News from ASCO Niven Mehra, Medical Oncologist Radboud UMC Institute of Cancer Research and The Royal Marsden Hospital
Disclosures Speaker fees: Merck, Bayer Advisory boards: Janssen-Cilag Research and travel grants: Sanofi-Aventis, Merck
The cancer-immunity cycle DS. Chen and I. Mellman. Oncology Meets Immunology: The Cancer- Immunity Cycle. Immunity 39, July 25, 2013
The cancer-immunity cycle DS. Chen and I. Mellman. Oncology Meets Immunology: The Cancer- Immunity Cycle. Immunity 39, July 25, 2013
# Abstracts and presentations at ASCO Immunotherapy PD-1/ PD-L1
# clinical trials clinicaltrials.gov with agents blocking PD-1/PD-L1 pathway www.clinicaltrials.gov keywords PD-1 or PD-L1
Clinical trials using agents targeting PD1 pathway Tumor Immunology: Basic Biology for Clinical Practice. Vamsidhar Velcheti
ASCO 2016 focus on PD-1 axis inhibitor therapy and on biomarker studies An insight on the complexities and contradictions surrounding PD-L1 as biomarker Updated follow-up data on long-term outcome of PD-1 blocking agents lessons to be learnt Which other (molecular subtypes of) cancers appear to have great benefit of checkpoint blockade
Question 1 PD-L1 IHC at present is not useful as sole complementary diagnostic biomarker and should be abandoned for assessment of suitability to anti-pd-1/pd-l1 therapy A. Disagree, useful for selection of NSLC pts B. Disagree, useful for selection of melanoma pts B. Disagree, useful for selection of bladder cancer pts C. Agree, more research is needed
Complexities in the use of PD-L1 in clinical trials Diagnostic PD-L1 immunohistochemistry assays may vary, with each pharmaceutical company utilizing its own test PD-L1 positivity, generally considered PD-L1 expression on tumor cells Different thresholds of PD-L1 positivity, ranging between 1 and 50 percent Considerable PD-L1 heterogeneity within tumors and between tumor sites, which may not be accurately accounted for in small tumor biopsy Gaule P et al. Jama Oncol 2016 specimens Where Does the Truth Lie in Immune Biomarker Development? Suzanne Topalian Primary melanoma, nodular subtype. 10% of tumor cells express PD-L1 Tumour cells Taube et al. Sci Transl Med 2012 Melanoma cells Macrophages Lymphocytes Lymphs
Complexity of the PD-L1 biomarker (2) Topalian et al. NEJM 2012 Variable expression of PD-L1 among multiple melanoma lesions from individual patients receiving anti-pd-1 therapy PD-L1+ tumour >5% tumor cells with cell surface PD-L1 expression by IHC PD-L1+ patient patient in whom any tumor is PD-L1+ Where Does the Truth Lie in Immune Biomarker Development? Suzanne Topalian
Atezolizumab in lung and bladder PD-L1 agent PD-L1 Ab negative low high highest IC/TC Atezolizumab (Roche) SP142 (Ventana) IC0 (<1%) IC1 ( 1% but <5%) IC2/3 ( 5%) IC3 ( 10%) TC0 (<1%) TC1 ( 1% but <5%) TC2/3 ( 5%) TC3( 50%) POPLAR phase II 7,8% 18,3% 22,3% 37,5% TC and IC ORR ImVigor210 Phase II 2 nd line ImVigor210 Platinum-unfit 8% 10% 26% N/A IC only 21% 23% 28% N/A IC only IC/TC compartments distinct, in particular the IC3 and TC3 Fehrenbacher et al. POPLAR. The Lancet Vol387 April 30, 2016 Rosenberg et al. NCT02108652. The Lancet Vol 387 May 7, 2016
FDA approvals for checkpoint blockers and PD-L1 IHC tests Where Does the Truth Lie in Immune Biomarker Development? Suzanne Topalian
New regulatory terminology companion vs complementary diagnostic Companion diagnostic: provides information that is essential for the safe and effective use of a corresponding drug or biological product Example: PD-L1 IHC 22C3 for pembrolizumab in NSCLC Complementary diagnostic: not required, but aids risk/benefit assessment for drug use in individual patients Example: PD-L1 IHC 28-8 for nivolumab in NSCLC and melanoma; PD-L1 IHC SP142 for atezolizumab in bladder cancer Where Does the Truth Lie in Immune Biomarker Development? Suzanne Topalian
Question 2 If possible I would treat all metastatic melanoma patients in the first line with the combination of a CTLA-4 and a PD-1 pathway inhibitor A. Yes (if performance status is 0-1) B. No, only BRAF wt patients B. No, only PD-L1 IHC low C. No, only PD-L1 IHC high
CheckMate-067 CheckMate-067 phase III updated results of nivolumab combined with ipilimumab. Jedd Wolchok
CheckMate-067: PFS by Tumour PD-L1 Expression CheckMate-067 phase III updated results of nivolumab combined with ipilimumab. Jedd Wolchok
Immune Response is Dynamic: Many Signals evolve over time to regulate T Cell responses Immune-editing MHC PD-1/PD-L1 As Predictive Biomarkers: Where do we stand. Padmanee Sharma
Considering PD-L1 expression as a predictive biomarker of clinical response Major Considerations Tumor PD-L1 expression may change over time and after systemic and local therapies; thus, archived tumor samples may not be ideal in determining current PD-L1 tumor status. PD-L1 expression at a single time point may not reflect an evolving immune response in the blood or tumour microenvironment Responses to PD-1 axis inhibitor therapy have been seen in 5 to 20 percent of patients with reported PD-L1- negative tumors across trials. Higher mutational load associates with increased clinical benefit to checkpoint inhibitors (CTLA-4/PD-1) Integration of multiple biological components (CD8 TIL, PD-L1 expression, IFNγ-signature genes, mutational load etc) Rooney et al. Cell 2015 PD-1/PD-L1 As Predictive Biomarkers: Where do we stand. Padmanee Sharma Hybrid capture-based next-generation sequencing (HC NGS) in melanoma to identify markers of response to anti-pd- 1/PD-L1. Douglas Johnson
Schumacher & Blank 2015
ASCO 2016 focus on PD-1 axis inhibitor therapy and on biomarker studies An insight on the complexities and contradictions surrounding PD-L1 as biomarker Updated follow-up data on long-term outcome of PD-1 blocking agents lessons to be learnt Which other (molecular subtypes of) cancers appear to have great benefit of checkpoint blockade
Keynote-001 phase Ib. Three-year survival update. Caroline Robert Keynote-001: Overall Survival
Keynote-001: Progression-free Survival Keynote-001 phase Ib. Three-year survival update. Caroline Robert
Complete responders (Pembro% for observation, N=61) Keynote-001 phase Ib. Three-year survival update. Caroline Robert
Complete responders (Pembro% for observation, N=61) Keynote-001 phase Ib. Three-year survival update. Caroline Robert
Complete responders (Pembro% for observation, N=61) Keynote-001 phase Ib. Three-year survival update. Caroline Robert
Complete responders (Pembro% for observation, N=61) Keynote-001 phase Ib. Three-year survival update. Caroline Robert
CheckMate-067 CheckMate-067 phase III updated results of nivolumab combined with ipilimumab. Jedd Wolchok
CheckMate-067: PFS (ITT) CheckMate-067 phase III updated results of nivolumab combined with ipilimumab. Jedd Wolchok
CheckMate-067: CheckMate-067 phase III updated results of nivolumab combined with ipilimumab. Jedd Wolchok
ASCO 2016 focus on PD-1 axis inhibitor therapy and on biomarker studies An insight on the complexities and contradictions surrounding PD-L1 as biomarker Updated follow-up data on long-term outcome of PD-1 blocking agents lessons to be learnt Which other (molecular subtypes of) cancers appear to have great benefit of checkpoint blockade
PD-1 Blockade in non-crc MMR Deficient Cancer Schumacher TN, Schreiber RD; Science 2015 PD-1 Blockade In MMR deficient cancer. Luis Diaz.
PD-1 Blockade in non-crc MMR Deficient Cancer Mismatch repair deficiency refers to deficiency in proteins responsible for DNA mismatch repair: MSH2, MSH6, MLH1, PMS2 Germline (Lynch syndrome) and/or sporadic mutations Epigenetic silencing (MLH1 hypermethylation) MMR deficiency leads to the microsatellite instability-high (MSI-H) phenotype MMR deficient tumors harbor thousands of mutations which could potentially be recognized by the immune system PD-1 Blockade In MMR deficient cancer. Luis Diaz.
Baseline characteristics non-crc MMR deficient cohort Characteristics MMR-deficient non CRC n=30 Median Age (range) years 56 (36-92) Gender-female no. (%) 14 (47) ECOG PS-zero 6 (20) Primary location endometrial ampullary biliary pancreatic small bowel gastric other (prostate/thyroid/sarcoma) 9 (30) 7 (23) 4 (13) 4 (13) 3 (10) 3 (10) Metastatic 30 (100) Liver metastasis 16 (53) Median Prior Regiments 2 Germline mutation/lynch Syndrome 5 (17) PD-1 Blockade In MMR deficient cancer. Luis Diaz.
Objective Responses non-crc MMR deficient cohort Type of Response Complete Response 9 (30) Partial Response 7 (23) Stable Disease (wk 12) 5 (17) Progressive disease 7 (23) Not Evaluable 2 (7) MMR-deficient non CRC n=30 Objective Response Rate (%) [95% CI] Disease Control Rate (%) [95% CI] Median follow up -months 10 16 (53) [36-70] 21 (70) [52-83] PD-1 Blockade In MMR deficient cancer. Luis Diaz.
Immunotherapy in Merkel Cell Carcinoma Aggressive skin cancer associated with poor survival outcome in patients with metastatic disease MCC polyomavirus (MCPyV) Exposure UV light Immunosuppression Advanced age 1 st line CT 2 nd line no SOC (following CT) Avelumab (MSB0010718C; anti-pd-l1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. Howard Kaufman.
Immunotherapy in Merkel Cell Carcinoma Rationale for immunotherapy Viral-mediated disease MCPyV-specific T cell dysfunction Checkpoints (PD-1 and Tim-3) expressed by MCC tumor cells and by adjacent immune cell infiltrates Improved PFS with high serum Ab titers against MCPyV CD8 T cells increase with larger tumor burden Improved OS with high CD3+, CD8+ TILs MCPyV-negative tumours have higher mutation and neo-antigen burden Avelumab (MSB0010718C; anti-pd-l1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. Howard Kaufman.
Baseline characteristics of MCC patients treated with PD-1 pathway inhibitors Characteristics 1 st line (n=26) PD-1 Phase II noncontrolled multicenter US trial 2 nd line (n=88) PD-L1 Phase II noncontrolled multicenter international Pembrolizumab Avelumab Age, median (range) 68 [57-91) 72.5 [33-88] Sex, female (%) 10 (38) 23 [26] Disease stage, no. (%) IIIB IV 2 (8) 24 (92) 0 88 (100) Virus-positive tumours, no. (%) 17 (65%) 46 (52.3) ECOG PS 0 1 N/A N/A 49 (55.7) 39 (44.3) PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. P.Nghiem et al. NEJM 2016 Avelumab (MSB0010718C; anti-pd-l1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. Howard Kaufman.
Outcome of MCC patients treated with PD-1 pathway inhibitors Overall response 1 st line (n=26) 2 nd line (n=88) Complete Response, no. (%) 4 (16) 9 (9.1) Partial Response, no. (%) 10 (40) 20 (22.7) Stable Disease, no. (%) 1 (4) 9 (10.2) Progressive Disease, no. (%) 9 (36) 32 (36.4) Non-evaluable 1 (4) 18 (20.5) Objective response rate (%) 56.0 31.8 PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. P.Nghiem et al. NEJM 2016 Avelumab (MSB0010718C; anti-pd-l1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. Howard Kaufman.
Avelumab in MCC: Tumour regression First-line pembrolizumab Second-line avelumab PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. P.Nghiem et al. NEJM 2016 Avelumab (MSB0010718C; anti-pd-l1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. Howard Kaufman.
Other news from ASCO Promising early results of PD-1 checkpoint axis inhibition TNBC Keynote-012 (Nanda JCO July 2016); Atezolizumab phase I (AACR 2016); Avelumab Javelin phase I Ongoing Keynote-086, Impassion130, Keynote-119, Keynote-173 Haematological cancers
Take Home Message PD-1/PD-L1 checkpoint inhibitors continue to dominate presentations at ASCO PD-L1 is a dynamic biomarker and in particular negative results should be interpreted with caution, in particular when used as sole biomarker (even for NSCLC with 22C3 companion diagnostic) A plethora of combination trial with CTLA-4 and co-stimulatory pathways are expected in 2017 Thank you for your attention