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