Immunotherapy for Melanoma Caroline Robert, MD, PhD Gustave Roussy and Université Paris Sud Villejuif, France
Overall Survival for Metastatic Melanoma Proportion Alive 1.0 0.8 0.6 0.4 0.2 Survival data from 42 phase II trials with over 2100 stage IV patients: 12-month OS: 25.5 %, Median OS: 6.2 months 0 12 24 36 Time, Months Korn EL, et al. J Clin Oncol. 2008;26(4):527-534. Dummer R, et al. Ann Oncol. 2008;19 Suppl 2:ii86-88. Garbe C, et al. Eur J Cancer. 2010;46(2):270-283.
Melanoma Immunotherapy Spontaneous regression Vitiligo Halo-nevus
High-Dose IL-2 Response rate: 15%, with 5% complete response Grades 3-5 >50% and 2% death Atkins MB, et al. J Clin Oncol. 1999;17(7):2105-2116.
Boutros C, et al. Nat Rev Clin Oncol. 2016;13(8):473-486.
Anti-CTLA-4: Ipilimumab Pretreated Patients +/- gp100 HLA-A2 3 mg/kg Reinduction possible Naïve Patients + DTIC 10 mg/kg Maintenance possible 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.
Anti-CTLA-4: Ipilimumab Plateau effect 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.
Pembrolizumab Anti-PD-1 Two Phase I Trials ORR 30 and 40% Toxicity: 15% grade 3 Nivolumab Overall Survival, % 100 90 80 70 60 50 40 30 20 2-year OS 49% 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time, Months n at risk 655 584 510 461 416 318 231 174 93 66 29 3 0 100 90 80 70 60 50 40 30 20 10 0 at Risk Total 2-year OS 48% 3-year OS 41% 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Months 107 97 86 71 63 54 50 47 44 31 25 22 22 19 18 9 3 2 1 0 Ribas A, et al. JAMA. 2016;3.135(15):1600-1609. Hodi FS, et al. J Clin Oncol. 2014;32(5s): Abstract 9002.
Phase III Nivolumab vs Chemotherapy Phase III Pembrolizumab vs Ipilimumab 1-yr OS 73% (n = 210) (n = 208) 1-yr OS 42% Treatment Arm Median (95% CI), mo Rate at 12 mo HR (95% CI) P Pembrolizumab Q2W NR (NR-NR) 74.1% 0.63 (0.47-0.83) Pembrolizumab Q3W NR (NR-NR) 68.4% 0.69 (0.52-0.90) <.00001 <.00001 Ipilimumab NR (12.7-NR) 58.2% Follow-up since randomization: 5.2 16.7 months Decreased risk of death by 58% compared to chemotherapy, and by 31% to 37% compared with ipilimumab Robert C, et al. N Engl J Med. 2015;372(4):320-330. Robert C, et al. N Engl J Med. 2015;372(26):2521-2532.
Early Effect of Checkpoint Inhibitors
Adjuvant Treatment With Ipilimumab Eggermont AM, et al. N Engl J Med. 2016;375(19):1845-1855.
Adjuvant Treatment With Nivolumab vs Ipilimumab: CheckMate 238 Enrollment period: March 30, 2015 to November 30, 2015 Patients with high-risk, completely resected stage IIIB/IIIC or stage IV melanoma 1:1 n = 453 n = 453 Stratified by: 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells NIVO 3 mg/kg IV q2w and IPI placebo IV q3w for 4 doses then q12w from week 24 IPI 10 mg/kg IV q3w for 4 doses then q12w from week 24 and NIVO placebo IV q2w Follow-up Maximum treatment duration of 1 year Weber J, et al. N Engl J Med. 2017;377(19):1824-1835. Weber J, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA8_PR.
Nivolumab Is Superior to Ipilimumab in the Adjuvant Setting 100 90 NIVO IPI Events/patients 154/453 206/453 80 Median (95% CI) NR NR (16.6, NR) RFS, % 70 60 50 71% 61% 66% 53% HR (97.56% CI) 0.65 (0.51, 0.83) Log-rank P value <.0001 40 30 20 10 0 Number of patients at risk NIVO IPI NIVO IPI 0 3 6 9 12 15 18 21 24 27 Months 453 399 353 332 311 291 249 71 5 0 453 364 314 269 252 225 184 56 2 0 Weber J, et al. N Engl J Med. 2017;377(19):1824-1835. Weber J, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA8_PR.
KEYNOTE-054: Adjuvant Pembrolizumab in High-Risk Stage III Melanoma Patients with high-risk, completely resected stage III melanoma R A N D O M I Z E Pembro 200 mg IV on day 1 of each 21-day cycle Placebo IV on day 1 of each 21-day cycle Follow-up Maximum treatment duration of 1 year Primary Endpoint: Recurrence-free survival (RFS) for all participants, RFS for participants with PD-L1 positive tumor expression Secondary Endpoints: Distant metastases-free survival (DMFS) for all participants, DMFS for participants with PD-L1 positive tumor expression, OS in all participants, OS in participants with PD-L1 positive tumor expression Results expected spring 2018 National Institutes of Health. https://clinicaltrials.gov/ct2/show/study/nct02362594. Accessed November 9, 2017.
CheckMate 067: Combination of Immunotherapies Progression-Free Survival Overall Survival Wolchok JD, et al. N Engl J Med. 2017;377(14):1345-1356.
First-Line Therapy: Overall Survival Mean survival curves created by weighted averaging of digitized Kaplan-Meier survival curves of metastatic melanoma patients treated in selected clinical trials. Ugurel S, et al. Eur J Cancer. 2016;53:125-134.
Unpublished data. Longer Follow-Up
Unpublished data. Longer Follow-Up
New Toxicity Profile
Which of the following adverse events would you NOT consider to be immune related in a patient receiving checkpoint inhibitor therapy for the treatment of melanoma? 1. Pneumonitis 2. Rash 3. Hypertension 4. Colitis 5. Hepatotoxicity
More Organs or Tissues Can Be Involved Michot JM, et al. Eur J Cancer. 2016;54:139-148.
But: High Toxicity of the Combination Grade 3/5 AE % Discontinuation for AE % Ipilimumab 3 mg/kg 1 19 16 Nivolumab 2 14 10 Pembrolizumab 3 14 4 Ipilimumab + nivolumab 4 59 39 1. Atkinson V, et al. Presented at: 9 th World Congress of Melanoma. October 18-21, 2017. Brisbane, Australia. 2. Weber J, et al. N Engl J Med. 2017;377(19):1824-1835. 3. Ribas A, et al. JAMA. 2016;315(15):1600-1609. 4. Wolchok JD, et al. N Engl J Med. 2017;377(14):1345-1356.
Immunotherapy Adverse Events Boutros C, et al. Nat Rev Clin Oncol. 2016;13(8):473-486.
Bompaire F, et al. Invest New Drugs. 2012;30(6):2407-2410.
Vitiligo With Anti-PD1 or Anti-PDL1
Vitiligo and Clinical Response to Pembrolizumab Patient CR PR SD PD P* Vitiligo (n = 17) 3 (18) 9 (53) 3 (18) 2 (12).002 No vitiligo (n = 50) 4 (8) 10 (20) 1 (2) 35 (70) Total (N = 67) 7 (10) 19 (28) 4 (6) 36 (54) *Complete/partial response versus stable/progressive disease/progression in patients with and without vitiligo, exact Fisher test Hua C, et al. JAMA Dermatol. 2016;152(1):45-51.
New Evaluation Criteria
New Types of Responses Wolchock JD, et al. Clin Cancer Res. 2009;15(23):7412-7420. Immune-Related Response Criteria
Baseline 12 weeks 24 weeks 52 weeks
New Reasons to Stop Treatment
Pembrolizumab Phase I: KEYNOTE-001 : Median Follow-Up 43 Months for 655 Patients On treatment: 16% Consent withdrawal 5% Discontinue for physician decision 11% Discontinued for PD: 42% Discontinued for AEs: 25% Range of follow-up: 36-57 months. Analysis cutoff date: September 1, 2016. Robert C, et al. Presented at: 13 th Congress of the European Association of Dermato Oncology; May 3-6, 2017; Athens, Greece.
Complete Responders: Disposition Median follow-up: 43 months 92 (88%) remained in CR a 105 (16%) patients had CR per irrc by investigator review 14 (13%) remained on pembrolizumab 24 (23%) discontinued for AEs (n = 12), PD (n = 2), or other reason (n = 10) 67 (64%) stopped pembrolizumab for observation a Patient was alive and without disease progression. Analysis cutoff date: September 1, 2016. Robert C, et al. Presented at: 13 th Congress of the European Association of Dermato Oncology; May 3-6, 2017; Athens, Greece.
Complete Responders Who Stopped Pembrolizumab for Observation (N = 67) Median time to CR: 13 mo ( 3-36 mo) 61 (91%) responses were maintained Median response duration: NR (6+ to 56+ mo) Time to PD or last assessment Last dose CR PR PD Time to death 0 6 12 18 24 30 36 42 48 54 60 Time, months Total bar length represents the time to the last scan. Analysis cutoff date: September 1, 2016. Robert C, et al. Presented at: 13 th Congress of the European Association of Dermato Oncology; May 3-6, 2017; Athens, Greece.
In KEYNOTE-006, what is the estimated PFS at follow-up in patients who completed protocolspecified time on treatment? 1. 61% 2. 71% 3. 81% 4. 91%
KEYNOTE-006 (NCT01866319) Patients Unresectable, stage III or IV melanoma 1 previous therapy, excluding anti CTLA-4, PD-1, or PD-L1 agents Known BRAF mutation status a ECOG PS 0-1 No active brain metastases No serious autoimmune disease R 1:1:1 Pembrolizumab 10 mg/kg intravenous q2w for 2 years Pembrolizumab 10 mg/kg intravenous q3w for 2 years Ipilimumab 3 mg/kg intravenous q3w 4 doses Stratification Factors ECOG PS (0 vs 1) Line of therapy (first vs second) PD-L1 status b (positive vs negative) Primary endpoints: PFS and OS Secondary endpoints: ORR, duration of response, safety Robert C, et al. J Clin Oncol. 2017;35(suppl): Abstract 9504. a Prior anti-braf targeted therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease. b Defined as 1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody).
KEYNOTE-006: Patients Who Completed Protocol-Specified Time on Pembrolizumab (Median Follow-Up, 9.7 mo) 556 patients received pembrolizumab 104 (19%) completed pembrolizumab 24 (23%) CR 68 (65%) PR 12 (12%) SD 23 ongoing responses 1 PD b 1 received second course of pembrolizumab 64 ongoing responses 4 PD b 3 received second course of pembrolizumab 10 ongoing SD 2 deaths b,c Robert C, et al. J Clin Oncol. 2017;35(suppl): Abstract 9504. a Includes patients completing 21.6 months of treatment. b From end of pembrolizumab treatment. c Both deaths were a result of PD. Data cutoff date: Nov 3, 2016.
PFS (irrc, Investigator) From Last Pembrolizumab Dose in Patients Who Completed Protocol-Specified Time on Treatment (n = 104) Progression-Free Survival, % 100 90 80 70 60 50 40 30 20 10 Patients Who Completed Protocol-Specified Time on Pembrolizumab, n Estimated PFS, % (95% CI) 102 (98%) patients were alive after a median of 9.7 months after completing pembrolizumab treatment Median PFS 104 91 (80-96) NR No. at risk 0 0 2 4 6 8 10 12 14 Time, Months 104 96 95 86 67 30 6 0 Robert C, et al. J Clin Oncol. 2017;35(suppl): Abstract 9504. Data cutoff date: Nov 3, 2016.
Ipilimumab + Nivolumab: Pooled Data From CheckMate 067 and 69 Schadendorf D, et al. J Clin Oncol. 2017 Aug 25. [Epub ahead of print].
Ipilimumab + Nivolumab: Pooled Data From CheckMate 067 and 09 PFS and OS not significantly different between the patients who discontinued for AE during the induction period and those who did not discontinue Schadendorf D, et al. J Clin Oncol. 2017 Aug 25. [Epub ahead of print].
Ipilimumab + Nivolumab: Pooled Data From CheckMate 067 and 09 Patients who discontinued treatment because of adverse events during the induction phase of treatment. Schadendorf D, et al. J Clin Oncol. 2017 Aug 25. [Epub ahead of print].
To Improve Benefit/Risk Ratio Recent Results on Combinations Combination targeted therapy + anti PD1/PDL-1 Cobimetinib/vemurafenib/atezolizumab Dabrafenib/trametinib/pembrolizumab Combination of immunotherapies Pembrolizumab/ipilimumab 1 mg/kg Pembrolizumab/TVEC Pembrolizumab/anti-IDO epacadostat In anti-pd1 refractory patients Nivolumab/anti-Lag3 relatlimab
Early Combination Studies KEYNOTE-022 1 Pembro + Dabra + Trame GP28384 2 Cobi + Vemu + Atezo KEYNOTE-037 3 Pembro + Epacadostat KEYNOTE 029 4 Pembro + Ipi1 mg Pembro + TVEC 5 Nivo+ Relatlimab 6 N 15 39 65 153 21 61 High LDH (%) NR 22.2 37 25 24 24 M1C (%) 53 25.6 55 56 38 * 47.5 ORR (%) 67 81.6 56 61 62 11.5 CR (%) 13 18.4 13 15 33 ** 1.6 Grade 3/5 AE (%) 73 41 20 45 38 10 Median FU (months) 19.7 10.1 10.35 17 18.6 4.1 * But 44% III or M1a; ** including injected lesions 1. Ribas A, et al. Ann Oncol. 2017;28(Suppl 6): Abstract 1216O. 2. Hwu P, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 1109PD. 3. Hamid O, et al. Ann Oncol. 2017;28(Suppl 6): Abstract 1214O. 4. Long GV, et al. Lancet Oncol. 2017;18(9):1202-1210. Ribas A, et al. Cell. 2017;170(6):1109-1119. 6. Ascierto PA, et al. Ann Oncol. 2017;28(Suppl 6): Abstract LBA18.
New Biomarkers
PD-L1 High Expression Associated With Clinical Response to Anti-PD1 100 ORR, RECIST v1.1 Correlation between PD-L1 expression and ORR (P<.0001) 90 80 ORR, % (95% CI) 70 60 50 40 30 PD-L1 Negative 0% Staining APS = 0 PD-L1 Positive 1-10% Staining APS = 2 APS, Allred proportion score. Analysis cut-off date: October 18, 2014. PD-L1 Positive 10-33% Staining APS = 3 PD-L1 Positive 66-100% Staining APS = 5 20 10 0 APS 0 n = 28 APS 1 n = 24 Negative Daud A. Presented at: 2015 American Society of Clinical Oncology Annual Meeting: Clinical Science Symposium Intersection of the Mutanome and the Immunome; May 29-June 2, 2015; Chicago, Illinois. APS 2 n = 72 APS 3 n = 54 APS 4 n = 32 Positive APS 5 n = 34
Which of the following is NOT a difference between PD-L1 testing platforms? 1. PD-L1 expression level cutoff 2. Use of immune cells for expression testing 3. Use of tumor cells for expression testing 4. Antibody used for testing
Heterogeneity of PD-L1 IHC Assays Clone Species Assay Developer Treatment Drug Target 22C3 Mouse Dako Pembrolizumab PD-1 28-8 Rabbit Dako Nivolumab PD-1 SP142 Rabbit Ventana Atezolizumab PD-L1 Relevant Cutoff From Clinical Trials TC 5% (melanoma) Any intensity TC 1% Any intensity TC 50%/5%/1% Moderate and strong intensity IC 10%/5%/1% SP263 Rabbit Ventana Durvalumab PD-L1 TC 25% Any intensity 04/12/2017 TC, tumor cells; IC: immune cells Courtesy Julien Adam, Gustave Roussy Other antibodies - 5H1 (Lieping Chen), mouse mab - E1L3N (Cell signaling technology), rabbit mab
Courtesy Julien Adam, Gustave Roussy
Among Several Markers, CD8+ Was the Most Predictive for Response to Pembrolizumab Tumeh PC, et al. Nature. 2014;515(7528):568-571.
Role of the Gut Microbiota? Baseline microbiota type is linked to the risk of colitis and response to immunotherapy Chaput N, et al. Ann Oncol. 2017;28(6):1368-1379.
Mutational Load and Neoantigens Number of nonsynonymous mutations Generation of neoantigens Anti-CTLA-4 in Melanoma Snyder A, et al. N Engl J Med. 2014;371(23):2189-2199. Rizvi NA, et al. Science. 2015;348(6230):124-128. Anti-PD-1 in NSCLC
Mutational Load and Neoantigens Alexandrov LB, et al. Nature. 2013;500(7463):415-421. Schumacher TN, et al. Science. 2015;348(6230):69-74.
New Mechanisms of Resistance
Genetic Resistances to Immunotherapies Mutation-derived modification of the INF-γ signaling pathway or loss of Cl I expression Zaretsky JM, et al. N Engl J Med. 2016;375(9):819-829. Gao J, et al. Cell. 2016;167(2):397-404.
Many Avenues Are Explored to Overcome the Resistance + radiotherapy + other IT 41BB OX-40 CD40 GITR ICOS IDO + other checkpoint-i TIM 3; LAG 3 + macrophage-i CSFR1 + chemo + local tt Ipi Oncol virus TLR agonist + cancer vaccines + Adopt C T + targeted therapies BRAF, MEK + epigenetic modifiers HDAC + NK activation
Genetic background: MHC DNA-repair system Immune background Tumor specific: Mutations, neoantigens DNA-repair capacity Immune targets: PD1, PDL-1, Lag-3 Metabolism: LDH, oxphos, glycolysis Translation initiation Microbiome Gut Skin Immune landscape : Immunoscore: CTL, repertoire, Treg, B cells, Tfh, MDSC, Immune biomarkers: PD1, PDL-1, PLA Lag-3,
This is the revolution Conclusion Real hope to cure some patients For some others, nothing has changed (high LDH, multiple brain metastases) We have to continue Clinical trials with translational research Combination, or sequences of drugs Biomarker identification
Clinical and Research Teams