Clinical Hot Topics 2016

Solid Tumors

Teresa Knoop, MSN, RN

Vanderbilt-Ingram Cancer Center

Nashville, TN

Disclosures

No conflicts to disclose

Objectives

• Identify new drugs approved in 2015/2016 for the treatment of solid tumors

• Discuss immunologic agents for drug therapy in solid tumors, including the adverse reactions associated with selecting these targets.

• Describe strategies for prevention, identification, and management of drug-related toxicities.

Progress in Cancer Therapy

2015/2016

18 new drugs gained FDA approval in 2015/2016; 13 for solid tumors with 16 drugs getting expanded indications in solid tumors in 2015/16

• Non-small cell lung cancer

• alectinib (ALK positive)• gefitinib (EGFR positive)• osimertinib (EGFR T790m positive)• necitumumab (squamous only)

• nivolumab (progressed on or after platinum-based tx)• pembrolizumab (metastatic with PD-L1 expression)• crizotinib (metastatic with ROS1 –positive tumors)• afatinib (squamous cell NSCLC)

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

Progress in Cancer Therapy

2015/2016

18 new drugs gained FDA approval in 2015/2016; 13 for solid tumors with 16 drugs getting expanded indications in solid tumors in 2015/16

• Breast• palbociclib (with letrozole first line ER+/HER2-)

• palbociclib (with fulvestrant for pretreated pts ER+/HER2-)

• Colorectal • trifluradine tipiracil

• ramucirumab (combination with FOLFIRI)

• Pancreatic• irinotecan liposomal

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

Progress in Cancer Therapy

2015/2016

18 new drugs gained FDA approval in 2015/2016; 13 for solid tumorswith 16 drugs getting expanded indications in solid tumors in 2015/16

• Melanoma• cobimetinib in combination with vemurafenib for

unresectable/metastatic BRAF v600e or v600k mutation positive)• talimogene laherparepvec (TVEC) unresectable cutaneous, subcutaneous

and nodal lesions

• pembrolizumab (now for initial use and pts with prior treatment unresectable/metastatic)

• trametinib and dabrafenib (combination for metastatic BRAF v600e or v600k mutation positive)

• ipilimumab (adjuvant with at least one mode positive and resected )• ipilimumab and nivolumab (combination in BRAF wild type

unresectable/metastatic)

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

Progress in Cancer Therapy

2015/2016

18 new drugs gained FDA approval in 2015/2016; 13 for solid tumorswith 16 drugs getting expanded indications in solid tumors in 2015/16

• Thyroid• Lenvatinib

• Basal cell• sonidegib

• Neuroblastoma• dinutuximab

• http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

Progress in Cancer Therapy

2015/2016

18 new drugs gained FDA approval in 2015/2016; 13 for solid tumorswith 16 drugs getting expanded indications in solid tumors in 2015/16

• Sarcoma• trabectedin(liposarcoma or leiomyosarcoma)

• eribulin (liposarcoma)

• Neuroendocrine of GI or lung origin• everolimus

• Renal cell• nivolumab expanded indication for RCC after anti-angiogenic therapy• cabozantinib expanded indication for advanced RCC after

anti-angiogenic therapy

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

SOLID TUMOR

TARGETS

ibs(ciclibs)

• Small molecules; inhibitor of cyclin dependent kinase (CDK) 4 & 6

• Oral

• Adherence

• Possible drug/food , drug/drug interactions

• Patient education regarding taking medication correctly

• Examples:

• palbociclib

http://www.ama-assn.org/ama/pub/physician-resources/medical-science/united-states-adopted-names-council/naming-guidelines/naming-biologics/monoclonal-antibodies.page

www.ibrance.com

palbociclib (IBRANCE®)

• palbociclib (IBRANCE®) Pfizer indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Additional approval in combination with fulvestrant for pretreated pts

• Monoclonal antibody or small molecule?

• Infusion rxns or drug/drug drug/food interactions?

• Target?

• Personalized?

• Side effects?

www.ibrance.com

palbociclib (IBRANCE®)

• palbociclib (IBRANCE®) Pfizer indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Additional approval in combination with fulvestrant for pretreated pts

• Small molecule; kinase inhibitor

• Drug/drug and drug/food interactions. CYP3A inducers, inhibitors and substrates, grapefruit

• Targets cyclin dependent kinase (CDK ) 4/6. Not personalized per se but is combined with letrozole or fulvestrant which are given for ER positive HER2 negative disease.

• Side effects: Cytopenias, infections, GI events, neuropathy, fatigue, epistaxis

Unleashing the Immune System

Checkpoint Inhibitors

• Targets that promote T-cell proliferation; allows immune system to recognize tumor antigens

• CTLA-4: cytotoxic T-lymphocyte-associated antigen-4

• PD-1: programmed cell death protein

• PD-L1: programmed cell death protein ligand 1

Brahmer, JR & Pardoll, Dm. Cancer Immunol Res August 2013

CTLA-4

Target

• .

Anti-CTLA-4

FDA Approved Drug in this Class

Ipilimumab (Yervoy®) Bristol-Myers Squibb

Yervoy.com

Anti-CTLA-4

Application in Cancer Treatment

• Ipilimumab (Yervoy®)

• unresectable or metastatic melanoma

• adjuvant treatment of melanoma after resection of regional lymph nodes greater than 1 mm

• unresectable or metastatic melanoma in combination with nivolumab

Yervoy.com

PD-1 and PD-L1:

Target

Anti PD-1 and PD-L1

FDA approved drugs in this class

• pembrolizumab (KEYTRUDA®) Merck Sharp and Dohme

• nivolumab (OPDIVO®) Bristol-Myers Squibb

keytruda.com; opdivo.com

Anti PD-L1

Application

pembrolizumab (KEYTRUDA®) :

• unresectable or metastatic melanoma progression after ipilimumab and, if BRAF V600 mutation positive, after a BRAF inhibitor

• metastatic non-small cell lung cancer whose tumors express PD-L1 progression on or after platinum-containing tx. Pts who have ALK or EGFR genomic tumor aberrations should also progress on specifically targeted therapies

keytruda.com

Anti PD-1

Application

nivolumab (OPDIVO®) :

• unresectable or metastatic melanoma BRAF V600 WT or BRAF V600 positive

• unresectable or metastatic melanoma in combination with ipilimumab

• metastatic non-small cell lung cancer progression on or after platinum-containing tx. Pts who have ALK or EGFR genomic tumor aberrations should also progress on specifically targeted therapies

• advanced renal cell after progression on anti-angiogenic tx

opdivo.com

Vignette 1

Question 1

Mrs. AK, 45 year old woman with relapsed metastatic melanoma, is going to start treatment with ipilimumab (Yervoy). Based on the generic name of this drug what potential side effects do you anticipate?

1. Cytotoxic effects like myelosuppression2. Proteinuria3. Immune related adverse events4. Hypertension

Vignette 1

Question 1

answer

Mrs. AK, 45 year old woman with relapsed metastatic melanoma, is going to start treatment with ipilimumab (Yervoy). Based on the generic name of this drug what potential side effects do you anticipate?

1. Cytotoxic effects like myelosuppression2. Proteinuria3. Immune related adverse events4. Hypertension

Vignette 1

Question 2

Ipilimumab is in a class of drugs called anti-CTLA agents. Common adverse events are immune mediated and result in inflammatory effects. Which of the following organs might be affected?

1) Pituitary gland2) Liver3) Skin4) GI tract5) Any of the above6) None of the above

Vignette 1

Question 2

answer

Ipilimumab is in a class of drugs called anti-CTLA agents. Common adverse events are immune mediated and result in inflammatory effects.. Which of the following organs might be affected?

1) Pituitary gland2) Liver3) Skin4) GI tract5) Any of the above6) None of the above

Vignette 1

Question 3

Patient education for Mrs. AK should include which of the following points?

1. Immediate reporting of changes in bowel movements, blood in stool or abdominal pain

2. Take blood pressure at home daily3. Avoid grapefruit4. Do not be concerned about a yellow tone in your skin or in the whites of your

eyes

Vignette 1

Question 3

answer

Patient education for Mrs. AK should include which of the following points?

1. Immediate reporting of changes in bowel movements, blood in stool or abdominal pain

2. Take blood pressure at home daily3. Avoid grapefruit4. Do not be concerned about a yellow tone in your skin or in the whites of your

eyes

Checkpoint Inhibitors

Common Side effects

• Rash/pruritis

• Fatigue

• Dyspnea/cough

• Decreased appetite

• Nausea

• Constipation/diarrhea

• Arthralgias

keytruda.com; opdivo.com; yervoy.com

Checkpoint Inhibitors

Immune Related Adverse Events

(IrAEs)

• Side effects mediated by the immune system; think autoimmunity (“itis”)

• Early recognition/treatment is key• Patient/caregiver education• Treat symptoms early• Monitor closely

Furlow B. ASCO. WCLC 2015

Checkpoint Inhibitors

Immune Related Adverse Events

• Potentially serious/life-threatening• GI (diarrhea>colitis)• Pulmonary (pneumonitis/interstitial lung

disease [ILD])• Endocrine (thyroid, adrenal, pituitary)• Liver (hepatitis)• Kidney (nephritis)• Skin• Neuro

keytruda.com; opdivo.com; yervoy.com

Checkpoint Inhibitors

Management of (IrAEs)

• Baseline assessment• Autoimmune conditions• Lung, liver, GI, endocrine, skin issues• Lab values (including liver, thyroid)

• Monitoring at treatment or follow up visits• Lab values (including liver, thyroid)• Symptoms• Reinforce early detection/prompt reporting

keytruda.com; opdivo.com; yervoy.com

Vignette 1

Question 4

Two days before her third dose of ipilimumab, Mrs. AK experiences moderate diarrhea (5 stools per day over baseline) and is instructed to take anti-diarrheal treatment. What are the recommended next steps for this patient?

1. Withhold the third dose of ipilimumab 2. If the diarrhea has not subsided in a week despite anti-diarrheal treatment,

start Mrs. AK on systemic corticosteroids3. Resume ipilimumab if diarrhea resolves or becomes mild (3 or less bowel

movements over baseline)4. All of the above are appropriate recommendations

Vignette 1

Question 4

answer

Two days before her third dose of ipilimumab, Mrs. AK experiences moderate diarrhea (5 stools per day over baseline) and is instructed to take anti-diarrheal treatment. What are the recommended next steps for this patient?

1. Withhold the third dose of ipilimumab 2. If the diarrhea has not subsided in a week despite anti-diarrheal treatment,

start Mrs. AK on systemic corticosteroids3. Resume ipilimumab if diarrhea resolves or becomes mild (3 or less bowel

movements over baseline)4. All of the above are appropriate recommendations

Checkpoint Inhibitors

Management of IrAEs

• Use algorithms

• No dose reductions• Give, hold or discontinue

keytruda.com; opdivo.com; yervoy.com

Checkpoint Inhibitors

Management of IrAEs

• Grade 2 IrAEs (mild to moderate; worsened from baseline)• Withhold drug• Treat symptoms• Exclude other causes• Reassess every 2-3 days• Treat with oral steroids and taper with resolution• Consult specialists/consider further diagnostic

testing

keytruda.com; opdivo.com; yervoy.com

Checkpoint Inhibitors

Management of IrAEs

• Grades 3/4 IrAEs (severe)• Permanently discontinue drug if persistent symptoms

or life-threatening• Treat symptoms• Reassess daily• Continue steroids/increase dosage• Add non-corticosteroid immunosuppressive

medication if needed• Consult specialists/consider further diagnostic

testing

keytruda.com; opdivo.com; yervoy.com

Vignette 2

Question 1

Mr. JL is a 62 year old with recurrent squamous cell lung cancer with metastasis to the liver. She is beginning treatment with nivolumab. What assessments should be done at baseline due to the potential serious adverse events associated with nivolumab?

1. Assessment of lung function and underlying lung conditions

2. Assessment of blood pressure

3. Assessment of protein in urine

4. Assessment of skin for lesions suspicious for skin cancer

Vignette 2

Question 1

answer

Mr. JL is a 62 year old with recurrent squamous cell lung cancer with metastasis to

the liver. She is beginning treatment with nivolumab. What assessments should be done at baseline due to the potential serious adverse events associated with nivolumab?

1. Assessment of lung function and underlying lung conditions

2. Assessment of blood pressure

3. Assessment of protein in urine

4. Assessment of skin for lesions suspicious for skin cancer

Vignette 2

Question 2

After 2 months of treatment Mrs. JL calls into clinic one morning and says she has been coughing for the last couple of days and is now noticing shortness of breath with exertion. Which of the following actions should be taken next?

1. You tell Mrs. JL that coughing is normal with lung cancer and to call again tomorrow to see if she has noticed any improvement.

2. You tell Mrs. JL that she should come into the clinic for assessment

3. You tell Mrs. JL it is probably a URI and you will ask the MD to call in an antibiotic for her.

Vignette 2

Question 2

Answer

After 2 months of treatment Mrs. JL calls into clinic one morning and says she has been coughing for the last couple of days and is now noticing shortness of breath with exertion. Which of the following actions should be taken next?

1. You tell Mrs. JL that coughing is normal with lung cancer and to call again tomorrow to see if she has noticed any improvement.

2. You tell Mrs. JL that she should come into the clinic for assessment

3. You tell Mrs. JL it is probably a URI and you will ask the MD to call in an antibiotic for her.

Vignette 2

Question 3

Mrs. JL comes into the clinic, is assessed and is sent for a chest CT scan. What is the hallmark sign on a CT scan for interstitial lung disease?

1. Large masses in the hilar area of the lung

2. Spiculated lesions

3. Ground-glass opacities, infiltrates

Vignette 2

Question 3

Answer

Mrs. JL comes into the clinic, is assessed and is sent for a chest CT scan. What is the hallmark sign on a CT scan for interstitial lung disease?

1. Large masses in the hilar area of the lung

2. Spiculated lesions

3. Ground-glass opacities, infiltrates

Vignette 2

Question 4

Mrs. JL is told she has signs of ILD on the CT scan . She would like to know what the next steps will be? You tell her:

1. The nivolumab will be held until there is symptom improvement and radiographic improvement

2. A course of oral steroids will be given

3. She will be reassessed in one week, but she is to call in to the office if symptoms worsen at any point

4. All of the above could be appropriate

Vignette 2

Question 4

AnswerMrs. JL is told she has signs of ILD on the CT scan . She would like to know what the next steps will be? You tell her:

1. The nivolumab will be held until there is symptom improvement and radiographic improvement

2. A course of oral steroids will be given

3. She will be reassessed in one week, but she is to call in to the office if symptoms worsen at any point

4. All of the above would be appropriate

Vignette 2

Question 5

If Mrs. JL calls back in to report worsening symptoms of ILD, which steps might be taken?

1. Hospitalization

2. Oxygen

3. High dose steroids

4. Permanent discontinuation of nivolumab

5. All of the above would be appropriate

Vignette 2

Question 5

Answer

If Mrs. JL calls back in to report worsening symptoms of ILD, which steps might be taken?

1. Hospitilization

2. Oxygen

3. High dose steroids

4. Permanent discontinuation of nivolumab

5. All of the above would be appropriate

References

• http://www.ama-assn.org/ama/pub/physician-resources/medical-science/united-states-adopted-names-council/naming-guidelines/naming-biologics/monoclonal-antibodies.page

• Brahmer, JR & Pardoll, Dm. Cancer Immunol Res August 2013

• http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies

• http://www.cancer.gov/dictionary

• http://www.cancer.net

• http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

• Furlow B. ASCO. WCLC 2015

• Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027

References• http://www.avastin.com

• http://www.caprelsa.com

• http://www.cometriq.com

• http://www.cyramza.com

• http://www.erbitux.com

• http://www.erivedge

• http://www.gilotrif.com

• http://www.herceptin.com

• http://www.inlyta.com

• http://iressa.com

References

• http://www.kadcyla.com

• http://www.keytruda.com

• http://www.lenvima.com

• http://www.lynparza.com

• http://www.mekinist.com

• http://www.nexavar.com

• http://www.odomzo.com

• http://www.opdivo.com

• http://www.perjeta.com

• http://www.stivarga.com

• http://sutent.com

References

• http://www.tafinlar.com

• http://www. tarceva.com

• http://www.tykerb.com

• http://www.vectibix.com

• http://www. votrient.com

• http://www. xalkori.com

• http:/www.yervoy.com

• http://www.zaltrap.com

• http://www.zelboraf.com

• http://www.zykadia.com