oncol 21, 1804-1809, 2010Reck et al, J Clin Oncol 27, 1227-1235, 2009

ECOG 4599: Carbo/TaxolECOG 4599: Carbo/Taxol AVAiL: Cis/GemAVAiL: Cis/Gem

NSCLC: Bevacizumab - Eligibility

Inclusion criteria Exclusion criteria non-squamous NSCLC

chemo-naïve

ECOG PS of 0–1

grade 2haemoptysis

radiological evidence of tumour invasion of major blood vessels

spinal cord compression

uncontrolled hypertension

history of thrombotic or haemorrhagic disorders

therapeutic anticoagulation within 10 days of first dose

Sandler et al N Engl J Med 355, 2542-2550, 2006 Crino et al, LancetOncol 11, 733-740, 2010Reck et al, J ClinOncol 27, 1227-1235, 2009 Reck et al, Ann Oncol 21, 1227-1234,2010Sandler et al J Thorac Oncol 5,1416-1423,2010 Soria et al Ann Oncol 24,20-30,2013

Advanced NSCLC: Basics of medical management


Advanced NSCLC:Medical Treatment in wild type tumors

Combinationor single agent CTdefined number

of cycles (4-6)


of cycles (4-6)

single agent , Non-cross-resistant

until progression

single agent , Non-cross-resistant

until progression

Tumor

progression

1st-line 2nd-/subsequent line

Traditional (standard) approach

one of the first line agents until progression (continuation)

„new“ non-cross-resistant agent until progression (switch)

one of the first line agents until progression (continuation)

„new“ non-cross-resistant agent until progression (switch)

1st-line Maintenance

New (maintenance) approach


of cycles (4-6)


of cycles (4-6)

Non-

progression2nd-/

subsequent line

Advanced NSCLC: Switch/continuation maintenance

Cappuzzo et al. Lancet Oncol 11, 521-529; 2010Ciuleanu T. et al. Lancet 374, 1432-1440; 2009Paz-Ares Lancet Oncol 13, 247-255, 2012 Zhang et al. Lancet Oncol 13, 466-475,2012

Fidias et al J Clin Oncol 27, 591-598, 2008Perol et al J Clin Oncol 30, 3516-3524, 2012Paz-Ares et al J Clin Oncol 31, 2895-2902, 2013

Advanced NSCLC: Maintenance

Switch type („early second line“)• Docetaxel

Fidias et al J Clin Oncol 27, 591-598, 2009

• Stage IIIb/IV • ECOG PS = 0–2• CNS Mets allowed

• Stage IIIb/IV • ECOG PS = 0–2• CNS Mets allowed

Gem, 1000 mg/m2, d1, 8 Carbo AUC 5, d1,q3w x 4

Gem, 1000 mg/m2, d1, 8 Carbo AUC 5, d1,q3w x 4

RANDOMIZE

ImmediateDocetaxel

75 mg/m2 d1, q3w x 6

DelayedDocetaxel

75 mg/m2 d1, q3w x 6

DelayedDocetaxel

75 mg/m2 d1, q3w x 6

CR, PRSD

Fidias et al., J Clin Oncol 27, 591-598, 2009

Immediate vs delayed (2nd-line) Docetaxel

Advanced NSCLC - Maintenance: Docetaxel following Standard Doublet Chemotherapy

n=552n=552 n=142/153n=142/153

n=91/154n=91/154n=307n=307Off study: n=245Off study: n=245

Primary endpoint: overall survival

Immediate Doc

(n=153)

Delayed Doc

(n=154)p-value

PFS, mos (95% CI)

6.5(4.4–7.2)

2.8(2.6–3.4)

<0.0001

1-yr-PFS, % (95% CI)

20%(13–26)

9%(5–14)

Overall survival time (months)

Immediate Doc

(n=153)

Delayed Doc

(n=154)p-value

MS, mos(95% CI)

11.9(10.0–13.7)

9.1(8.0–11.2)

0.071

1-yr-S %(95% CI)

48.5%(39.9–57.1)

38.3(30.0–46.5)

Advanced NSCLC - Maintenance: Extension by Docetaxel following Standard Doublet Chemotherapy

Immediate vs delayed (2nd-line) Docetaxel

Fidias et al., J Clin Oncol 27, 591-598, 2009


Switch type („early second line“)• Erlotinib

Cappuzzo et al, Lancet Oncol 11, 521-529, 2010

Advanced NSCLC: Erlotinib switch maintenance (Saturn)

1:11:1

Chemonaïve advanced

NSCLCn=1,949

Chemonaïve advanced

NSCLCn=1,949

Non-PDn=889

Non-PDn=889

4 cycles of first-line platinum

doublet chemotherapy

*

4 cycles of first-line platinum

doublet chemotherapy

*PlaceboPlacebo PDPD

Erlotinib150mg/day

Erlotinib150mg/day PDPD

Mandatory tumour sampling

Mandatory tumour sampling

Stratification factors:• EGFR IHC (positive vs negative vs indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs others)• Smoking history (current vs former vs never)• Region

Co-primary endpoints:• PFS in all patients• PFS in patients with EGFR IHC+ tumours

Secondary endpoints:• OS in all patients and those with EGFR IHC+

tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

Advanced NSCLC: Erlotinib switch maintenanceProgression free survival

Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

Progression free Survival

Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

Advanced NSCLC: Erlotinib switch maintenanceOverall survival

Overall Survival

Ove

rall

Surv

ival

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

9.6 11.9

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

12.012.0 12.5

Log-rank p=0.0019HR=0.72 (0.59–0.89)

Erlotinib (n=252)

Placebo (n=235)

Log-rank p=0.6181HR=0.94 (0.74–1.20)

Erlotinib (n=184)

Placebo (n=210)

Stable disease CR/PR

Measured from time of randomisation into the maintenance phase

Advanced NSCLC: Erlotinib switch-maintenance Overall survival by response

Coudert et al. Ann Oncol 23, 388-394, 2012Cappuzzo et al. Lancet Oncol 11, 521-529; 2010


Switch type („early second line“)• Pemetrexed

Ciuleanu et al Lancet 374, 1432-1440, 2009

Advanced NSCLC: Pemetrexed switch maintenance

• Stage IIIB/IV NSCLC

• PS 0-1• 4 prior cycles of

gem, doc, or tax + cis or carb, with CR, PR, or SD

• Randomization factors:

• gender• PS• stage• best tumor

response to induction

• non-platinum induction drug

• brain mets

Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*

Primary Endpoint = PFS

Placebo (d1, q21d) + BSC (N=222)*Placebo (d1, q21d) + BSC (N=222)*

*B12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS

2:1 Randomization

Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

Advanced NSCLC: Pemetrexed switch maintenanceProgression free survival by histology

Time (months)

Pro

gres

sion

-fre

e P

roba

bilit

y

Time (months)

Non-squamous Squamous

Placebo: 1.8 mos

Pemetrexed: 4.4 mos Placebo: 2.5 mos

Pemetrexed: 2.4 mos

HR=0.47 (95% CI: 0.37-0.6)p <0.00001

HR=1.03(95% CI: 0.77-1.5)p=0.896


Non-squamous Squamous

Time (months) Time (months)

Ove

rall

Su

rviv

al

Placebo: 10.3 mos

Pemetrexed: 15.5 mos

HR=0.70 (95% CI: 0.56-0.88)p=0.002

Placebo: 10.8 mos

Pemetrexed: 9.9 mos

HR=1.07(95% CI: 0.49-0.73)p=0.678


Advanced NSCLC: Pemetrexed switch maintenance Overall survival by histology

Advanced NSCLC: switch maintenance ASCO recommendations 2011

For patients with SD or response after 4 cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with non-squamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered

(alternative to second-line therapy!)

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011Fidias et al. J Clin Oncol 27, 591-598, 2009Coudert et al. Ann Oncol 23, 388-394, 2012Cappuzzo et al. Lancet Oncol 11, 521-529; 2010Paz-Ares Lancet Oncol 13, 247-255, 2012


Continuation type („true maintenance“)

• Pemetrexed

Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT)

Stadium IVNon-squamousSD nach 4-6x Induktions-CTCisplatin/Pemetrexed

Stadium IVNon-squamousSD nach 4-6x Induktions-CTCisplatin/Pemetrexed

Rand

omis

ation

2:1 Pemetrexed

3qw bis PDPemetrexed3qw bis PD

Placebo3qw bis PD Placebo3qw bis PD

Non PDNon PD

Paz-Ares et al Lancet Oncol 13, 247-255, 2012 Paz-Ares et al J Clin Oncol 31, 2895-2902, 2013

Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) – Overall survival by response

Paz-Ares et al. J Clin Oncol 31, 2895-2902, 2013Paz-Ares et al. J Clin Oncol 31, 2895-2902, 2013

Advanced NSCLC: Pemetrexed registration Continuation maintenance therapy

......as single agent following platinum based

therapy - predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy……

EMA: 2011

Advanced NSCLC - Maintenance

Comparison switch vs continuation• Erlotinib (switch)

• Gemcitabine (continuation)

Perol et al J Clin Oncol 30, 3516-3524, 2012

• Patients stratified by sex, histology, smoking status, treatment center, and response/stabilization following first-line therapy

• Primary endpoint: PFS • Other endpoints: OS, safety, symptom control, effect of EGFR status

Gemcitabine(n = 154)

Observation(n = 155)

Erlotinib(n = 155)

Chemotherapy-naive patients with

stage IIIB/IV NSCLC

(N = 834)

Cisplatin/Gemcitabinefor 4 cycles

Patients without disease progression randomized 1:1:1

Perol M et al, J Clin Oncol 30, 3516-3524, 2012

Pem74 %

Pem84%

Pem75%

Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)

Perol M et al, J Clin Oncol 30, 3516-3524, 2012

Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)

Advanced NSCLC: Basics of medical management


Current ASCO Guidelines for NSCLC

Docetaxel, EGFR-TKI’s, and Pemetrexed are acceptable as second-line therapy for patients with advanced NSCLC with adequate performance status when the disease has progressed during or after first-line platinum-based therapy

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011Shepherd et al. N Engl J Med 353, 123-132, 2005 Thatcher et al. Lancet 366, 1527-1537, 2005Hanna et al. J Clin Oncol 22, 1589-1597, 2004

Advanced NSCLC: EGFR-TKIs as second-line therapy

Kim et al. Cancer 116, 3025-3033, 2010Karampazis et al. Cancer 119, 2754-2764, 2013Garassino et al. Lancet Oncol 14, 981-988, 2013Ciuleanu et al. Lancet Oncol 13, 300-308, 2012

Shepherd et al. N Engl J Med 353, 123-132, 2005 Kim et al. Lancet 372, 1809-1818, 2008Thatcher et al. Lancet 366, 1527-1537, 2005

Lee et al. JAMA 311,1430-1437, 2014

Meta-analysis in wild-type NSCLC favors CT over EGFR-TKI therapy: First- / second-line

Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (1)

• Chemotherapy remains standard for the majority of patients

- (first-line; platinum doublets; 4 – 6 cycles)

• The selection of the platinum-partner should depend on tumor histo-type

- (non-squamous vs squamous; pemetrexed vs gemcitabine etc.)

• Modification of the first-line standard is clinically advisable according to co-morbidity, performance status, and patient’s age

- (single agent; platinum-free; BSC only)

• Treatment until progression by the anti-angiogenic bevacizumab as recommended in selected patients

- (eligibility criteria; group toxicity)

Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (2)

• Prolongation of induction chemotherapy beyond 4 – 6 cycles for maintaining “response” until progression has been established as a new strategy

- (switch/continuation maintenance)

• Second/subsequent – line chemotherapy is recommended in patients with acceptable performance status

- (single agent; docetaxel; pemetrexed)• EGFR-TKI’s have also been licensed for wild-type tumors

- (maintenance; second/third-line therapy)

• A tight cooperation between the pathologist and the clinician is critical

- (histology – subtyping; molecular testing; result reporting)

1st-line

Platinum-Doublets

(Pem!) plus Bev

Non-Squamous

Advanced NSCLC: Current Treatment algorithm

EGFR-TKIEGFR-TKI Platinum-Doublets

(No Pem, no Bev)

Maintenance

Switch:Pemetrexed

ErlotinibContinuous:Pemetrexed

Switch:Erlotinib

2nd-line

ALK-Inhibitor



Squamous

Mutant tumors

Oligo progression:Cont. TKI + Local

therapy

Diffuse progression

Cont. TKI + ChemoChemo TKI re-expo

2nd generation TKI

Treatment until

progression

Wild type tumors

Advanced NSCLC: EGFR-TKIs as first line therapy

Mok et al. N Engl J Med, 361, 947-957, 2009Rosell et al Lancet Oncol 13;239-246;2012Lee et al Lancet Oncol 13, 1161-1170, 2012Zhou et al. Lancet Oncol 12, 735-742, 2011

Mitsudomi et al Lancet Oncol 11, 121-128, 2010Sequist et al. J Clin Oncol 31, 3327-3334, 2013Gridelli et al J Clin Oncol 30, 3002-3011, 2012

First-line trials of EGFR tyrosine kinase inhibitors vs. chemotherapy in pts with EGFR mutations

EGFRTKI

Comparator N (Tota

l)

EGFR mut-

positive

Response rate

(%)

Progression-free survival

(months)

Overall survival(months)

IPASS1,2 Gefitinib

Carboplatin/paclitaxel

1217 261 71 vs 47p=0.0001

9.5 vs 6.3HR 0.48 (0.36‒0.64)

21.6 vs 21.9HR 1.0 (0.76–1.33)

First-SIGNAL3

Gefitinib

Gemcitabine/cisplatin

309 42 85 vs 38p=0.002

8.0 vs 6.3HR 0.54 (0.27–1.10)

27.2 vs 25.6HR 1.04 (0.50–2.18)

NEJ0024 Gefitinib

Carboplatin/paclitaxel

224 224 74 vs 31p<0.001

10.8 vs 5.4HR 0.30 (0.22–0.41)

30.5 vs 23.6

WJTOG-34055

Gefitinib

Cisplatin/docetaxel

172 172 62 vs 32p<0.0001

9.2 vs 6.3HR 0.5 (0.34–0.71)

30.9 vs NRHR 1.64 (0.75–3.6)

OPTIMAL6 Erlotinib

Gemcitabine/carboplatin

154 154 83 vs 36p<0.0001

13.1 vs 4.6HR 0.16 (0.10–0.26)

Not mature

EURTAC7 Erlotinib

Chemotherapy

173 173 58 vs 15 9.7 vs 5.2HR 0.37 (0.25–0.54)

19.3 vs 19.5 HR 1.04 (0.65–1.68)

LUX-LUNG 38

Afatinib

Pemetrexed/cisplatin

345 345 56 vs 23p<0.0001

11.1 vs 6.9HR 0.58 (0.43–0.78)

Not mature

LUX-LUNG 69

Afatinib

Gemcitabine/cisplatin

364 364 67 vs 23p<0.0001

11.0 vs 5.6HR 0.28 (0.20–0.39)

Not mature1. Mok T et al., N Engl J Med 2009;361:947–957; 2. Fukuoka M et al., J Clin Oncol 2011; 29:2866‒2874; 3. Han J-Y et al., J Clin Oncol 2012; 30:1122‒128; 4.

Maemondo M et al., N Engl J Med 2010;362:2380–2388; 5. Mitsudomi T et al., Lancet Oncol 2010;:121–128; 6. Zhou C et al., Lancet Oncol 2011;12:735‒742; 7. Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol 2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not

reported

… EGFR-TKI therapy should be prescribed for patients with tumors bearing activated EGFR-mutations …… Patients with PS 3-4 may also be offered EGFR-TKI treatment …

Advanced NSCLC: First-line EGFR-TKI therapyASCO / ESMO-recommendation

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

EGFR mutations: whom to test? (1)

EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics

Lindeman et al., J Thorac Oncol, 823-859, 2013

EGFR mutations: whom to test ? (2)

In the setting of more limited lung cancer specimens (biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing.


Laboratories should follow similar quality control and

quality assurance policies and procedures for EGFR

testing in lung cancers as for other clinical laboratory

assays. In particular, laboratories performing EGFR

testing for TKI therapy should enroll in proficiency

testing, if available.

EGFR mutations: laboratory issues


Second-line therapy in case of progression in first-line EGFR-TKI therapy

• Oligo progression:– Continuous TKI + Local therapy

• Diffuse progression– Continuous TKI + Chemotherapy– Chemotherapy TKI re-exposition– 2nd generation TKI

Advanced NSCLC:EMA registration for Erlotinib

• Second / third line:In patients after failure of at least one prior chemotherapy

• Maintenance:In patients with stable disease after 4 cycles of platinum based first-line chemotherapy

CHMP, 18 March 2010

Shaw et al. N Engl J Med 368, 2385-2394, 2013

Advanced NSCLC: Crizotinib for ALK-positive diseasePhase III (PROFILE 1007) – 2nd line

Advanced NSCLC: Crizotinib for ALK-positive diseasePhase III (PROFILE 1007) – 2nd line

347 patients,Advanced NSCLC,

Prior platinumbased CT,all histologies,

EML4-ALK Translocation

Primary Endpoint: PFS

Randomization

Randomization

Shaw et al. N Engl J Med 368, 2385-2394, 2013

Crizotinib 250 mg bid

Pemetrexedor

Docetaxel

Crizotinib 250 mg bid

PD

Advanced NSCLC: Systemic therapy in existence of driver mutations-

Role of TKI’s• Has changed significantly the treatment algorithm

– (treatment by genotype)• Is specifically relevant for mutant tumors

– (First-line therapy) • Has been licensed and recommended in wild type

tumors and tumors with unknown EGFR-status– (Maintenance, second/third-line therapy)

• Has underlined the importance of the pathologist’s and its tight cooperation with the clinicians – (molecular testing)

4th International Thoracic Oncology Congress Dresden

September 12th – 14th 2014Maritim Hotel and International Congress CenterDresden, Germany

Organizers:Christian Manegold - MannheimGiorgio V. Scagliotti - TorinoNico van Zandwijk - Sydney

Advances through Molecular Biology in Thoracic Cancer

More Information:

www.itocd.com

Save the date!

Documents

Advanced NSCLC: Treatment algorithms 2014 Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg