Optimizing Outcomes in Advanced Non-Small Cell Lung Cancer: Integrating Novel Personalized Therapy into the Treatment Paradigm. Joel W.

Transcription

1 Optimizing Outcomes in Advanced Non-Small Cell Lung Cancer: Integrating Novel Personalized Therapy into the Treatment Paradigm Joel W. Neal, MD, PhD Assistant Professor of Medicine/Oncology Stanford University/Stanford Cancer Institute

2 Thoracic Oncology Attendings Kavitha Ramchandran Clinical Assistant Professor Heather Wakelee Associate Professor Sukhmani Padda Assistant Professor Joel Neal Assistant Professor Millie Das Clinical Assistant Professor Jane Huang Adjunct Clinical Instructor

3 Lung Cancer Facts & Figures Leading cause of cancer-related mortality in US Accounts for more deaths than breast, prostate and colorectal cancers combined Histologically and molecularly a very heterogeneous disease Unfavorable stage distribution at the time of diagnosis Smoking remains the major risk factor; med age ~ ,000 never smoking Americans will develop lung cancer this year (more than esophageal, gastric, ovarian, testicular, Hodgkin s, myeloma, CML) Siegel, R.L., Miller, K.D., & Jemal, A. Cancer Statistics CA Cancer J Clin; 2016.

4 Stage at Diagnosis FEMALE BREAST All Races White Black LUNG & BRONCHUS Siegel, R.L., Miller, K.D., & Jemal, A. Cancer Statistics CA Cancer J Clin; 2016.

5 TNM Staging of NSCLC Stage IA Stage IB Stage II T1 N0 M0 T2 N0 M0 T1-2 N1 M0 Surgery Surgery +/- chemo Surgery + chemo *T indicates primary tumor; N, nodal involvement ; M, distant metastasis.

6 TNM Staging of NSCLC Stage IIIA T1-3 T3 N2 N1 M0 Chemo +radiation +/- surgery Stage IIIB T4 Any T Any N N3 M0 Chemo +radiation Stage IV Any T Any N M1 Systemic treatment *T indicates primary tumor; N, nodal involvement ; M, distant metastasis.

7 Major Paradigm Shifts in Advanced NSCLC Past 2 Decades Importance of histology to select therapy Squamous vs. non-squamous Addition of maintenance and second line chemotherapy Introduction of anti-angiogenic therapy VEGF Discovery and targeting of oncogenic driver mutations EGFR, ALK and others Emergence of immunotherapy Anti PD-1 and PD-L1

8 Chemotherapy + histology targeted therapy 2 nd line docetaxel Major Milestones in the Treatment of Advanced NSCLC 2 nd /3 rd line erlotinib EML4 ALK rearrangements described Maintenance therapy improves survival Genotypedirected therapy 1 st platinumbased therapy EGFR mutations described Bevacizumab for non squamous Pemetrexed nonsquamous Erlotinib for EGFRm NSCLC Ceritinib/Alectinib approved for ALK+ Crizotinib approved for ALK+ Genomic analysis: squamous and nonsquamous Ramucirumab in all 2nd line Crizotinib approved for ROS1+ Afatinib/Erlotinib/Gefitinib approved for EGFRm Osimertinib approved for EGFRm More driver targets: ROS1, RET, HER2, BRAF Necitumumab for 1 st line squamous Era of immunotherapy Nivolumab, pembrolizumab, atezolizumab approved in 2 nd line NSCLC 1st line pembrolizumab for PD L1 + NSCLC

9 Modern Agents With NSCLC Activity Chemotherapy Carboplatin Cisplatin Etoposide Vinorelbine Gemcitabine Irinotecan Topotecan Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Targeted Therapy Bevacizumab Ramucirumab Erlotinib Afatinib Gefitinib Osimertinib Crizotinib Ceritinib Alectinib Necitumumab Immunotherapy Nivolumab Pembrolizumab Atezolizumab Not all of these agents are indicated for use as a single agent or in combination for the treatment of NSCLC.

10 Pathological Consideration How well established is the histologic diagnosis? NSCLC adenocarcinoma Adenocarcinoma is a malignant epithelial tumor with glandular differentiation or mucin production, showing acinar, papillary, bronchoalveolar, or solid with mucin growth patterns or a mixture of these patterns. NSCLC large cell carcinoma Large cell carcinoma is an undifferentiated non-small cell carcinoma that lacks the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. NSCLC squamous cell carcinoma Squamous cell carcinoma is a malignant epithelial tumor showing keratinization and/or intercellular bridges that arise from bronchial epithelium. These features vary with degree of differentiation, being prominent in well-differentiated tumors and focal in poorly differentiated tumors. Images copyright 2007 Asterand PLC Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARCPress. 2004:26-30.

11 What s the optimal first-line treatment selection for stage IV NSCLC: non-squamous cell histology and without an EGFR-sensitizing mutation or ALK gene rearrangement? Should platinum be used? Which second agent? Yes, carbo or cis in every 3- week dosing Multiple options Should an anti-angiogenic agent be added? How many cycles? Maybe 4-6 cycles, depending on response and tolerance Continuation maintenance therapy? Depending on response and tolerance Switch maintenance? Less popular strategy

12 ECOG 1594: Comparison of 4 first-line platinum-based doublet regimens Cisplatin + Paclitaxel (n=288) Cisplatin + Gemcitabine (n=288) Cisplatin + Docetaxel (n=289) Carboplatin + Paclitaxel (n=290) Overall Response Rate (%) Median Overall Survival (95% CI) months 7.8 ( ) 8.1 ( ) 7.4 ( ) 8.1 ( ) 1-yr Survival (95% CI), % 31 (26-36) 36 (31-42) 31 (26-36) 34 (29-40) 2-yr Survival (95% CI), % 10 (5-12) 13 (7-15) 11 (7-14) 11 (7-14) Time to Progression (95% CI), months 3.4 ( ) 4.2 ( ) 3.7 ( ) 3.1 ( ) Schiller JH, et al. N Engl J Med. 2002;346(2):92-98.

13 Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC Subsets Scagliotti GV, et al. J Clin Oncol. 2008;26(21):

14 Angiogenesis is a function of multiple signals from multiple cell types Pericyte PDGF, TGFβ VEGF, Ang-2, bfgf O 2 Nutrients Endothelial cell Paracrine factors Tumor cell PDGF=platelet-derived growth factor; TGFβ=transforming growth factor beta; VEGF=vascular endothelial growth factor; Ang-2=angiopoietin; bfgf=basic fibroblast growth factor.

15 Bevacizumab in Nonsquamous NSCLC: Key Results E AVAiL 2,3 Outcome PCB PC CGB (7.5) CGB (15) PC ORR, % HR for PFS Median PFS, months P <.001 P <.0001 P = (P <.001) HR for OS 0.79 (P =.003) 0.75 (P =.003) 0.82 (P =.03) (NS) 1.03 (NS) Median OS, months Sandler A, et al. N Engl J Med. 2006;355(24): Reck M, et al. J Clin Oncol. 2009;27(8): Reck M, et al. Ann Oncol. 2010;21(9):

16 First line treatment for squamous NSCLC

17 Phase III Study Design: nab-paclitaxel/cb vs sb-paclitaxel/cb in Advanced NSCLC Albumin-bound paclitaxel 100 mg/m2 d1, 8, 15 Carboplatin AUC 6 d1 Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 1:1 21 Day Cycles No Premedication Primary Endpoint - ORR Paclitaxel 200 mg/m2 d1 Stratification factors: Stage (IIIb vs IV) Age (<70 vs >70) Sex Histology (squamous vs nonsquamous) Geographic region Carboplatin AUC 6 d1 21 Day Cycles With Premedication of Dexamethasone + Antihistamines Socinski MA et al. J Clin Oncol 30: , 2012

18 Nab-paclitaxel + Carboplatin vs solvent-based Paclitaxel + Carboplatin for first-line therapy OS Socinski, MA et al. J Clin Oncol. 2012;30(17):

19 Nab-Paclitaxel Objective Responses by Histology Response Rate (%) 50% 40% 30% 20% 10% P < RR = % P = RR= % 24% 25% nab-p/c P/C Interaction p-value for Histology: % n = 228 n = 221 n = 292 n = 310 Squamous Non-squamous Socinski MA et al. J Clin Oncol 30: , 2012

20 SQUIRE Trial Schema: Necitumumab: 1st line therapy in patients with stage IV squamous NSCLC Patients 184 sites in 26 countries Stage IV squamous NSCLC ECOG PS 0-2 No previous chemotherapy Adequate organ function Stratification factors: ECOG PS Geographical region R 1:1 Max six 3- wk cycles Gemcitabine (1250 mg/m 2 IV over 30 min, days 1 & 8 of 3-wk cycle) + Cisplatin (75 mg/m 2 IV over 120 min, day 1 of 3-wk cycle) Gemcitabine (1250 mg/m 2 IV over 30 min, days 1 & 8 of 3-wk cycle) + Cisplatin (75 mg/m 2 IV over 120 min, day 1 of 3-wk cycle) + Necitumumab (800mg IV over 50 min minimum, days 1 & 8 until PD or intolerable AEs) End points Primary: OS Secondary: PFS, ORR, time to treatment failure, change from baseline in patient reported outcomes Thatcher, N et al. Lancet Oncol. 2015;16:

21 Necitimumab for 1 st line chemo-naïve advanced squamous NSCLC: SQUIRE trial results Thatcher, N et al. Lancet Oncol. 2015;16:

22 Treatment of squamous NSCLC First Line: Platinum doublets remain standard of care Gemcitabine- or taxane-based regimens including nab-paclitaxel Consider cisplatin/gemcitabine/necitumumab Bevacizumab contraindicated due to bleeding complications Pemetrexed not appropriate for squamous NSCLC Second Line: - Anti-PD-1 therapy - Docetaxel +/- ramucirumab, other single agent chemotherapy

23 Should continuation maintenance chemotherapy be used?

24 PARAMOUNT: Study Design Randomized, placebo-controlled, double-blind phase III study Pemetrexed 500 mg/m 2 ; Cisplatin 75 mg/m 2 Folic acid and vitamin B 12 administered to both arms Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 Pemetrexed + BSC Placebo + BSC Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)

25 Continuation maintenance pemetrexed: Final OS PARAMOUNT trial results Luis G. Paz-Ares et al. JCO 2013;31:

26 Second line chemotherapy for NSCLC

27 Docetaxel or Pemetrexed as 2 nd line therapy for NSCLC Shepherd F et al. J Clin Oncol. 2000;18: Hanna N et al. J Clin Oncol. 2004;22(9):

28 Docetaxel + Ramucirumab REVEL Improves overall survival as second-line treatment for patients with stage IV NSCLC: Approved in 2014 Garon, E.B. et al. Lancet. 2014;384:

29 Immunotherapy for NSCLC!

30 Anti-PD-1/PD-L1 Antibodies: Mechanism of Action PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function 3 Approved Drugs: Nivolumab/pembrolizumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-L2 to restore T-cell antitumor function Atezolizumab binds PD-L1 receptors IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Nivolumab/Pembrolizumab: PD-1 Receptor Blocking Ab

31 Changes in the Therapeutic Landscape of Stage IV Lung Cancer PD-L1+ HER2 EGFR mutants ALK ROS/RET/BRAF/Others KRAS KRAS Adeno LCC-NOS SqCC SCLC

32 x PD-L1 as a Predictive Immune Biomarker PD-L1 Assay Sample Source and Collection Definition of Positivity Assays, Sample Collection, and Analyses in NSCLC Studies Pembrolizumab Merck FDA approved companion diagnostic IHC assay (22C3 Ab) 1 Surface expression of PD-L1 on tumor specimen* Ph I: Fresh tissue Ph II/III: Archival or fresh tissue 2 IHC Staining: Strong vs weak expression 2 PD-L1 expression required for NSCLC for enrollment 2 Note that one arm of KEYNOTE 001 trial requires PD-L1 - tumors 1 Tumor PD-L1 expression: 1 50% PD-L1 + cut-off: 32% (41/129) 1-49% PD-L1 + cut-off: 36% (46/129) Nivolumab Bristol-Myers Squibb FDA approved complemetary diagnostic; Dako automated IHC assay (28-8 Ab) 3,4 Surface expression of PD-L1 on tumor cells* MPDL3280A Atezolizumab Roche/Genentech Ventana automated IHC assay Surface expression of PD-L1 on TILs 5 MEDI4736 Durvalumab AstraZeneca 1 st generation or Ventana automated IHC (BenchMark ULTRA) assay (Ventana PD-L1 (SP263) clone) 7,8 Surface expression of PD- L1 on TILs Archival 4 or fresh tissue Archival or fresh tissue PhI: Fresh tissue IHC Staining: Strong vs weak expression 3,4 Patients not restricted in PD- L1 status in 2nd- & 3 rd -line 4 Ph III 1st-line trial in PD- L1+ 3 Tumor PD-L1 expression: 4 5% PD-L1 + cut-off: 49% (33/68) 4 IHC Staining intensity (0, 1, 2, 3): IHC 3 ( 10% PD-L1 + ): Ph III trial 5 IHC 2,3 ( 5% PD-L1 + ) 5 IHC 1,2,3 ( 1% PD-L1 + ) 5 IHC 1, 0, or unknown PD-L1 expression required for NSCLC for enrollment TIL PD-L1 expression: 5,6 IHC 3 ( 10% PD-L1 + ): 11% (6/53) PD-L1 low (IHC 1, 0): 75% (40/53) IHC Staining intensity: Not presented to date 7,8,9 TIL PD-L1 expression: Not presented to date 7,8,9 1. Garon EB, et al. Presented at ESMO 2014 (abstr. LBA43); 2. Rizvi NA, et al. Presented at ASCO 2014 (abstr. 8007); 3. Gettinger S et al. Poster p38 presented at ASCO 2014 (abstr. 8024); 4. Brahmer JR et al. Poster 293 presented at ASCO 2014 (abstr. 8112); 5. Rizvi NA et al. Poster presented at ASCO 2014 (abstr. TPS 8123); 6. Soria J-C, et al. ESMO 2014 (abstr. 1322P); 7. Brahmer JR, et al. Poster presented at ASCO 2014 (abstr. 8021); 8. Segal NH, et al. Presented at ASCO 2014 (abstr. 3002); 9. Segal NH, et al. ESMO 2014 (abstr. 1058PD).

33 Examples of PD-L1 IHC Staining of NSCLC Samples Using the Clinical Trial Assay Brown chromogen:pd-l1 staining with 22C3 antibody Blue color: hematoxylin counterstain Garon, EB, et al. N Engl J Med. 2015;372(21):

34 Nivolumab vs Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell NSCLC CheckMate017 phase III trial schema for 2 nd line squamous NSCLC 2L+ NSCLC (n=264) multicenter, randomized Squamous, stage IIIB/IV or recurrent NSCLC Disease recurrence or progression following one prior platinum doubletbased chemotherapy No prior treatment with PD-1 agent or prior treatment with docetaxel ECOG 0-1 NCT :1 Nivolumab (3mg/kg) IV infusion over 60 minutes every two weeks until PD Docetaxel (75mg/m 2 ) IV every three weeks Start date June 2012 Enrollment 2014 complete 1EP Overall survival 2EP Objective response rate Progression free survival Potential association between PD L1 expression and efficacy measures Quality of life Brahmer J, et al. N Engl J Med. 2015;373:

35 CheckMate 017: Nivolumab vs Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell NSCLC Kaplan-Meier Curves for Overall Survival Brahmer J, et al. N Engl J Med. 2015;373:

36 CheckMate 057: Nivolumab vs Docetaxel 2 nd -line Non-Squamous NSCLC Phase III, 582 patients randomized Nivolumab 3 mg/kg Q2W vs docetaxel 75 mg/m 2 Q3 Primary endpoint OS Trial stopped early by DSMC, met its primary endpoints at interim analysis Nivolumab (n=292) Docetaxel (n=290) ORR 19% 12% P value Median DOR, mos (24%) patients on nivolumab were treated beyond RECIST v1.1 defined progression Non conventional benefit was observed in 16 patients (not included in best overall response) Paz-Ares L et al. Presented at: American Society of Clinical Oncology, 2015 Annual Meeting; (Abstract LBA109).

37 CheckMate 057: Nivolumab vs Docetaxel 2 nd -line Non-Squamous NSCLC Treatment Effect on OS in Predefined Subgroups N Unstratified HR (95% CI) Paz-Ares L et al. Presented at: American Society of Clinical Oncology, 2015 Annual Meeting; (Abstract LBA109).

38 Phase 3 CheckMate 026 Study Design: Nivolumab vs Chemotherapy in First-line NSCLC Key eligibility criteria: Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression a CNS metastases permitted if adequately treated at least 2 weeks prior to randomization Randomize 1:1 Nivolumab 3 mg/kg IV Q2W n = 271 Chemotherapy (histology dependent) b Maximum of 6 cycles n = 270 Tumor scans Q6W until wk 48 then Q12W Disease progression Disease progression or unacceptable toxicity Crossover nivolumab c (optional) Stratification factors at randomization: PD-L1 expression (<5% vs 5%) a Histology (squamous vs non-squamous) Primary endpoint: PFS ( 5% PD-L1+) d Secondary endpoints: PFS( 1% PD-L1+) d OS ORR d a Dako 28-8 validated; archival tumor samples obtained 6 months before enrollment were permitted; PD-L1 testing was centralized b Squamous: gemcitabine 1250 mg/m 2 + cisplatin 75 mg/m 2 ; gemcitabine 1000 mg/m 2 + carboplatin AUC 5; paclitaxel 200 mg/m 2 + carboplatin AUC 6; Non-squamous: pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 ; pemetrexed 500 mg/m 2 + carboplatin AUC 6; option for pemetrexed maintenance therapy c Permitted if crossover eligibility criteria met, including progression confirmed by independent radiology review d Tumor response assessment for PFS and ORR per RECIST v1.1 as determined by independent central review 38

39 Primary Endpoint (PFS per IRRC in 5% PD-L1+) CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC PFS (%) Median PFS, months (95% CI) Nivolumab n = (3.0, 5.6) Chemotherapy n = (5.4, 6.9) 1-year PFS rate, % HR = 1.15 (95% CI: 0.91, 1.45), P = Nivolumab 0 0 Chemotherapy Months No. of patients at risk: Nivolumab Chemotherapy All randomized patients ( 1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)

40 OS ( 5% PD-L1+) CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC OS (%) % in the chemotherapy arm had subsequent nivolumab therapy 43.6% in the nivolumab arm had subsequent systemic therapy Median OS, months (95% CI) Nivolumab n = (11.7, 17.4) No. of patients at risk: Nivolumab Months Chemotherapy Chemotherapy n = (10.7, 17.1) 1-year OS rate, % HR = 1.02 (95% CI: 0.80, 1.30) Chemotherapy Nivolumab All randomized patients ( 1% PD-L1+): HR = 1.07 (95% CI: 0.86, 1.33)

41 Pembrolizumab in NSCLC FDA approved October 2015 for 2 nd -line NSCLC, if PDL1 + KEYNOTE 001: 495 patients, phase IB study Allowed front-line and prior chemo-treated patients Randomized 2 mg/kg Q3w vs 10 mg/kg Q3w Recent Bx required, training vs validation group: PD-L1+ >50% expression KEYNOTE 010 study pembro vs docetaxel FDA approved October 2015 for 1 st -line NSCLC, if PDL1+ (>50%) KEYNOTE 026 study pembro vs first line chemotherapy Garon EB et al. N Engl J Med. 2015;372:

42 KEYNOTE-001 Trial Pembrolizumab for Treatment of NSCLC PS = proportion score % positivity of PD-L1 membrane staining on tumor Garon EB et al. N Engl J Med. 2015;372:

43 KEYNOTE-010 Trial Pembrolizumab vs Docetaxel Patients Advanced NSCLC Confirmed PD after > line of chemotherapy No active brain metastases ECOG PS 0-1 PD-L1 TPS >1% * No serious autoimmune disease No ILD or pneumonitis requiring systemic steroids R 1:1:1 Pembrolizumab 2 mg/kg IV Q3W for 24 months Pembrolizumab 10 mg/kg IV Q3W for 24 months Docetaxel 75 mg/m 2 Q3W per local guidelines Stratification factors: ECOG PS (0 vs 1) Region (East Asia vs non- East Asia PD-L1 status* (TPS>50% vs 1%-49%) End points in the TPS >50% stratum and TPS >1% population Primary: PFS and OS Secondary: ORR, duration or response, safety *PD L1 status assessed by 22C3 immunohistochemistry Herbst RS et al. Lancet Dec 18; [Epub ahead of print].

44 KEYNOTE-010 Trial Pembrolizumab vs Docetaxel Overall Survival PS 50% positive and higher PS 50% positive and higher PS 1% positive and higher PS 1% positive and higher PS = proportion score; % positivity of PD-L1 membrane staining on tumor Herbst RS et al. Lancet Dec 18; [Epub ahead of print].

45 KEYNOTE-024 Study Design (NCT ) Key Eligibility Criteria Untreated stage IV NSCLC PD-L1 TPS 50% ECOG PS 0-1 No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy R (1:1) N = 305 Pembrolizumab 200 mg IV Q3W (2 years) Platinum-Doublet Chemotherapy (4-6 cycles) PD a Pembrolizumab 200 mg Q3W for 2 years Key End Points Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, safety Exploratory: DOR a To be eligible for crossover, progressive disease (PD) had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.

46 Keynote 024: Progression-Free Survival Events, n Median, mo HR (95% CI) P PFS, % Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, % 50% Pembro Chemo ( ) No. at risk Time, months 48% 15% <0.001

47 Keynote 024: Overall Survival Events, n Median, mo HR (95% CI) P OS, % Data cut-off: May 9, % 72% No. at risk Pembro 44 NR 0.60 Chemo 64 NR ( ) Time, months 70% 54% DMC recommended stopping the trial because of superior efficacy observed with pembrolizumab 0.005

48 ATEZOLIZUMAB: PHASE III OAK STUDY DESIGN Locally Advanced or Metastatic NSCLC 1 2 prior lines of chemo including at least 1 platinum based Any PD-L1 status N = 1,225 enrolled a Stratification factors PD-L1 expression Histology Prior chemotherapy regimens R 1:1 Atezolizumab 1200 mg IV q3w Docetaxel 75 mg/m 2 q3w PD or loss of clinical benefit PD Primary Endpoints (first 850 enrolled patients): OS in the ITT population OS in patients with PD-L1 expression on 1% TC or IC Secondary Endpoints: ORR, PFS, DoR, Safety a A prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup ( 1% PD-L1 expression). TC, tumor cells; IC, tumor-infiltrating immune cells. Barlesi et al, Atezolizumab Phase III OAK Study. 48

49 ATEZOLIZUMAB: OAK OVERALL SURVIVAL, ITT (N = 850) Overall Survival (%) Atezolizumab Docetaxel Median 9.6 mo (95% CI, 8.6, 11.2) Median 13.8 mo (95% CI, 11.8, 15.7) HR, 0.73 a (95% CI, 0.62, 0.87) P = Minimum follow up = 19 months Months a Stratified HR. Barlesi et al, Atezolizumab Phase III OAK Study. 49

50 Immune Adverse Events Onset: Average is 6-12 weeks after initiation of therapy Can occur within days of the first dose, or months after discontinuation Patient complaints are autoimmune and drug-related until proven otherwise Rule out infections, metabolic causes, tumor effects, etc. Early recognition, evaluation, and treatment are critical Primary management is corticosteroids (oral/iv) and sometimes anti-tnfalpha drugs

51 KEYNOTE-010 Trial Immune-Related Adverse Events Herbst RS et al. Lancet Dec 18; [Epub ahead of print].

52 Identification of Immune-Related AEs Organ system Lung Gastrointestinal Liver Skin Neurologic Endocrine Hematologic Cardiovascular Ocular Renal Signs/symptoms Pneumonitis Diarrhea, colitis Elevation in liver function tests AST >2.5 x ULN ALT >2.5 x ULN Total bilirubin >1.5 x ULN Pruritus, rash Motor and sensory neuropathy Unilateral and bilateral weakness Sensory alterations Paresthesia Fatigue, headache, changes in mental status, abdominal pain, unusual bowel habits, hypotension, abnormal thyroid function tests and/or serum chemistry values (endocrinopathies) Hemolytic anemia, thrombocytopenia Myocarditis, pericarditis, vasculitis Blepharitis, conjunctivitis, iritis, uveitis Nephritis ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

53 Immunotherapy in NSCLC Year in Review March 2015 Nivolumab approved in squamous cancers following platinum-based therapy - CheckMate 017 October 2015 Pembrolizumab approved in PD-L1+ NSCLC following platinum-based therapy (required 22C3 IHC companion diagnostic) KEYNOTE-001 October 2015 Nivolumab indication expanded to non-squamous NSCLC (optional 28-8 IHC complementary diagnostic) CheckMate 057 December 2015 Pembrolizumab - positive results presented from KEYNOTE-010 study (pembrolizumab vs docetaxel in PD-L1 + previously treated NSCLC patients)

54 Immunotherapy in NSCLC 2016 ESMO presentations June KEYNOTE-024: Pembrolizumab monotherapy provides long-term OS benefit for treatment-naïve patients with advanced NSCLC. These data support PD-L1 as a predictive biomarker for pembrolizumab response. In Oct 2016 the FDA approved pembrolizumab for first line treatment of PD-L1 positive (50% or higher) NSCLC. August 2016 CheckMate-026: Nivolumab monotherapy in first-line advanced NSCLC patient population did not meet it s primary endpoint of PFS in patients whose tumors expressed PD-L1 at 5%. August 2016 OAK: Increased OS with atezolizumab vs docetaxel in locally advanced or metastatic NSCLC whose disease progressed on platinum based chemotherapy. Based on these positive results from this phase 3 OAK trial, in Oct 2016 the FDA has approved atezolizumab for the treatment of PD-L1 positive NSCLC patients whose disease has progressed during or after platinum based chemotherapy (and appropriate targeted therapy for those with EGFR-positive or ALK-positive tumors).

55 Molecular-directed therapy in NSCLC

56 NSCLC as One Disease Evolution of NSCLC Subtyping from Histologic to Molecular-Based Adenocarcinoma Squamous Cell Cancer FGFR1 Amp EGFRvIII Unknown PI3KCA EGFR DDR2 Gandara et al: J Clin Oncol (adapted from Pao et al)

57 First-line Molecular Testing Molecular Profiling to Guide Therapeutic Decision Making for Advanced NSCLC: Guidelines for 2016 Who to test What to test for When to test What specimen How to test How long a turnaround time is acceptable When to re-biopsy All patients with advanced-stage lung adenocarcinoma or tumors with an adenocarcinoma component EGFR DNA mutation and ALK (IHC or FISH), or more At the time of diagnosis (not just when treatment decision needed) Core needle biopsy (or multi-pass FNA), cytology cell block, surgical biopsy (bone biopsy problematic) Concurrently (not sequentially test-by-test) 5-10 working days with <3 days transport time After a targeted therapy intervention (to assess for tumor evolution in the molecular profile) Rekhtman N, et al. CAP/IASLC/AMP Guidelines. J Onc Pract

58 Why Does Testing Matter? Survival By Use of Targeted Therapy Genotype/Therapy Median OS 95% CI Oncologic driver + targeted therapy 3.49 yrs Oncologic driver + no targeted therapy 2.38 yrs No targeted therapy 2.08 yrs Kris MG, et al. JAMA. 2014;311(19):

59 EGFR Mutation: Distribution and Incidence Y Y Y Y Y Kinase domain P-loop αc helix A-loop Exon Insertion, L858R Others G719 Deletion T790M Incidence (N = 569) 3.2% 48.2% * 3.7% ** 42.7% * 2.2% * Activating mutations with increased EGFR-TKI sensitivity ** Resistance mutations Mitsudomi T et al. Cancer Sci. 2007;98: Common Mutations

60 Incidence of EGFR Mutations According to Patient Backgrounds (N=2880) Asian 32 Male 10 Female 38 Never smoker Ethnicity Gender Smoking Hx Histology 47 Smoker 7 Adeno 30 Non- Asian Non- Adeno 2 Mitsudomi et al. Cancer Science 2007

61 Randomized Studies of First Line EGFR TKI vs Platinum Chemo in Patients With EGFR Mutations Author Study Agent N (EGFR mut +) RR Median PFS (mo) OS (mo) Mok et al IPASS Gefitinib % vs 47.3% 9.8 vs vs 21.9 Han et al First-SIGNAL Gefitinib % vs 37.5% 8.0 vs vs 25.6 Mitsudomi et al WJTOG 3405 Gefitinib % vs 32.2% 9.2 vs vs NR Maemondo et al NEJGSG002 Gefitinib % vs 30.7% 10.8 vs vs 23.6 Zhou et al OPTIMAL Erlotinib % vs 36% 13.7 vs vs 28.9 Rosell et al EURTAC Erlotinib % vs 15% 9.7 vs vs 19.5 Sequist et al LUX-Lung 3 Afatinib % vs 23% 13.6 vs vs 28.2 Wu et al LUX-Lung 6 Afatinib % vs 23% 11.0 vs vs 23.5 Crossover to an EGFR TKI in the control group nullifies any chance of an OS benefit Mok TS, et al. N Engl J Med. 2009;361(10): Han J-Y, et al. J Clin Oncol. 2012; 30: Mitsudomi T, et al. Lancet Oncol. 2010;11(2): Maemondo M, et al. N Engl J Med. 2010;362(25): Zhou C, et al. Lancet Oncol. 2011;12(8): Zhou C, et al. J Clin Oncol. 2012;30(suppl): abstract Rosell R, et al. Lancet Oncol. 2012;13: Sequist LV, et al. J Clin Oncol. 2013;31(27): Wu YL, et al. Lancet Oncol. 2014;15(2): , Wu YL, et al. J Clin Oncol. 2013;31(suppl): abstract 8016, Yang JC-H, et al. Lancet Oncol. 2015;16:

62 What s the optimal first-line treatment for NSCLC with non-squamous cell histology and with an EGFRsensitizing mutation? First-line Erlotinib, afatinib, and gefitinib are FDA approved Afatinib appears more effective, but has more diarrhea, stomatits, and paronychia Second-line (after progression on first-line TKI): Combination chemotherapy Switch to another EGFR TKI Immunotherapy? Masters2015; NCCN guidelines

63 EGFR T790M Acquired Resistance Acquired exon 20 second-site mutation found in >50% of patients with acquired resistance to EGFR TKI Increases relative affinity of mutant EGFR for ATP, may also cause steric hindrance to erlotinib EGFR T790M More likely to show progression in lungs/pleura Less commonly detected in CNS May have better prognosis than non-t790m Oxnard GR, et al. Clin Cancer Res. 2011;17:

64 Osimertinib (AZD9291) EGFR T790M inhibitor Response rate = 61% Accelerated FDA approval Nov 2015 Jänne PA et al. N Engl J Med. 2015;372:

65 Management of EGFR-mutation positive patients Test all non-squamous and selected squamous Standard of care = first line EGFR TKI (erlotinib, afatinib, or gefitinib) At progression: Think local therapy (radiation) if limited progression Tolerate slow PD Re-biopsy growing areas at progression for T790M (can consider liquid biopsy too) Osimertinib if T790M positive Don t continue TKI with chemotherapy - IMPRESS Responses to anti-pd1 average

66 Management of stage IV NSCLC with an ALK rearrangement

67 First line treatment options for ALK positive NSCLC Crizotinib 1 PROFILE 1014 phase III trial Alectinib 2 J-ALEX phase III study: First-line option in ALK-inhibitor-naïve ALKpositive NSCLC Demonstrated significantly prolonged PFS in alectinib-treated patients (median PFS was not reached in alectinib arm vs 10.2 months in the crizotinib arm) and was well-tolerated with favorable AE profile. 1. Solomon, BJ et al. N Engl J Med. 2014;371(23): Nokihara H et al. J Clin Oncol 34:2016 (suppl;abstr 9008).

68 Second line treatment options for ALK positive NSCLC Ceritinib, a 2 nd generation ALK inhibitor approved in Apr 2014 for patients who have progressed on or are intolerant of crizotinib Alectinib, a highly potent-selective ALK inhibitor approved in Dec 2015 for patients who have progressed on or are intolerant of crizotinib Significant reduction in metastatic brain tumors observed Solomon, BJ et al. N Engl J Med. 2014;371(23):

69 Selected Other Mutations in NSCLC Oncogene Prevalence % Available drugs with potential benefit** Therapeutic pathways being targeted KRAS mutations Selumetinib, trametinib, cobimetinib KRAS G12C inhibitors, MEK and PI3K inhibitors, JAK/TBK1/KK inhibitors ROS1 rearrangements 1-3 Crizotinib**, ceritinib ROS inhibitors, Hsp90 inhibitors HER2 mutations 1-3 afatinib, trastuzumab, T-DM1 HER2 inhibitors, Hsp90 inhibitors BRAF mutations 1-3 Vemurafenib, dabrafenib, selumetinib, trametinib BRAF inhibitors, MEK inhibitors RET rearrangements 1 Cabozantinib, vandetanib, RET inhibitors, Hsp90 inhibitors MET amplification 1 Crizotinib, cabozantinib MET inhibitors MET exon 14 mutation 3 Crizotinib, cabozantinib MET inhibitors NTRK1 rearrangements <1 Crizotinib TRK inhibitors * Evidence level: Bold Strong clinical evidence, Plain weak clinical evidence ** FDA approved

70 NSCLC Summary Chemotherapy Cytotoxic chemotherapy improves survival and palliates symptoms in first line, maintenance, and subsequent treatment settings Histology important at diagnosis to select agents: Pemetrexed effective in non-squamous, necitumumab effective in squamous Targeting angiogenesis improves survival in 1 st and 2 nd line treatment

71 Summary Targeted therapy Molecular genotyping is now the standard in advanced NSCLC (adenocarcinoma) Multidisciplinary approach assuring adequate tissue for molecular testing Histology and selected molecular biomarkers (EGFR, ALK, ROS1, others) drive therapeutic choices EGFR/ALK/ROS1 - molecularly targeted therapies offer longer time to progression in the first line setting than conventional chemotherapy, but chemo can be effective too Other targetable drivers may also respond to off label use of available targeted therapies, which is reasonable following chemotherapy failure Re-biopsy should be considered routinely after progression on targeted agents, and drugs to overcome initial resistance are available

72 Summary Immunotherapy Immunotherapy is now a reality in the treatment of advanced NSCLC Clearly effective in the 2nd+ line setting and data strong for 1st line therapy for selected patients PD-L1 IHC testing is available and can be helpful clinically to estimate probability of response and to select the therapeutic Toxicity patterns are unique; grade > 3 toxicities occur in <5% of patients Education at all levels (MD,PA/NP, nurses and patients & caregivers) about the nature of immune-related adverse events is necessary 72

73 Thank you! 73