Overview of clinical development of checkpoint inhibitors in solid tumors

(1)

Overview of clinical development of checkpoint inhibitors in 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.

(2)

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 which can extend out for years and years”

Clinical trials have

demonstrated the

strenght of IO to

increase the number

of patients belonging

to the right part of

the curve.

(3)

At a glance : immunotherapy into the standards of care

→ EMA (and FDA) approval Immune checkpoint inhibitors

Melanoma Non 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) +

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

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

(4)

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)

(5)

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

(6)

n Phase treatment Primary endpoint

Hodi FS 676 III Ipilimumab + gp100

Ipilimumab gp100

OS

Robert C 502 III Ipilimumab + Dacarbazine

Dacarbazine + Placebo OS

CheckMate 037 405 III Nivolumab

CT investigator’s choice OS

KEYNOTE-002 540 II Pembrolizumab

CT investigator’s choice PFS

CheckMate 066 418 III Nivolumab

Dacarbazine 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

(7)

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 /2w Pembrolizumab / 3w Ipilimumab

279277 278

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 + Ipilimumab Nivolumab

Ipilimumab

314316 315

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)

(8)

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

Ipilimumab

6880 75

14 mo.

3.9 mo.

n PFS

Ipilimumab

210208 202

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

(9)

 Combination or sequential IO

 Optimal sequencing of targeted therapy and immunotherapy (BRAF V600)

Melanoma - Key issues

 Adjuvant setting

 phase 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

(10)

Fehrenbacher L, et al. Lancet. 2016 Herbst 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/kg

Docetaxel 75 mg/m² OS

CheckMate 057 582 III Nivolumab 3 mg/kg

KEYNOTE 010 1,034 II/III Pembrolizumab 2 or 10 mg/kg

Docetaxel 75 mg/m² OS and PFS

POPLAR 287 II Atezolizumab 1200 mg

OAK 850 III Atezolizumab 1200 mg

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

(11)

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

CheckMate 057 (Advanced nonsqNSCLC)

n OS PFS

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)

CheckMate 017 (Advanced sqNSCLC)

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 in advanced NSCLC

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

(12)

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 9.0 10.4 vs 10.1

18.2 vs 8.1 9.7 vs 10.1

19.4 vs 8.0 9.9 vs 10.3

(13)

Atezolizumab in advanced NSCLC : OAK study

n OS PFS

Atzolizumab

Docetaxel 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

(14)

Atezolizumab in advanced NSCLC : OAK study

Rittmeyer A, et al. Lancet 2017

Median OS by PD-L1 expression Median PFS by PD-L1 expression

On study Prevalence

(15)

Herbst RS, et al. Lancet 2016

n OS* PFS**

Pembrolizumab 2 Pembrolizumab 10 Docetaxel

345346 343

10.4 mo.

12.7 mo.

8.5 mo.

3.9 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 least 1% of tumour cells (ie, a tumour proportion score

≥1%).

(16)

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

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

n Phase treatment Primary endpoint

KEYNOTE - 024 305 III Pembrolizumab 200 mg

Platinum doublet chemotherapy PFS

CheckMate 026 541 III Nivolumab 3 mg/kg

Investigator’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

(17)

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

Pembrolizumab Chemoterapy (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) NR

6.3 mo.

(18)

CheckMate 026 : PD-L1 positive ≥ 1 %

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

Nivolumab

Chemotherapy 271

270 76.8 %

77.8 % 48.7 %

60.7 % 32.5 %

46.7 % 20.7 %

27.4 %

n PFS OS

Nivolumab Chemotherapy

(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

(19)

KEYNOTE 021 (randomized phase II)

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

n PFS OS ORR mDOR

Pemetrexed + Carbo + Pembrolizumab

Pemetrexed + Carbo 60

63 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 arm cross over to anti-PD-1/PD-L1 : 51 %

(20)

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)

(21)

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

(22)

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

(23)

Sharma P, et al. Lancet Oncol 2017.

Nivolumab : advanced urothelial carcinoma

→ second-line therapy (phase II, CheckMate 275)

 n = 265

 ORR = 19.6 %

(24)

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

Pembrolizumab : advanced urothelial carcinoma

→ second-line therapy (phase III, KEYNOTE-045)

n PFS OS

Pembrolizumab

Chemotherapy 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)

(25)

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.

(26)

Immune checkpoint inhibitors : an overview

Confirmed indications Potential indications Probably 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

(27)

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 %

(28)

Avelumab in advanced Merckel-Cell carcinoma

Kaufman HL et al. Lancet Oncol 2016

 N=88 ; ORR = 31.8 % [8 CR ; 20 PR]

(29)

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

(30)

Le DT, et al. N Engl J Med 2015 Le 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

(31)

MSI-H in mCRC : Nivolumab + Ipilimumab

Overman M, et al. ASCO 2016

n ORR Stable Disease mPFS mOS

Nivolumab

Nivolumab + Ipilimumab 47

27 25.5 %

33.3 %. 29.8 %

51.9 % 5.3 mo.

NR 17.1 mo.

NR

(32)

Conclusion (1)

 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)

Immune checkpoint antibodies are now incorporated in the standard treatments

Pardoll DM, et al. Nature Reviews Cancer 2012

(33)

Conclusion (2)

→ hyper- or rapid progressors after immunotherapy

Kato S, et al. Clin Cancer Res 2017

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