6th Meeting on external quality assessment in molecular pathology, Naples, May 12-13, 2017 Overview of clinical development of checkpoint inhibitors in solid tumors Pr Jaafar BENNOUNA University of Nantes - France Nantes University Hospital - France Out of 129 patients with NSCLC treated with Nivolumab in a phase I trial, the OS rate at 5-y was about 16 %, clearly higher than historical rates.
The Median isn't the message by Stephen Jay Gould The issue is how to be the good candidate for the right part of the curve which can extend out for years and years Ribas A, et al. Clin cancer Res 2012;18:336-41. Clinical trials have demonstrated the strenght of IO to increase the number of patients belonging to the right part of the curve.
At a glance : immunotherapy into the standards of care EMA (and FDA) approval Immune checkpoint inhibitors Melanoma Non pre-treated NSCLC Pre-treated NSCLC Pre-treated RCC Pre-treated UC Merckel cell carcinoma Pre-treated SCCHN Ipilumumab (3 mg/kg IV q3w x 4) +* Nivolumab (240 mg IV q2w) + + + +** + Pembrolizumab (200 mg IV q3w) + TPS PDL1 50 %** PD-L1 1 %** +** Atezolizumab (1200 mg IV q3w) +** +** Avelumab (10 mg/kg IV q2w) +** Ipi (3 mg/kg) + Nivo (1 mg/kg) + NSCLC : Non Small Cell Lung Cancer ; RCC : Renal Cell Carcinoma ; UC : Urothelial Carcinoma ; SCCHN : squamous cell cancer of the head and neck * Ipilumimab : EMEA approval for unresectable or metastatic melanoma and also FDA approval as adjuvant in stage III ** FDA approval Nivolumab: PD-1 blocking antibody Pembrolizumab: PD-1 blocking antibody Atezolizumab: PD-L1 blocking antibody Avelumab: PD-L1 blocking antibody Ipilimumab : CTLA-4-blocking antibody
Adjuvant Ipilimumab in stage III melanoma 951 patients (control arm : placebo) Advantage for 3 efficacy measures : RFS, OS, DM-FS (HR 0.76, 0.72, 0.76) In adjuvant setting, the chosen dose is 10 mg/kg for Ipilimumab Eggermont AMM, et al. N Engl J Med 2016
Adjuvant Ipilimumab in stage III melanoma Forest Plot for Overall survival Is there a benefit for stage IIIA? Better benefit for microscopic nodal + Better benefit for ulcerated primary Eggermont AMM, et al. N Engl J Med 2016
Immunotherapy in advanced melanoma KEYNOTE-002 - CheckMate 037 after progression following Ipilimumab and if BRAF V600 mutation, a BRAF inhibitor CheckMate 066: non pretreated patients with wtbraf melanoma n Phase treatment Primary endpoint Hodi FS 676 III Ipilimumab + gp100 Ipilimumab gp100 Robert C 502 III Ipilimumab + Dacarbazine Dacarbazine + Placebo CheckMate 037 405 III Nivolumab CT investigator s choice KEYNOTE-002 540 II Pembrolizumab CT investigator s choice CheckMate 066 418 III Nivolumab Dacarbazine Hodi FS, et al. N Engl J Med 2010;363(8):711-723. Robert C, et al. N Engl J Med 2011;364(26):2517-2526 OS OS OS PFS OS Weber JS, et al. Lancet Oncol 2015;16(4):375-384.. Ribas A, et al. Lancet Oncol 2015;16(8):908-918. Robert C, et al. N Engl J Med 2015;372:320-330.
Melanoma first choice KEYNOTE-006 (Pembrolizumab) CheckMate 067 (Nivolumab) n 1 year OS* PFS** n PFS Pembrolizumab /2w Pembrolizumab / 3w Ipilimumab 279 277 278 74.1 % 68.4 %. 58.2 % 5.5 mo. 4.1 mo. 2.8 mo. Nivolumab + Ipilimumab Nivolumab Ipilimumab 314 316 315 11.5 mo. 6.9 mo. 2.9 mo. *OS : pembro/2w vs docetaxel HR 0.63 (0.47 0.83) pembro/3w vs docetaxel HR 0.69 (0.52 0.90) **PFS : pembro /2w vs docetaxel HR 0.58 (0.46 0.72) pembro /3w vs docetaxel HR 0.58 (0.46 0.72) PFS : Nivo + Ipi [vs Ipi HR 0.42 (0.31 0.57)]; [vs Nivo HR 0.74(0.60-0.92)] Nivo vs Ipi HR 0.57 (0.43 0.76) Robert C, et al. N Engl J Med 2015; 372(26):2521-2532. Larkin J, et al. N Engl J Med 2015;373(1):23-34.
Melanoma : CheckMate 067 and PD-L1 Only 25 % of patients had PD-L1 positive tumors 41 % of patients with PD-L1 negative tumors responded to nivolumab PD-L1 + tumors PD-L1 - tumors n PFS n PFS Nivolumab + Ipilimumab Nivolumab Ipilimumab 68 80 75 14 mo. 14 mo. 3.9 mo. Nivolumab + Ipilimumab Nivolumab Ipilimumab 210 208 202 11.2 mo. 5.3 mo. 2.8 mo. Robert C, et al. N Engl J Med 2015; 372(26):2521-2532. Larkin J, et al. N Engl J Med 2015;373(1):23-34.
Melanoma - Key issues Advance disease Combination or sequential IO Optimal sequencing of targeted therapy and immunotherapy (BRAF V600) Adjuvant setting phase III trial : dabrafenib + trametinib in BRAF mutant stage III melanoma Phase III trial : (1) nivolumab versus ipilimumab ; (2) pembrolizumab versus placebo Atkins MB and Larkin J. J Natl Cancer Inst 2016;108(6):djv414
PD-1/PD-L1 inhibitors in NSCLC after platin-based chemo. 5 randomized phase II or III trials CheckMate 017 restricted to squamous histology CheckMate 057 restricted to nonsquamous histology Disease progression after platine based chemotherapy POPLAR and OAK studies allowed 1 2 previous lines KEYNOTE 010 : PD-L1 positive with TPS 1 % n Phase treatment Primary endpoint CheckMate 017 272 III Nivolumab 3 mg/kg Docetaxel 75 mg/m² CheckMate 057 582 III Nivolumab 3 mg/kg Docetaxel 75 mg/m² KEYNOTE 010 1,034 II/III Pembrolizumab 2 or 10 mg/kg Docetaxel 75 mg/m² POPLAR 287 II Atezolizumab 1200 mg Docetaxel 75 mg/m² OAK 850 III Atezolizumab 1200 mg Docetaxel 75 mg/m² OS OS OS and PFS OS OS Brahmer J, et al. N Engl J Med. 2015 Borghaei H, et al. N Engl J Med. 2015 Fehrenbacher L, et al. Lancet. 2016 Herbst RS, et al. Lancet. 2016 Rittmeyer A, et al. Lancet 2017
Nivolumab in advanced NSCLC CheckMate 017 (Advanced sqnsclc) CheckMate 057 (Advanced nonsqnsclc) n OS PFS n OS PFS Nivolumab Docetaxel 135 137 9.2 mo. 6.0 mo. HR 0.59 (0.44 0.79) 3.5 mo. 2.8 mo. HR 0.62 (0.47 0.81) Nivolumab Docetaxel 292 290 12.2 mo. 9.4 mo. HR 0.73 (0.59 0.89) 2.3 mo. 4.2 mo. HR 0.92 (0.77 1.11) Nivolumab : PD-1 inhibitor (IgG4 fully human antibody) Brahmer J, et al. N Engl J Med. 2015 Borghaei H, et al. N Engl J Med. 2015
Nivolumab in advanced NSCLC CheckMate 017 : the OS benefit is independant of PD-L1 expression CheckMate 057 : PD-L1 expression is a predictive biomarker for OS CheckMate 017 (Advanced sqnsclc) CheckMate 057 (Advanced nonsqnsclc) 10.4 vs 10.1 9.7 vs 10.1 9.9 vs 10.3 17.2 vs 9.0 18.2 vs 8.1 19.4 vs 8.0 PD-L1 expression was assessed using Dako clone 28-8 antibody Brahmer J, et al. N Engl J Med. 2015. Borghaei H, et al. N Engl J Med. 2015 Paz-Ares L, et al. ASCO 2015. Abstract LBA109.
Atezolizumab in advanced NSCLC : OAK study Atzolizumab Docetaxel n OS PFS 425 425 13.8 mo. 9.6 mo. HR 0.73 (0.62 0.87) 2.8 mo. 4.0 mo. HR 0.95 (0.82 1.10) Rittmeyer A, et al. Lancet 2017
Atezolizumab in advanced NSCLC : OAK study On study Prevalence Median OS by PD-L1 expression Median PFS by PD-L1 expression Rittmeyer A, et al. Lancet 2017
Pembrolizumab in NSCLC The KEYNOTE-010 trial : Overall population PD-L1 expression on at least 1% of tumour cells (ie, a tumour proportion score 1%). Pembrolizumab 2 Pembrolizumab 10 Docetaxel n OS* PFS** 345 346 343 10.4 mo. 12.7 mo. 8.5 mo. 3.9 mo. 4.0 mo. 4.0 mo. *OS : pembro 2 vs docetaxel HR 0.71 (0.58 0.88) pembro 10 vs docetaxel HR 0.61 (0.49 0.75) **PFS : pembro 2 vs docetaxel HR 0.88 (0.74 1.05) pembro 10 vs docetaxel HR 0.79 (0.66 0.94) Pembrolizumab : PD-1 inhibitor (IgG4 humanized antibody) Herbst RS, et al. Lancet 2016
PD-1/PD-L1 inhibitors in 1st line metastatic NSCLC 3 randomized trials KEYNOTE-024 : PD-L1 positive with TPS 50 % CheckMate 026 PD-L1 positive 1 % KEYNOTE-021 : restricted for patients with nonsquamous histology n Phase treatment Primary endpoint KEYNOTE - 024 305 III Pembrolizumab 200 mg Platinum doublet chemotherapy CheckMate 026 541 III Nivolumab 3 mg/kg Investigator s choice (platinum doublet) KEYNOTE - 021 123 II Pemetrexed + carbo + Pembrolizumab 200 mg Pemetrexed + carbo PFS PFS ( 5 % PD-L1+) ORR Reck M, et al. ESMO 2016 and N Engl J Med 2016 Socinscki MA, et al. ESMO 2016 Langer CJ, et al. ESMO 2016 and Lancet Oncol 2016
KEYNOTE-024 : PD-L1 positive with TPS 50 % 1934 patients screened 1729 submitted samples 1653 evaluable for PD-L1 500 TPS 50 % (30 %) Pembrolizumab Chemoterapy (platin-based) n PFS OS ORR mdor 154 151 10.3 mo. 6.0 mo. HR 0.50 (0.37 0.68) NR NR HR 0.60 (0.41 0.89) 45 % (n=63) 28 % (n=41) NR 6.3 mo. Reck M, et al. ESMO 2016 ; N Engl J Med 2016
CheckMate 026 : PD-L1 positive 1 % Nivolumab Chemotherapy n PD-L1 5% PD-L1 25% PD-L1 50% PD-L1 75% 271 270 76.8 % 77.8 % 48.7 % 60.7 % 32.5 % 46.7 % 20.7 % 27.4 % Primary Endpoint (PFS per IRRC in 5% PD-L1+) Overall Survival ( 5% PD-L1+) Nivolumab Chemotherapy (platin-based) n PFS OS 211 212 4.2 mo. 5.9 mo. HR 1.15 (0.91 1.45) 14.4 13.2 HR 1.02 (0.8 1.30) Socinscki MA, et al. ESMO 2016
KEYNOTE 021 (randomized phase II) Median PFS Median OS Pemetrexed + Carbo + Pembrolizumab Pemetrexed + Carbo n PFS OS ORR mdor 60 63 13.0 mo. 8.9 mo. HR 0.53 (0.31 0.91) In the chemotherapy alone arm cross over to anti-pd-1/pd-l1 : 51 % NR NR HR 0.90 (0.42 0.1.91) 55 % 29 % P=0.0016 NR NR Langer CJ, et al. ESMO 2016 and Lancet Oncol 2016
Conclusion Keynote-024 : validation of pembrolizumab for non pretreated NSCLC with TPS 50 % OAK, CheckMate 017, CheckMate 057 validation of nivolumab and atezolizumab for pre-treated NSCLC KEYNOTE-010 validation of pembrolizumab for pre-treated NSCLC with TPS 1 % Future directions IO combinations, chemo and IO combinations Multiline strategy Other stages of disease: (neo) - adjuvant, locally advanced Other histology (SCLC)
Pre-treated advanced renal carcinoma Nivolumab vs everolimus (CheckMate 025) 821 patients pre-treated with one or two regimens of anti-angiogenic therapy the benefit is observed irrespective of PD-L1 expression Motzer RJ, et al. N Engl J Med 2015;373:1803-13.
Atezolizumab : urothelial carcinoma Phase II study with Atezolizumab IMvigor210 OS is associated with PD-L1 expression on immune cells Rosenberg JE, et al. Lancet 2016; 387: 1909 20
Nivolumab : advanced urothelial carcinoma second-line therapy (phase II, CheckMate 275) n = 265 ORR = 19.6 % Sharma P, et al. Lancet Oncol 2017.
Pembrolizumab : advanced urothelial carcinoma second-line therapy (phase III, KEYNOTE-045) Pembrolizumab Chemotherapy n PFS OS 270 272 2.2 mo. 3.3 mo. HR 0.98 (0.81 1.19) 10.3 mo. 7.4 mo. HR 0.73 (0.59 0.1.91) Bellmunt J, et al. N Engl J Med 2017.
Recurrent or metastatic SCCHN Phase 3 CheckMate-141 (after platinum therapy) SCCHN : Squamous Cell Carcinoma of Head and Neck Ferris RL, et l. N Engl J Med 2016.
Immune checkpoint inhibitors : an overview RCC : renal cell carcinoma ; UC : urothelial carcinoma ; SCCHN : squamous cell carcinoma head and neck; NSCLC : non small cell lung cancer ; mcrc : metastatic colorectal cancer Confirmed indications Potential indications Probably not indicated
Pembrolizumab in advanced Merckel-Cell carcinoma N=26 ; ORR (n=25) = 56 % [5 CR ; 10 PR] ; PFS-6 month rate : 67 % Indentification of two major factors ultraviolet (UV) light Merkel-cell polyomavirus (MCPyV) : 80 % Nghiem PT, et al. N Engl J Med 2016
Avelumab in advanced Merckel-Cell carcinoma N=88 ; ORR = 31.8 % [8 CR ; 20 PR] Kaufman HL et al. Lancet Oncol 2016
Solid tumors with microsatellite instability A high level of genetic mutations is described in MSI-H tumors. Expression of neoantigens on tumor cells induces inflamed microenvironment with high expression of immune checkpoints, such as PD-1. Volgestein B, et al. Science 2013
MSI-H in solid tumors : a phase II trial 3 cohorts of patients treated with pembrolizumab 10 mg/kg/14 days dmmr mcrc (n=28) pmmr mcrc (n=25) dmmr noncrc* (n=30) ORR 57 % 0 % 71 % Disease control rate 89 % 16 % 71 % mpfs NR 2.3 mo. mos NR 5.98 mo. mcrc : metastatic Colorectal Cancer *ampullary/cholangiocarcinoma; endometrial, small bowel, and gastric cancer. NR : not reached Le DT, et al. N Engl J Med 2015 Le DT, et al. ASCO 2016. Abstract 103
MSI-H in mcrc : Nivolumab + Ipilimumab Nivolumab Nivolumab + Ipilimumab n ORR Stable Disease mpfs mos 47 27 25.5 % 33.3 %. 29.8 % 51.9 % 5.3 mo. NR 17.1 mo. NR Overman M, et al. ASCO 2016
Conclusion (1) Immune checkpoint antibodies are now incorporated in the standard treatments for a number of metastatic disease, eventually depending of certain biomarkers (PD-L1, MSI-H, high mutational load, others) there is a need to evaluate other stages of disease there is a need to evaluate new checkpoint inhibitors (OX40, LAG-3) there is a need to evaluate new combinations, especially for tumors remaining highly resistant to immunotherapy (ex. MEK 1 inhibition promotes T-cell inhibition) Pardoll DM, et al. Nature Reviews Cancer 2012
Conclusion (2) hyper- or rapid progressors after immunotherapy Identification of genomic alterations MDM2/MDM4 and EGFR alterations correlated with TTF<2 months TGR (Tumor Growth Rate) prior (REF) and upon (EXP) anti-pd-1/pd-l1 Endometrial stromal carcinoma Kato S, et al. Clin Cancer Res 2017 Champiat S, et al. Clinical Cancer res 2017 Saada-Bouzid E, et al. Ann Oncol 2017