Data Supplement

Figure S1

A schematic representation of the immune synapse in health and disease. Immune checkpoint ligand-receptor interactions suppress T cell-mediated cellular toxicity in health (T cell suppression by antigen presenting cells (dendritic cells and macrophages) and cardiomyocytes in normal physiology) and disease (cancer cells).

Table S1. Clinical benefits of ICIs in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, Hodgkin lymphoma and colorectal carcinoma. [PFS: progression-free survival; ORR: overall response rate; OS: overall survival; CR: complete response; NR: not reached]

Melanoma

Pembrolizumab

KEYNOTE-00221

Pembrolizumab 2mg/kg q3w vs 10mg/kg q3w vs chemotherapy (Carboplatin/Paclitaxel, Paclitaxel, Dacarbazine or Temozolomide)

Palliative - Ipilimumab-refractory

Improved 24-month PFS rates (16% vs 22% vs 0.6%)

Improved ORR (22% vs 26% vs 4%)

Improved OS (13.4 vs 14.7 vs 11.0 months)

KEYNOTE-0062

Pembrolizumab 10mg/kg q2w vs 10mg/kg q3w vs Ipilimumab 3mg/kg q3w (x4)

Palliative - No prior immunotherapy

Improved 24-month PFS (31% vs 28% vs 14%)

Improved ORR (Pembro: 55% vs Ipi: 50%)

Improved 2 year-OS (37% vs 13%)

Nivolumab

CheckMate 0373

Nivolumab vs chemotherapy (Dacarbazine or Carboplatin/Paclitaxel)

Palliative - After anti-CTLA-4 therapy

Improved ORR (27% vs 10%)

Longer median duration of response (32 vs 13 months)

No OS difference

CheckMate 0664

Nivolumab vs Dacarbazine

Palliative - Treatment-naïve

Improved 1-year OS (73% vs 42%)

Improved median PFS (5.1 vs 2.2 months)

CheckMate 2385

Nivolumab vs Ipilimumab

Adjuvant - Stage IIIB-C and IV

Improved 18-month RFS (66.4% vs 52.7%)

OS data awaited

Ipilimumab

NCT000946536

Ipilimumab/gp100 vaccine vs Ipilimumab vs gp100

Palliative – Prior chemotherapy or IL-2

Improved 24-month OS (22% vs 24% vs 14%)

Improved ORR (5.7% vs 10.9% vs 1.5%)

NCT003241557,8

Ipilimumab/Dacarbazine vs placebo/Dacarbazine

Palliative – Treatment-naïve

Improved median OS (11.2 vs 9.1 months)

Improved 5-year OS (18% vs 9%)

EORTC 180719,10

Ipilimumab vs placebo

Adjuvant – Stage IIIA-B-C

Improved 5-year RFS (40.8% vs 30.3%)

Improved 5-year DFMS (48.3% vs 38.9%)

Improved 5-year OS (65.4% vs 54.4%)

Nivolumab/ Ipilimumab

CheckMate 06711,12

Nivolumab/Ipilimumab vs single-agent immunotherapy (Nivolumab or Ipilimumab)

Palliative – treatment-naïve

Improved 3-year PFS (39% vs 32% vs 10%)

Improved 3-year OS (58% vs 52% vs 34%)

Improved ORR (58% vs 44% vs 19%)

Non-small cell lung cancer (NSCLC)

Nivolumab

CheckMate 01713,14

Nivolumab vs Docetaxel

Palliative – Squamous histology – After platinum

Improved median OS (9.2 vs 6.0 months)

Improved ORR (20% vs 9%)

Improved duration of response (NR vs 8 months)

CheckMate 05714,15

Nivolumab vs Docetaxel

Palliative – Non-squamous histology – After platinum

Improved median OS (12.2 vs 9.4 months)

Improved ORR (19% vs 12%)

Improved duration of response (17 vs 8 months)

CheckMate 02616

Nivolumab vs platinum-doublet chemotherapy

Palliative – PD-L1+ (≥1%) – Treatment-naïve

Not superior in PFS and OS if PD-L1>5%

Pembrolizumab

KEYNOTE-01017

Pembrolizumab 2mg/kg vs 10mg/kg vs Docetaxel

Palliative – PD-L1+ (≥1%) – Pretreated

Improved OS (10.4 vs 12.7 vs 8.5 months)

Similar PFS (approximately 4 months)

Improved ORR (18% vs 18% vs 9%)

KEYNOTE-02418,19

Pembrolizumab vs platinum-doublet chemotherapy

Palliative – PD-L1+ (≥50%) – Treatment-naïve

Improved median PFS (10.3 vs 6 months)

Improved OS (HR 0.60)

Improved ORR (45% vs 28%)

Improved median duration of response (12.1 vs 5.7 months)

KEYNOTE-021

Pembrolizumab/Carboplatin/Pemetrexed vs Carboplatin/Pemetrexed

Palliative – PD-L1-unselected - Treatment-naïve

Improved median PFS (13 vs 6 months)

Improved ORR (55% vs 29%)

Atezolizumab

OAK20

Atezolizumab vs Docetaxel

Palliative – PD-L1-unselected – Pretreated

Improved median OS (13.8 vs 9.6 months)

No improved median PFS (2.8 vs 4 months)

Improved median duration of response (16.3 vs 6.2 months)

Durvalumab

PACIFIC21

Durbvalumab vs placebo

Unresectable stage III without progression after ≥2 cycles of platinum-based chemoradiotherapy

Improved median PFS (16.8 vs 5.6 months)

Improved ORR (28% vs 16%)

Improved median time to death or distant metastasis (23.2 versus 14.6 months)

Head and neck squamous cell carcinoma

Nivolumab

CheckMate 14122,23

Nivolumab to single-agent investigator’s choice (Methotrexate, Docetaxel or Cetuximab)

Palliative – Platinum-refractory

Improved median OS (7.5 vs 5.1 months)

Improved ORR (13.3% vs 5.8%)

Renal cell carcinoma

Nivolumab

CheckMate 02524-27

Nivolumab vs Everolimus

Palliative – 1-2 prior anti-angiogenic therapies

Improves median OS (25.0 vs 19.6 months)

No difference in PFS

Improved ORR (25% vs 5%)

Nivolumab/Ipilimumab

CheckMate 21428,29

Nivolumab/Ipilimumab vs Sunitinib

Palliative – Untreated

Improved median OS (NR vs 32.9 months)

Improved ORR (39% vs 32%)

No difference in PFS

Improvement more pronounced in intermediate- or poor-risk or if PDL1≥1%

Atezolizumab/ Bevacizumab

IMmotion15129

Atezolizumab/Bevacizumab vs Sunitinib

Palliative – Untreated

Improved median PFS (11.2 vs 8.4 months)

Improved ORR (37% vs 33%)

Improvement more pronounced in PD-L1+

Urothelial carcinoma

Pembrolizumab

KEYNOTE-05230

Phase II – Pembrolizumab single arm

Palliative – Untreated and not eligible for Cisplatin-based chemotherapy

ORR 29%

Median duration of response NR

ORR higher if PD-L1>10%

KEYNOTE-04531,32

Phase III – Pembrolizumab vs investigator's choice chemotherapy (paclitaxel, docetaxel, or vinflunine)

Palliative – After platinum

Improved median OS (10.3 vs 7.4 months)

No difference in PFS

Improved ORR (21.1% vs 11.0%)

Improved responses at 12 months (68% vs 35%)

Atezolizumab

IMvigor21033

Phase II – Atezolizumab single arm

Palliative – Untreated and not eligible for cisplatin-based chemotherapy

ORR 27%

Median duration of response NR

Median OS 16 months

IMvigor21134

Phase III - Atezolizumab vs investigator's choice chemotherapy (paclitaxel, docetaxel, or vinflunine)

Palliative – After platinum

No improved OS

No improved ORR

Higher ORR if increased PDL1 expression

Improved median duration of response (21.7 vs 7.4 months)

Hodgkin lymphoma

Nivolumab

NCT0159237035

Phase I – Nivolumab single arm

Relapsed/refractory disease

ORR 87%

CR 17%

NCT0218173836,37

Phase II – Nivolumab single arm

Relapsed/refractory disease after autologous HCT and/or Brentuximab Vedotin

ORR 66%

CR 9%

Median duration of response 7.8 months

Pembrolizumab

KEYNOTE-08738

Phase II – Pembrolizumab single arm

Relapsed/refractory disease – heavily pretreated

ORR 69%

CR 22%

Microsatellite instability high colorectal carcinoma

Nivolumab/ Ipilimumab

CheckMate-14239

Phase II - Nivolumab/Ipilimumab single arm

Palliative – Pretreated

ORR 55%

Disease control rate 12 weeks 80%

Median duration of response NR

12-month PFS 71%

12-month OS 85%

Pembrolizumab

NCT0187651137

Phase II – Pembrolizumab single arm

Palliative – Pretreated

ORR 50%

Disease control rate 89%

PFS and OS NR

References

1.Hamid O, Puzanov I, Dummer R, et al. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. European journal of cancer (Oxford, England : 1990) 2017; 86: 37-45.

2.Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017; 390(10105): 1853-62.

3.Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16(4): 375-84.

4.Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. The New England journal of medicine 2015; 372(4): 320-30.

5.Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. The New England journal of medicine 2017; 377(19): 1824-35.

6.Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine 2010; 363(8): 711-23.

7.Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. The New England journal of medicine 2011; 364(26): 2517-26.

8.Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015; 33(10): 1191-6.

9.Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. The Lancet Oncology 2015; 16(5): 522-30.

10.Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. The New England journal of medicine 2016; 375(19): 1845-55.

11.Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. The New England journal of medicine 2015; 373(1): 23-34.

12.Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. The New England journal of medicine 2017; 377(14): 1345-56.

13.Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England journal of medicine 2015; 373(2): 123-35.

14.Horn L, Spigel DR, Vokes EE, et al. Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017; 35(35): 3924-33.

15.Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. The New England journal of medicine 2015; 373(17): 1627-39.

16.Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. The New England journal of medicine 2017; 376(25): 2415-26.

17.Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387(10027): 1540-50.

18.Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 2016; 375(19): 1823-33.

19.Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. The Lancet Oncology 2016; 17(11): 1497-508.

20.Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389(10066): 255-65.

21.Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine 2017; 377(20): 1919-29.

22.Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. The New England journal of medicine 2016; 375(19): 1856-67.

23.Harrington KJ, Ferris RL, Blumenschein G, Jr., et al. Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. The Lancet Oncology 2017; 18(8): 1104-15.

24.Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England journal of medicine 2015; 373(19): 1803-13.

25.Cella D, Grunwald V, Nathan P, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. The Lancet Oncology 2016; 17(7): 994-1003.

26.Escudier B, Sharma P, McDermott DF, et al. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. European urology 2017; 72(6): 962-71.

27.Escudier B, Motzer RJ, Sharma P, et al. Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. European urology 2017; 72(3): 368-76.

28.Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England journal of medicine 2018.

29.Motzer RJ, Powell SF, Atkins MB, Escudier B, McDermott DF, Suarez C. IMmotion151: A Randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma. 2018 Genitourinary Cancers Symposium; 2018.

30.Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18(11): 1483-92.

31.Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. The New England journal of medicine 2017; 376(11): 1015-26.

32.Bajorin DF, De Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L. Plans survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (abstract 4501). 2017 annual meeting of the American Society for Clinical Oncology; 2017.

33.Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389(10064): 67-76.

34.Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018; 391(10122): 748-57.

35.Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England journal of medicine 2015; 372(4): 311-9.

36.Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. The Lancet Oncology 2016; 17(9): 1283-94.

37.Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The New England journal of medicine 2015; 372(26): 2509-20.

38.Chen R, Zinzani PL, Fanale MA, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017; 35(19): 2125-32.

39.Overman MJ, Kopetz S, McDermott RS, Leach J, Lonardi S, Lenz HJ. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results (abstract 3501). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016; 34.

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