Patient Selection: The Search for Immunotherapy Biomarkers

Transcription

1 Patient Selection: The Search for Immunotherapy Biomarkers Mark A. Socinski, MD Executive Medical Director Florida Hospital Cancer Institute Orlando, Florida

2 Patient Selection Clinical smoking status Histologic Molecular - EGFR mutants Biomarkers - PD-L1 - Mutational load

3 Available PD-L1 Assays, Platforms, and Scoring PD-L1 Drug Nivolumab Pembrolizumab Atezolizumab Durvalumab Clone and source IVD class III partner Scoring method 28-8 Abcam 22c3 Dako SP142 Spring Bio SP263 Spring Bio Dako Dako Ventana Ventana % cells with membrane staining at any intensity % cells with membrane staining at any intensity Thresholds 1%, 5%, or 10% >1% 1% to 49% >50% Method Pathologist/ subjective Pathologist/ subjective TC = Tumor cell IC = Immune cell Combine both percentage and subjective intensity TC3 = TC>50% IC3 = IC>10% TC2/IC2 = TC or IC >5% TC1/IC1 = TC or IC >1% Pathologist/ subjective % cells with membrane staining at any intensity >25% Pathologist/ subjective

4 Available PD-L1 Assays, Platforms, and Scoring PD-L1 Drug Nivolumab Pembrolizumab Atezolizumab Durvalumab Clone and source IVD class III partner Scoring method 28-8 Abcam 22c3 Dako SP142 Spring Bio SP263 Spring Bio Dako Dako Ventana Ventana % cells with membrane staining at any intensity % cells with membrane staining at any intensity Thresholds 1%, 5%, or 10% >1% 1% to 49% >50% Method Pathologist/ subjective Pathologist/ subjective FDA- Approved TC = Tumor cell IC = Immune cell Combine both percentage and subjective intensity TC3 = TC>50% IC3 = IC>10% TC2/IC2 = TC or IC >5% TC1/IC1 = TC or IC >1% Pathologist/ subjective % cells with membrane staining at any intensity >25% Pathologist/ subjective

5 Expression of PD-L1 Is Heterogeneous and Varies With Antibody Used H&E E1L3N SP142 Negative 1 mm Positive Immunofluorescence shows stroma and epithelial staining are often concordant and adjacent Green = Cytokeratin Blue = Nuclei Red = PD-L1 (SP142) Unpublished Data: J McLaughlin, K Schalper, R. Herbst, and D Rimm (Yale Pathology).

6 PD-L1 Immunohistochemistry (IHC): Expression Heterogeneity and Potential for Sampling Error Biopsy Core 1 18 g needle = 800 µm Biopsy Core 2

7 PREVALENCE of PD-L1 Expression in NSCLC From CheckMate 017, KEYNOTE-001, and POPLAR Clinical Trials Trial/ IHC Antibody Drug Histology Cells Scored for PD-L1 Expression 1%, % (n) 5%, % (n) 10%, % (n) 50%, % (n) CheckMate 017/ Dako 28-8 Ab Nivolumab 1 Squamous Tumor 44 (119) 30 (81) 25 (69) Keynote001/ Merck 22C3 Ab Pembrolizumab 2 NSCLC Tumor 38 (310) 23 (191) POPLAR/ Spring Bioscience SP142 Ab Atezolizumab (MPDL3280A) 3 NSCLC Tumor and/or immune Cells 68 (195) 37 (105) 16 (47) 1. Brahmer J, et al. N Engl J Med. 2015;373(2): Garon EB, et al. N Engl J Med. 2015;372(21): Spira AI, et al. J Clin Oncol. 2015;33(suppl): Abstract 8010.

8 PD-L1 IHC Biomarker: Challenges Focal PD-L1 expression in some tumors may be missed in small biopsy specimens, such as needle biopsies PD-L1 expression among multiple tumor lesions from individual patients can vary over time and by anatomic site PD-L1 expression in tumor biopsies collected months or years earlier might not accurately reflect PD-L1 status at the time of treatment initiation; therapies given after biopsy but before administration of PD-1 pathway blockade (radiation therapy, chemotherapy, or kinase inhibitors) may alter PD-L1 expression PD-L1 epitopes detected by some antibodies are potentially unstable with prolonged specimen fixation or inadequate tissue handling before fixation (see NCI guidelines for tissue handling) Antibodies used for PD-L1 detection have different affinities and specifications PD-L1 protein expression can be membranous and/or cytoplasmic; however, only membranous PD-L1 is functionally relevant, by contacting PD-1+ T cells PD-L1 can be expressed by multiple cell types within the tumor microenvironment, which poses challenges for scoring and interpretation Topalian SL, et al. Nat Rev Cancer. 2016;16(5):

9 The PD-L1 Blueprint Working Group (IASLC-Industry) 39 cases x 4 assays, scored for % tumor cell and % immune cell expression of PD-L1. Three assays showed consistent pattern SP 142 labeled fewer cells 39%- discrepant results Too preliminary for definitive conclusions- ongoing project Hirsch FR, et al. Presented at: American Association of Cancer Research; April 16-20, 2016: New Orleans, Louisiana.

10 Analytical Evaluation Results: Mean TPS per Case Based on 3 Readers Analytical comparison of TPS by case for each assay Data points represent the mean score from 3 pathologists for each assay on each case No clinical diagnostic cutoff applied Conclusion: 3 of 4 assays are analytically similar for tumor cell staining % Tumor Staining C SP142 SP Cases TPS, tumor proportion score Hirsch FR, et al. Presented at: American Association of Cancer Research; April 16-20, 2016: New Orleans, Louisiana.

11 Agreement Between Assays for PD-L1 Expression Based on Specified Cutoffs Total cases: N = 38 Total number of cases expressing PD-L1 specified cutoff for each assay summarized in parentheses Numbers appearing in each Venn diagram segment represent the number of cases with agreement of PD-L1 expression specified cutoff between assays Cases that show agreement with all 4 assays regardless of which matched assay cutoff is employed: n = 19 (red circle) SP142 TC1/IC1 (30/38) Atezo 6 22C3 1% TPS (26/38) Pembro % TPS (26/38) Nivo SP263 25% (20/38) Durva Hirsch FR, et al. Presented at: American Association of Cancer Research; April 16-20, 2016: New Orleans, Louisiana.

12 1. Garon EB, et al. J Clin Oncol. 2014;32(5s): Abstract Soria J-C, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract Hellman MD, et al. Ann Oncol. 2014;25(suppl_4): Abstract 1229PD. Tobacco Exposure and PD-1 Response in NSCLC Chiron M, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract Smokers or Ex-smokers Never Smokers Pembrolizumab 1 33/129 (26%) 5/60 (8%) MPDL3280A 2 11/43 (26%) 1/10 (10%) Nivolumab 3 20/75 (26%) 0/13 (0%) Govindan R, et al. Cell. 2012;150(6):

13 Nivolumab Randomized Trials in Second-Line (Refractory) NSCLC CheckMate 17 Squamous NSCLC Stage IIIB/IV squamous NSCLC 1 prior platinum doublet-based chemotherapy ECOG PS 0-1 N = 272 Archived or fresh tissue required for all patients Randomized 1:1 Nivolumab 3 mg/kg IV q2w until PD or unacceptable toxicity N = 135 Docetaxel 75 mg/m 2 IV q3w until PD or unacceptable toxicity N = 137 Patients stratified by region and prior paclitaxel use Endpoints Primary OS Secondary Investigator-assessed ORR Investigator-assessed PFS Correlation between PD-L1 expression and efficacy (ORR, OS, and PFS) Quality of live (LCSS) CheckMate 57 Nonsquamous NSCLC N = 582 Stage IIIB/IV nonsquamous NSCLC ECOG PS prior PT-DC Prior maintenance therapy with premetrexed, bevacizumab, or erlotinib allowed Randomized 1:1 Nivolumab 3 mg/kg IV q2w until PD or unacceptable toxicity N = 292 Docetaxel 75 mg/m 2 IV q3w until PD or unacceptable toxicity N = 290 Endpoints Primary OS Secondary ORR PFS Efficacy by tumor PD- L1 expression Disease-related symptom improvement rate by week 12 ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status

14 Nivolumab in Squamous NSCLC Brahmer J, et al. N Engl J Med. 2015;373(2):

15 Nivolumab in Squamous NSCLC Brahmer J, et al. N Engl J Med. 2015;373(2):

16 Nivolumab in Nonsquamous NSCLC Brahmer J, et al. N Engl J Med. 2015;373(2):

17 Nivolumab: CheckMate 057 Study N Unstratified HR (95% CI) Overall (0.62, 0.91) Age Categorization (years) < (0.62, 1.04) 65 and < (0.45, 0.89) (0.43, 1.87) Gender Male (0.56, 0.96) Female (0.58, 1.04) Baseline ECOG PS (0.44, 0.93) (0.63, 1.00) Smoking Status Current/Former Smoker (0.56, 0.86) Never Smoked (0.64, 1.61) EGFR Mutation Status Positive (0.69, 2.00) Not Detected (0.51, 0.86) Not Reported (0.51, 1.06) All randomized patients (nivolumab, n = 292; docetaxel, n = 290) Nivolumab Docetaxel 3 mg/kg q2w 75 mg/m 2 q3w Patients with EGFR mutation positive NSCLC who received docetaxel had a numerical OS advantage over patients who received nivolumab No nivolumab treatment effect on OS in patients with EGFR mutation positive NSCLC (n = 82): HR = 1.18 (95% CI: 0.69, 2.00) ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PS, performance status; q2w, every 2 weeks; q3w, every 3 weeks Borghaei H, et al. New Engl J Med. 2015; 373(17):

18 Nivolumab in Nonsquamous NSCLC Borghaei H, et al. N Engl J Med. 2015;373(17):

19 Pembrolizumab Biomarker Development Pembrolizumab DAKO-22c3 Ab 0 1% to 49% >50% Low High Garon EB, et al. N Engl J Med (21):

20 KEYNOTE-010 Randomized Study of Pembrolizumab vs Docetaxel in Patients With Previously Treated PD-L1 Positive* NSCLC Patients: Metastatic NSCLC Previously treated (progression after 2 cycles of platinum-doublet OR prior EGFR TKI in mutant) Measurable disease ECOG PS 0-1 Newly obtained formalin-fixed specimens strongly encouraged PD-L1 positive (defined as staining in 1% of tumor cells) Treated and stable CNS metastases R A N D O M I Z A T I O N 1:1:1 N = 1034 Pembrolizumab 2 mg/kg Q3W Pembrolizumab 10 mg/kg Q3W Docetaxel 75 mg/m 2 Primary endpoints: OS, PFS, safety (adverse events and drug continuations) Secondary endpoints: ORR and response duration (RECIST 1.1) *Positive defined as 1% tumor PD-L1 expression determined using a prototype IHC assay (22C3 antibody) Herbst RS, et al. Lancet. 2016;387(10027):

21 Overall Survival, PD-L1 TPS 50% Stratum Overall Survival, % Treatment Arm Median (95% CI), months HR a (95% CI) P Pembro 2 mg/kg 14.9 (10.4-NR) 0.54 ( ).0002 Pembro 10 mg/kg 17.3 (11.8-NR) 0.50 ( ) <.0001 Docetaxel 8.2 ( ) 2 mg/kg vs 10 mg/kg: HR 1.12, 95% CI Time, Months Herbst RS, et al. Lancet. 2016;387(10027): Analysis cut-off date: September 30, 2015 a Comparison of pembrolizumab vs docetaxel

22 Overall Survival, % Overall Survival, PD-L1 TPS 1% (Total Population) Treatment Arm Median (95% CI), months Rate at 1 year HR a (95% CI) P Pembro 2 mg/kg 10.4 ( ) 43.2% 0.71 ( ).0008 Pembro 10 mg/kg 12.7 ( ) 52.3% 0.61 ( ) <.0001 Docetaxel 8.5 ( ) 34.6% 2 mg/kg vs 10 mg/kg: HR 1.17, 95% CI Time, months Herbst RS, et al. Lancet. 2016;387(10027): Analysis cut-off date: September 30, 2015 a Comparison of pembrolizumab vs docetaxel

23 Overall Survival in Key Subgroups, PD-L1 TPS 1% a Subgroup Overall Sex Male New Histology Squamous Adenocarcinoma No. of Events/ No. of Patients 521/ / /399 Female Age <65 years 317/ years 204/429 ECOG performance status 0 149/ /678 PD-L1 tumor proportion score 50% 204/442 1% to 49% 317/591 Tumor sample Archival EGFRstatus Mutant Wildtype 266/ / / /708 46/86 447/875 Herbst RS, et al. Lancet. 2016;387(10027): Hazard Ratio (95% CI) Favors Pembrolizumab Favors Docetaxel 0.67 ( ) 0.65 ( ) 0.69 ( ) 0.63 ( ) 0.76 ( ) 0.73 ( ) 0.63 ( ) 0.53 ( ) 0.76 ( ) 0.70 ( ) 0.64 ( ) 0.74 ( ) 0.63 ( ) 0.88 ( ) 0.66 ( ) Analysis cut-off date: September 30, 2015 a Data for the pembrolizumab doses were pooled

24 Overall Response Rate (RECIST v1.1, Central Review) PD-L1 TPS 50% Pembro 2 mg/kg n = 139 Pembro 10 mg/kg n = 151 Docetaxel n = 152 ORR, % (95% CI) 30 (23-39) P<.0001 a 29 (22-37) P<.0001 a 8 (4-13) PD-L1 TPS 1% Pembro 2 mg/kg n = 344 Pembro 10 mg/kg n = 346 Docetaxel n = 343 ORR, % (95% CI) 18 (14-22) P =.0005 a 18 (14-23) P =.0002 a 9 (6-13) Analysis cut-off date: September 30, 2015 a Comparison of pembrolizumab vs docetaxel Herbst RS, et al. Lancet. 2016;387(10027):

25 NSCLC: Overall Survival in Durvalumab-Treated Patients, by PD-L1 Status PD-L1 25% PD-L1 <25% Rizvi NA, et al. J Clin Oncol. 2015;33(suppl): Abstract 8032.

26 POPLAR: A Randomized, All-Comer Phase II Study Metastatic or locally advanced NSCLC (2L/3L) Disease progression on a prior platinum therapy N = 287 Stratification Factors: PD-L1 IC expression (0 vs 1 vs 3) a Histology (squamous vs nonsquamous) Prior chemotherapy regimens (1 vs 2) R 1:1 Atezolizumab 1200 mg IV q3w until loss of clinical benefit Docetaxel 75 mg/m 2 IV q3w until disease progression Primary study objective: Estimate OS in PD-L1 selected and ITT populations Secondary study objectives Evaluate PFS, ORR, and DOR in PD-L1 selected and ITT populations Evaluate safety Interim analysis is based on 153 events with a minimum follow-up of 10 months a Archival or fresh tissue required for pre-dose testing DOR, duration of response; ITT, intent to treat Spira AI, et al. J Clin Oncol 2015;33(suppl): Abstract 8010.

27 PD-L1 Expression on TC and IC Is a Potential Predictive Biomarker for Atezolizumab in NSCLC SP142 IHC assay is sensitive and specific for PD-L1 expression on both TC and IC Intrinsic PD-L1 expression in tumor cells (TC) Distinct TC and IC subpopulations exist at each of four cutoff levels a Gettinger SN, et al. J Clin Oncol. 2015;33(suppl): Abstract PD-L1 expression on TC and IC was independently predictive of response Horn L, et al. J Clin Oncol. 2015;33(suppl): Abstract Adaptive PD-L1 expression in tumor-infiltrating immune cells (IC) PD-L1 expression levels and TC/IC overlap in POPLAR a TC scored as percentage of tumor cells and IC scored as percentage of tumor area. TC3 or IC3 = TC 50% or IC 10% PD-L1+; TC2/3 or IC2/3 = TC or IC 5% PD-L1+; TC1/2/3 or IC1/2/3 = TC or IC 1% PD-L1+; TC0 and IC0 = TC and IC <1% PD-L1+, respectively Spira AI, et al. J Clin Oncol 2015;33(suppl): Abstract 8010.

28 MPDL3280 Biomarker Development TC3 or IC3 TC0 and IC0 n = M 24 D 23 M 51 D 41 OS Median, months MPDL3280A Ventana-SP142 Ab HR 95% CI NR TC3 or IC n= OS 1.22 M D TC2/3 or IC2/3 M 50 D 55 TC1/2/3 or IC1/2/3 M 93 D 102 TC0 and IC0 M 51 D 41 M 144 ITT D 143 Median, months NR NR HR 95% CI Spira AI, et al. J Clin Oncol 2015;33(suppl): Abstract 8010.

29 1. Garon EB, et al. J Clin Oncol. 2014;32(5s): Abstract Soria J-C, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract Hellman MD, et al. Ann Oncol. 2014;25(suppl_4): Abstract 1229PD. Tobacco Exposure and PD-1 Response in NSCLC Chiron M, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract Smokers or Ex-smokers Never Smokers Pembrolizumab 1 33/129 (26%) 5/60 (8%) MPDL3280A 2 11/43 (26%) 1/10 (10%) Nivolumab 3 20/75 (26%) 0/13 (0%) Govindan R, et al. Cell. 2012;150(6):

30 Alexandrov LB, et al. Nature. 2013;500(7463): Mutational Burden

31 Mutations in Tumor (NSCLC) HR 0.23 (95% CI ) P value.002 N = 16 N = 18 Rizvi NA, et al. Science. 2015;348(6230):

32 Neoepitopes in Lung Cancer TCGA Project Campbell JD, et al. Nat Genet. 2016;48(6):

33 Mismatch Repair Deficiency in Colon Cancer PD-1 Blockage in Tumors With Mismatch-Repair Deficiency Le DT, et al. N Engl J Med. 2015;372(26):

34 Mismatch Repair Deficiency in Colon Cancer PD-1 Blockage in Tumors With Mismatch-Repair Deficiency P =.03 by log-rank test Le DT, et al. N Engl J Med. 2015;372(26):

35 Immune Therapy Response Signature (IPRES)in Melanoma Hugo W, et al. Cell. 2016;165(1):35-44.

36 Response to PD-1 Blockade Multifactorial Factors Topalian SL, et al. Nat Rev Cancer. 2016;16(5):

37 Biomarkers for PD-1/PD-L1 Inhibitors Evolving area PD-L1 IHC enriches a group of responders to PD-1 blockade Combination of biomarkers may help to identify patients most likely to respond to PD-1 blockade Rational combination strategies should be guided by biomarkers

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