Non-Small Cell Lung Cancer:

Transcription

1 Non-Small Cell Lung Cancer: Where We Are Today Sila Shalhoub, PharmD PGY2 Oncology Pharmacy Resident Pharmacy Grand Rounds September 26, MFMER slide-1

2 Objectives Identify the impact of known risk factors on patients with specific subtypes of NSCLC Classify different treatment options based on staging and tumor characteristics Discuss the updated 2017 ASCO guidelines for stage IV NSCLC Outline a therapy strategy based on patient considerations and pathologic profile 2017 MFMER slide-2

3 Lung Cancer Second most common cancer #1 leading cause of cancer death Deaths from lung cancer > colon + breast + prostate combined 2017 estimates: 222,500 new cases 155,870 deaths Types Non-small cell lung cancer (NSCLC) -85% Small cell lung cancer (SCLC) -15% Chalela R, et al. J Thorac Dis Jul;9(7): American Cancer Society. Key Statistics for Lung Cancer MFMER slide-3

4 Risk Factors Genetic/ family history Radiation Diet SMOKING Chemical exposure Air pollution Molina JR, et al. MayoClinProc May;83(5): National Cancer Institute. Lung Cancer American Cancer Society. What Is Non-Small Cell Lung Cancer MFMER slide-4

5 NSCLC Subtypes Adenocarcinoma Most common (40%) Originate in mucus secreting cells, outer part of the lung Common in young, non-smokers, females Squamous cell carcinoma Second most common (25%-30%) Originate in the cells that line the inside of the airways Large cell carcinoma Account for 10%-15% Can appear in any part of the lung Grow and spread quickly NSCLC not otherwise specified (NOS) American Cancer Society. What Is Non-Small Cell Lung Cancer Chalela R, et al. J Thorac Dis July;9(7): MFMER slide-5

6 Presentation & Diagnosis Sign & Symptoms Cough Dyspnea Hemoptysis Infection Pain Weight loss Malaise Loss of appetite Diagnostic CT MRI vs. PET Tissue biopsy CT: computed tomography MRI: magnetic resonance imaging PET: positron-emission tomography American Cancer Society. What Is Non-Small Cell Lung Cancer MFMER slide-6

7 Staging and Prognosis AJCC 7 th edition TNM system T: Tumor N: Node M: Metastasis 8 th edition published in Jan 2017 Divided stage IA to IA1-3 Addition of stage IIIC Divided stage IV to IVA and IVB Stage 5-year survival rate IA 49% IB 45% IIA 30% IIB 31% IIIA 14% IIIB 5% IV 1% AJCC: American Joint Committee on Cancer Goldstraw P, et al. J Thorac Oncol 2016; 11:39 NCCN. Non-Small Cell Lung Cancer American Cancer Society. Non-Small Cell Lung Cancer Survival Rates MFMER slide-7

8 Treatment Stage I Surgical resection Stage II Surgical resection +/- Chemotherapy Stage III Surgical resection Chemo-radiotherapy Stage IV Surgical resection Chemo-radiotherapy Targeted therapy Immunotherapy American Cancer Society. What Is Non-Small Cell Lung Cancer NCCN. Non-Small Cell Lung Cancer MFMER slide-8

9 40yo F non-smoker with newly diagnosed stage III NSCLC. Which of the following subtypes is she most likely to have? A. Adenocarcinoma B. Squamous cell carcinoma C. Large cell carcinoma D. NSCLC not otherwise specified (NOS) 2017 MFMER slide-9

10 Treatment of Stage IV NSCLC 2017 MFMER slide-10

11 Treatment of Stage IV NSCLC Historically Two-drug platinum-based combination Carboplatin + paclitaxel Median survival time Untreated: ~ 4 6 months Treated: ~ 8 11 months Currently Focusing on biomarkers Abbasi S, et al. Lung Cancer International MFMER slide-11

12 PD-L1 status ROS1 gene rearrangement Biomarkers EGFR mutation BRAF mutation ALK gene rearrangement PD-L1: Programmed Death-Ligand 1 EGFR: Epidermal Growth Factor Receptor ALK: Anaplastic lymphoma kinase BRAF: human gene that encodes a protein called B-Raf ROS1: proto-oncogene receptor tyrosine kinase 2017 MFMER slide-12

13 Signaling Pathway Janku F, et al. Nature Reviews Clinical Oncology. 2010;7: MFMER slide-13

14 Mutation Prevalence ROS1 gene rearrangment 2% BRAF mutation 3% ALK gene rearrangement 5% EGFR mutation 15% 0% 5% 10% 15% 20% Pikor LA, et al. Lung Cancer Nov;82(2): MFMER slide-14

15 Treatment Algorithm for Stage IV NSCLC Squamous cell NSCLC PD-L1 status NSCLC EGFR mutation BRAF mutation Non- Squamous-cell NSCLC ALK gene rearrangement ROS gene rearrangement PD-L1 status Reck M, et al. N Engl J Med. 2017;377: MFMER slide-15

16 ALK Gene Rearrangement Fusion oncogene arises from EML4- ALK translocation: results from an inversion in the short arm of chromosome 2 Occur in 3-5% in NSCLC Associated with light/never smokers, younger age, and adenocarcinoma subtype ALK inhibitors include: 1 st generation: crizotinib 2 nd generation: alectinib, ceritinib, brigatinib ALK: Anaplastic lymphoma kinase EML4: Echinoderm Microtubule-Associated Protein-Like 4 Camidge DR, et al. Clin Cancer Res Nov;16(22): Pikor LA, et al. Lung Cancer Nov;82(2): MFMER slide-16

17 Mechanism of Action Burns MW, et al. Lung Cancer: Targets and Therapy. 2015:6; MFMER slide-17

18 Evolution From Chemotherapy to Targeted Therapy (ALK+, NSCLC) Traditionally platinum doublet Crizotinib FDA approved in 2013 Progression-free survival: 7.7 months in crizotinib group vs. 3 months in chemotherapy group Response rate: 65% with crizotinib vs. 20% with chemotherapy CNS disease and resistance Shaw AT, et al. N Engl J Med. 2013;368: MFMER slide-18

19 Alectinib vs. Crizotinib ALEX trial Study design: International, randomized, open-label, phase 3 trial Participants: Previously untreated, advanced ALK-positive NSCLC including asymptomatic CNS disease Interventions: Patients were assigned in 1:1 ratio to either: Alectinib 600mg twice daily OR Crizotinib 250mg twice daily End points: Primary: Investigators-assessed progression-free survival Secondary: Independent review committee-assessed progression free survival, time to CNS progression, objective response rate, overall survival Peters S, et al. N Engl J Med Aug;377(9): MFMER slide-19

20 Results Outcomes Alectinib n=152 (%) Crizotinib n=151 (%) p value Number of disease progressions or death 12-month progression-free survival Independent review committee-assessed progression free survival 62 (41%) 102 (68%) % 48.7% < months 10.4 months <0.001 Rate of events of CNS progression 18 (12%) 68 (45%) <0.001 Peters S, et al. N Engl J Med Aug;377(9): MFMER slide-20

21 Peters S, et al. N Engl J Med Aug;377(9): MFMER slide-21

22 Peters S, et al. N Engl J Med Aug;377(9): MFMER slide-22

23 Adverse Events Adverse events Alectinib (%) Crizotinib (%) Any adverse event / Grade % / 50% 97% / 41% Anemia 20% 5% Myalgia 16% 2% Increased bilirubin 15% 1% Weight gain 10% 0% Musculoskeletal pain 7% 2% Photosensitivity reaction 5% 0% Nausea / Vomiting / Diarrhea 14% / 7% / 12% 48% / 38% / 45% Increased ALT / AST 15% / 14% 30% / 25% Peters S, et al. N Engl J Med Aug;377(9): MFMER slide-23

24 Conclusion Longer progression-free survival - HR 0.47 Investigator s assessed Independent review committee-assessed Active against brain metastases and CNS disease Time to CNS progression Overall survival? Safety Less GI symptoms More anemia, myalgia, increase bilirubin 2017 MFMER slide-24

25 2017 ASCO Guidelines 1 st line Non-Squamous-Cell Carcinoma EGFR mutation ALK gene rearrangement ROS1 gene rearrangement Wild Type Afatinib Or Erlotinib Or Geftinib Crizotinib Crizotinib PD-L1 50% PD-L1 <50% Pembrolizumab Hanna N, et al. J Clin Oncol Combination of platinum based chemotherapy +/- bevacizumab 2017 MFMER slide-25

26 Adverse Effects, Dosing, and Pricing Adverse events Dosing Pricing Alectinib (Alecensa ) Fatigue, constipation, edema, myalgia 600mg PO BID with food $15,532 for 30-day supply Crizotinib (Xalkori ) Vision disorder, nausea, diarrhea/constipation, vomiting, edema, fatigue, URTI, dizziness, neuropathy, elevated LFT s 250mg PO BID with/without food $14,846 for 30-day supply Ceritinib (Zykadia ) Nausea, vomiting, diarrhea, fatigue, abdominal pain, decreased appetite, weight loss 750mg PO daily on an empty stomach $14,750 for 28-day supply Brigatinib (Alunbrig ) Nausea, diarrhea, fatigue, cough, headache 90mg PO daily x 7days 180mg PO daily with/without food $14,250 for 30-day supply URTI: Upper Respiratory Tract Infection LFT: Liver Function Tests Alecensa [package insert]. Genentech USA, Inc., South San Francisco, CA Xalkori [package insert]. Pfizer, Inc., New York, NY Zykadia [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ Alunbrig. [package insert]. Ariad Pharmaceuticals, Inc., Cambridge, MA MFMER slide-26

27 What percentage of NSCLC patients express the ALK gene mutation? A. Less than 10% B % C % D % 2017 MFMER slide-27

28 Treatment Algorithm for Stage IV NSCLC Squamous cell NSCLC PD-L1 status NSCLC EGFR mutation BRAF mutation Non- Squamous-cell NSCLC ALK gene rearrangement ROS gene rearrangement PD-L1 status Reck M, et al. N Engl J Med. 2017;377: MFMER slide-28

29 Atezolizumab Immune Checkpoint Inhibitors Pembrolizumab Nivolumab 2017 MFMER slide-29

30 Mechanism of Action Atezolizumab Nivolumab, Pembrolizumab PD-1: programmed cell death protein -1 PD-L: programmed cell death ligand _upload_image/ajho_may14_schilder_figure_3.jpg 2017 MFMER slide-30

31 Evolution From Chemotherapy to Targeted Therapy (PD-L 50%, NSCLC) Traditionally platinum doublet as 1 st line Targetable genomic alteration targeted therapy No targetable genomic alteration Risk of chemotherapy toxicity vs. benefit Median overall survival ~ 8 10 months One-year survival rate ~30 40% Dang TO, et al. Expert Rev Anticancer Ther. 2016; 16(1): MFMER slide-31

32 Pembrolizumab vs. Chemo KEYNOTE-024 Study design: International, randomized, open-label, phase 3 trial Participants: Stage IV advanced NSCLC with PD-L1 expression 50% and no previous treatment Interventions: Patients were assigned in 1:1 ratio to either: Pembrolizumab IV 200mg q3weeks x35 cycles OR Investigator s choice of a platinum based chemotherapy End points: Primary: progression-free survival Secondary: overall survival, objective response rate, safety Reck M, et al. N Engl J Med. 2016;375: MFMER slide-32

33 Results Outcomes Pembrolizumab n=154 (%) Chemotherapy n=151 (%) p value Median progression-free survival Estimated rate of overall survival at 6 months 10.3 months 6 months < % 72.4% Response rate 44.8% 27.8% --- *66 patients (43.7%) in the chemotherapy group crossed over to received pembrolizumab after disease progression Reck M, et al. N Engl J Med. 2016;375: MFMER slide-33

34 Reck M, et al. N Engl J Med. 2016;375: MFMER slide-34

35 Reck M, et al. N Engl J Med. 2016;375: MFMER slide-35

36 Adverse Events Adverse events Pembrolizumab (%) Chemotherapy (%) Any adverse event / Grade % / 26.6% 90% / 53.3% Immune-mediated 29.2% 4.7% Pyrexia 10.4% 5.3% Nausea / vomiting / diarrhea 9.7% / 2.6% / 14.3% 43.3% / 20% / 13.3% Anemia 5.2% 44% Neutropenia 0.6% 22.7% Thrombocytopenia 0% 11.3% Fatigue 10.4% 28.7% Reck M, et al. N Engl J Med. 2016;375: MFMER slide-36

37 Conclusion Pembrolizumab Progression-free survival vs. chemotherapy 10.3 months vs. 6 months - HR 0.5 Overall survival at 6 months vs. chemotherapy 80.2% vs. 72.4% - HR st line agent in stage IV and PD-L1 tumor expression of 50% 2017 MFMER slide-37

38 2017 ASCO Guidelines 1 st line Squamous-Cell Carcinoma PD-L1 50% PD-L1 <50% Pembrolizumab Combination of platinum based chemotherapy Hanna N, et al. J Clin Oncol MFMER slide-38

39 Adverse Events, Dosing, and Pricing Adverse events Dosing Pricing/ 6-weeks Pembrolizumab (Keytruda ) fatigue, diarrhea/constipation, nausea, rash, pruritus, pyrexia, decreased appetite, cough, dyspnea, musculoskeletal pain 200mg IV q3weeks $18,052 for 1-dose Nivolumab (Opdivo ) fatigue, diarrhea/constipation, nausea, rash, pruritus, pyrexia, decreased appetite, cough, dyspnea, URTI, asthenia, arthralgia, back pain, musculoskeletal pain 240mg IV q2weeks $18,324 for 1-dose Atezolizumab (Tecentriq ) Fatigue, constipation, nausea decreased appetite, cough, dyspnea, musculoskeletal pain 1200mg IV q3weeks $17,240 for 1-dose URTI: Upper Respiratory Tract Infection Keytruda [package insert]. Merck & CO., Inc,. Whitehouse Station, NJ Opdivo [package insert]. Bristol-Myers Squibb Company, Princeton, NJ Tecentriq [package insert]. Genentech USA, Inc., South San Francisco, CA MFMER slide-39

40 Immune Related Adverse Effects Adverse Effect Incidence Colitis 10-20% Pneumonitis 1-3% Endocrine disorder Thyroid dysfunction Hypophysitis Type-1 diabetes mellitus 5 10% Hepatitis 5% Dermatitis 5-20% Michot JM, et al. European Journal of Cancer. 2016;54: Keytruda [package insert]. Merck & CO., Inc,. Whitehouse Station, NJ Opdivo [package insert]. Bristol-Myers Squibb Company, Princeton, NJ Tecentriq [package insert]. Genentech USA, Inc., South San Francisco, CA MFMER slide-40

41 Guideline Directed Treatment Options 2017 MFMER slide-41

42 2017 ASCO Guidelines 1 st line NSCLC EGFR mutation ALK gene rearrangement ROS1 gene rearrangement Wild Type Afatinib Or Erlotinib Or Geftinib Crizotinib Crizotinib PD-L1 50% PD-L1 <50% Pembrolizumab Hanna N, et al. J Clin Oncol Combination of platinum based chemotherapy +/- bevacizumab 2017 MFMER slide-42

43 2017 ASCO Guidelines 2 nd line No Known mutation No prior immune therapy Prior immune therapy PD-L1 1% & No prior immune therapy Pembrolizumab Or Nivolumab Or Atezolizumab Unknown or negative PD-L1 <1% Nivolumab Or Atezolizumab Or Combination of chemotherapy Combination of platinum based chemotherapy Hanna N, et al. J Clin Oncol MFMER slide-43

44 2017 ASCO Guidelines 2 nd line EGFR mutation BRAF mutation ROS1 gene rearrangement T790M mutation Osimertinib No T790M mutation Platinum doublet No prior immune therapy & PD-L1 1% Pembrolizumab Or Nivolumab Or Atezolizumab Previous immune therapy Dabrafinib Crizotinib (If no previously received) Or Platinum based therapy +/- bevacizumab Hanna N, et al. J Clin Oncol MFMER slide-44

45 What Did ASCO Not Cover? 1 st line therapy in BRAF mutation Dabrafenib + trametinib Doublet chemotherapy PD-L1 50% pembrolizumab 2 nd line therapy in ALK gene rearrangement Alectinib, crizotinib, ceritinib, brigatinib Non-Small Cell Lung Cancer. NCCN. Version MFMER slide-45

46 65yo F with newly diagnosed, large cell, stage IV NSCLC, no known mutation, PD-L1 expression is unknown. What would you recommend as a 1 st line option? A. Pembrolizumab B. Carboplatin + paclitaxel C. Gemcitabine + paclitaxel D. Alectinib 2017 MFMER slide-46

47 50yo M, non-smoker, with newly diagnosed, ALK +, PD-L1 50%, stage IV NSCLC with brain metastases. What would you recommend as a 1 st line option? A. Pembrolizumab B. Alectinib C. Crizotinib D. Erlotinib 2017 MFMER slide-47

48 Summary NSCLC Very common disease Leading cause of cancer death Choice of therapy presence/absence of biomarkers Individualized approach Patients goals and co-morbidities Distinct improvement in outcomes for select subtype 2017 MFMER slide-48

49 Non-Small Cell Lung Cancer: Where We Are Today Questions & Discussion Sila Shalhoub, PharmD PGY2 Oncology Pharmacy Resident 2017 MFMER slide-49