Overview of clinical development of checkpoint inhibitorsin solid tumors

Pr Jaafar BENNOUNA University of Nantes - France Nantes University Hospital - France

6th Meeting on external quality assessment in molecular pathology, Naples, May 12-13, 2017

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.

Ribas A, et al. Clin cancer Res 2012;18:336-41.

“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 whichcan extend out for years and years”

Clinical trials havedemonstrated thestrenght of IO toincrease the numberof patients belongingto the right part ofthe curve.

At a glance : immunotherapy into the standards of care→ EMA (and FDA) approval Immune checkpoint inhibitors

Melanoma Non pre-treatedNSCLC

Pre-treatedNSCLC

Pre-treatedRCC

Pre-treatedUC

Merckel cellcarcinoma

Pre-treatedSCCHN

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) +

Nivolumab: PD-1 blocking antibodyPembrolizumab: PD-1 blocking antibodyAtezolizumab: PD-L1 blocking antibodyAvelumab: PD-L1 blocking antibodyIpilimumab : CTLA-4-blocking antibody

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

Eggermont AMM, et al. N Engl J Med 2016

Adjuvant Ipilimumab in stage III melanoma

In adjuvant setting, the chosen dose is 10 mg/kg for Ipilimumab

951 patients (control arm : placebo) Advantage for 3 efficacy measures : RFS, OS, DM-FS (HR 0.76, 0.72, 0.76)

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

n Phase treatment Primary endpoint

Hodi FS 676 III Ipilimumab + gp100Ipilimumab

gp100

OS

Robert C 502 III Ipilimumab + DacarbazineDacarbazine + Placebo

OS

CheckMate 037 405 III NivolumabCT investigator’s choice

OS

KEYNOTE-002 540 II PembrolizumabCT investigator’s choice

PFS

CheckMate 066 418 III NivolumabDacarbazine

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.

KEYNOTE-002 - CheckMate 037 after progression following Ipilimumab and if BRAF V600 mutation, a BRAF inhibitor

CheckMate 066: non pretreated patients with wtBRAF melanoma

Immunotherapy in advanced melanoma

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

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 – first choice

KEYNOTE-006 (Pembrolizumab)

n 1 – year OS* PFS**

Pembrolizumab /2wPembrolizumab / 3wIpilimumab

279277278

74.1 %68.4 %.58.2 %

5.5 mo.4.1 mo.2.8 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)

n PFS

Nivolumab + IpilimumabNivolumabIpilimumab

314316315

11.5 mo.6.9 mo.2.9 mo.

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)

CheckMate 067 (Nivolumab)

Melanoma : CheckMate 067 and PD-L1

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.

PD-L1 + tumors

n PFS

Nivolumab + IpilimumabNivolumabIpilimumab

688075

14 mo.14 mo.3.9 mo.

n PFS

Nivolumab + IpilimumabNivolumabIpilimumab

210208202

11.2 mo.5.3 mo.2.8 mo.

Only 25 % of patients had PD-L1 positive tumors 41 % of patients with PD-L1 negative tumors responded to nivolumab

PD-L1 - tumors

Combination or sequential IO Optimal sequencing of targeted therapy

and immunotherapy (BRAF V600)

Melanoma - Key issues

Adjuvant settingphase III trial : dabrafenib + trametinib in BRAF mutant stage III melanoma Phase III trial : (1) nivolumab versus ipilimumab ; (2) pembrolizumab versus placebo

Advance disease

Atkins MB and Larkin J. J Natl Cancer Inst 2016;108(6):djv414

Fehrenbacher L, et al. Lancet. 2016Herbst RS, et al. Lancet. 2016

Rittmeyer A, et al. Lancet 2017

PD-1/PD-L1 inhibitors in NSCLC after platin-based chemo.

n Phase treatment Primary endpoint

CheckMate 017 272 III Nivolumab 3 mg/kgDocetaxel 75 mg/m²

OS

CheckMate 057 582 III Nivolumab 3 mg/kgDocetaxel 75 mg/m²

OS

KEYNOTE 010 1,034 II/III Pembrolizumab 2 or 10 mg/kgDocetaxel 75 mg/m²

OS and PFS

POPLAR 287 II Atezolizumab 1200 mgDocetaxel 75 mg/m²

OS

OAK 850 III Atezolizumab 1200 mgDocetaxel 75 mg/m²

OS

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 %

Brahmer J, et al. N Engl J Med. 2015Borghaei H, et al. N Engl J Med. 2015

Brahmer J, et al. N Engl J Med. 2015Borghaei H, et al. N Engl J Med. 2015

CheckMate 057 (Advanced nonsqNSCLC)

n OS PFS

NivolumabDocetaxel

292290

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)

CheckMate 017 (Advanced sqNSCLC)

n OS PFS

NivolumabDocetaxel

135137

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 in advanced NSCLC

Nivolumab : PD-1 inhibitor (IgG4 fully human antibody)

CheckMate 057 (Advanced nonsqNSCLC)CheckMate 017 (Advanced sqNSCLC)

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.

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

PD-L1 expression was assessed using Dako clone 28-8 antibody

17.2 vs 9.010.4 vs 10.1

18.2 vs 8.19.7 vs 10.1

19.4 vs 8.09.9 vs 10.3

Atezolizumab in advanced NSCLC : OAK study

n OS PFS

AtzolizumabDocetaxel

425425

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

Rittmeyer A, et al. Lancet 2017

Median OS by PD-L1 expression Median PFS by PD-L1 expressionOn study Prevalence

Herbst RS, et al. Lancet 2016

n OS* PFS**

Pembrolizumab 2Pembrolizumab 10Docetaxel

345346343

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 in NSCLC

The KEYNOTE-010 trial : Overall population

Pembrolizumab : PD-1 inhibitor (IgG4 humanized antibody)

PD-L1 expression on at least1% of tumour cells (ie, atumour proportion score≥1%).

Reck M, et al. ESMO 2016 and N Engl J Med 2016Socinscki MA, et al. ESMO 2016

Langer CJ, et al. ESMO 2016 and Lancet Oncol 2016

PD-1/PD-L1 inhibitors in 1st line metastatic NSCLC

n Phase treatment Primary endpoint

KEYNOTE - 024 305 III Pembrolizumab 200 mgPlatinum doublet chemotherapy

PFS

CheckMate 026 541 III Nivolumab 3 mg/kgInvestigator’s choice (platinum doublet)

PFS (≥ 5 % PD-L1+)

KEYNOTE - 021 123 II Pemetrexed + carbo + Pembrolizumab 200 mg Pemetrexed + carbo

ORR

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

Reck M, et al. ESMO 2016 ; N Engl J Med 2016

KEYNOTE-024 : PD-L1 positive with TPS ≥ 50 %

1934 patients screened → 1729 submitted samples → 1653 evaluable for PD-L1 → 500 TPS ≥ 50 % (30 %)

n PFS OS ORR mDOR

PembrolizumabChemoterapy(platin-based)

154151

10.3 mo.6.0 mo.

HR 0.50 (0.37 – 0.68)

NRNR

HR 0.60 (0.41– 0.89)

45 % (n=63)28 % (n=41)

NR6.3 mo.

CheckMate 026 : PD-L1 positive ≥ 1 %

n PD-L1≥5% PD-L1≥25% PD-L1≥50% PD-L1≥75%

NivolumabChemotherapy

271270

76.8 %77.8 %

48.7 %60.7 %

32.5 %46.7 %

20.7 %27.4 %

n PFS OS

NivolumabChemotherapy

(platin-based)

211212

4.2 mo.5.9 mo.

HR 1.15 (0.91 – 1.45)

14.413.2

HR 1.02 (0.8– 1.30)

Primary Endpoint (PFS per IRRC in ≥5% PD-L1+)

Overall Survival (≥5% PD-L1+)

Socinscki MA, et al. ESMO 2016

KEYNOTE 021 (randomized phase II)

Langer CJ, et al. ESMO 2016 and Lancet Oncol 2016

n PFS OS ORR mDOR

Pemetrexed + Carbo + PembrolizumabPemetrexed + Carbo

6063

13.0 mo.8.9 mo.

HR 0.53 (0.31 – 0.91)

NRNR

HR 0.90 (0.42– 0.1.91)

55 %29 %

P=0.0016

NRNR

Median PFS Median OS

In the chemotherapy alone armcross over to anti-PD-1/PD-L1 : 51 %

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)

Motzer RJ, et al. N Engl J Med 2015;373:1803-13.

Pre-treated advanced renal carcinoma→ Nivolumab vs everolimus (CheckMate 025)

the benefit is observed irrespective of PD-L1 expression

821 patients pre-treated with one or two regimens of anti-angiogenic therapy

Rosenberg JE, et al. Lancet 2016; 387: 1909–20

OS is associated with PD-L1 expression on immune cells

Phase II study with Atezolizumab – IMvigor210

Atezolizumab : urothelial carcinoma

Sharma P, et al. Lancet Oncol 2017.

Nivolumab : advanced urothelial carcinoma→ second-line therapy (phase II, CheckMate 275)

n = 265 ORR = 19.6 %

Bellmunt J, et al. N Engl J Med 2017.

Pembrolizumab : advanced urothelial carcinoma→ second-line therapy (phase III, KEYNOTE-045)

n PFS OS

PembrolizumabChemotherapy

270272

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)

Recurrent or metastatic SCCHNPhase 3 CheckMate-141 (after platinum therapy)

SCCHN : Squamous Cell Carcinoma of Head and NeckFerris RL, et l. N Engl J Med 2016.

Immune checkpoint inhibitors : an overview

Confirmed indicationsPotential indicationsProbably not indicated

RCC : renal cell carcinoma ; UC : urothelial carcinoma ; SCCHN : squamous cell carcinoma head and neck;NSCLC : non small cell lung cancer ; mCRC : metastatic colorectal cancer

Nghiem PT, et al. N Engl J Med 2016

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 %

Avelumab in advanced Merckel-Cell carcinoma

Kaufman HL et al. Lancet Oncol 2016

N=88 ; ORR = 31.8 % [8 CR ; 20 PR]

Volgestein B, et al. Science 2013

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.

Solid tumors with microsatellite instability

Le DT, et al. N Engl J Med 2015Le DT, et al. ASCO 2016. Abstract 103

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.

3 cohorts of patients treated with pembrolizumab 10 mg/kg/14 days

mCRC : metastatic Colorectal Cancer*ampullary/cholangiocarcinoma; endometrial, small bowel, and gastric cancer.NR : not reached

MSI-H in solid tumors : a phase II trial

MSI-H in mCRC : Nivolumab + Ipilimumab

Overman M, et al. ASCO 2016

n ORR Stable Disease mPFS mOS

NivolumabNivolumab + Ipilimumab

4727

25.5 %33.3 %.

29.8 %51.9 %

5.3 mo. NR

17.1 mo.NR

Conclusion (1)

for a number of metastatic disease, eventuallydepending of certain biomarkers (PD-L1, MSI-H, highmutational 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 toimmunotherapy (ex. MEK 1 inhibition promotes T-cellinhibition)

Immune checkpoint antibodies are now incorporated in the standard treatments

Pardoll DM, et al. Nature Reviews Cancer 2012

Conclusion (2) → hyper- or rapid progressors after immunotherapy

Kato S, et al. Clin Cancer Res 2017Champiat S, et al. Clinical Cancer res 2017Saada-Bouzid E, et al. Ann Oncol 2017

Identification of genomic alterations MDM2/MDM4 and EGFR alterations correlatedwith TTF<2 months

TGR (Tumor Growth Rate) prior (REF) and upon (EXP) anti-PD-1/PD-L1

Endometrial stromal carcinoma