MELANOMA METASTASICO: NUEVAS COMBINACIONES. Dr Ana Arance MD PhD Oncología Médica Hospital Clínic Barcelona

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1 MELANOMA METASTASICO: NUEVAS COMBINACIONES Dr Ana Arance MD PhD Oncología Médica Hospital Clínic Barcelona

2 Summary of OS accross clinical trials in patients with metastatic melanoma Ugurel et al. Eur J Cancer 2017

3 Overall Survival: Anti-PD1 Nivolumab CA year OS Median OS: 20.3 months Pembrolizumab KEYNOTE year OS Median OS 23.8 months ECOG PS lines prior therapy (no prior ipi or anti-pd-1) 66% 2 prior therapies ECOG PS 0/1 Untreated or pretreated (inc. prior ipi) 44% 2 prior therapies 24% BRAF mut 1. Hodi FS, et al. AACR Hamid et al. ASCO 2018

4 Proportion Alive Melanoma: Long Term Overall Survival year OS rate, 34% Pembrolizumab Phase I 5-year OS rate, 35% Nivolumab Phase I Ipilimumab CENSORED 3-year OS rate, 21% Ipilimumab Pool analysis Months

5 Types of tumor microenviroments to tailoring cancer immunotherapy 38%

6 CTLA-4 & PD-1/PD-L1 Combos

7 Ipilimumab+Nivolumab or Nivolumab vs Ipilimumab Checkmate 067 Wolchok at al. NEJM % BRAF mut, n=298

8 Proportion Alive Melanoma: Long Term Overall Survival year OS rate, 58% Ipi + Nivo Phase III 5-year OS rate, 34% Pembrolizumab Phase I 5-year OS rate, 35% Nivolumab Phase I Ipilimumab CENSORED 3-year OS rate, 21% Ipilimumab Pool analysis Months

9 Is there a better combination coming?

10 Reversing the enzymatic inhibition of T cell activation Indoleamine 2,3 dioxygenase (IDO) catalyzes the degradation of tryptophan to N-formyl-kynurenine In mouse models, IDO inhibition slows tumor growth. In combination with chemotherapy or immune checkpoint inhibitors, IDO inh can promote tumor regressions Inh of IDO (Epacadostat, Indoximod) have shown single agent safety data in early phase clinical trials with stable disease reported as the best response 1.Tryp Starvation -Cell cycle arrest -Apoptosis 2. Accumulation of metabolites: -Treg -Dysfunctional Th2 and cell death Ongong studies are testing IDO inh with checkpoint inhibitors (CTLA-4, PD-1, PDL-1) and dendritic cellbased immunotherapy Am Soc Clin Oncol Educ Book :e168

11 Pembrolizumab +/- Epacadostat/Placebo Keynote 252 N=706 13% Prior therapy 32% BRAF mutant tx naive Long et al. ASCO 2018 Max 2 years

12 Pembrolizumab +/- Epacadostat/Placebo Keynote 252 Long et al. ASCO 2018

13 T-VEC and Pembrolizumab Ribas et al. Cell 2017; 170:

14 MASTERKEY-265 Phase 3 Study Design N = 660 Unresectable stage III or IV melanoma Treatment naive Injectable lesions No clinically active brain mets No active herpetic skin lesions or prior complications from herpetic infection T-VEC: talimogene laherparepvec R 1:1 T-VEC intralesional Up to 4 ml per treatment 1 st dose 10 6 PFU/mL Then 10 8 PFU/mL Q2W T-VEC Intralesional Pembrolizumab 200mg IV Q3W T-VEC placebo Intralesional Pembrolizumab 200mg IV Q3W N = 330 N = 330 Treatment until whichever occurs first: Complete Response (CR) Progressive disease (PD) per irrc-recist Intolerance All injectable tumors disappeared (T-VEC only) 2 Years S A F E T Y F O L L O W - U P 30 (+7) days after end of treatment

15 Targeting LAG 3 Nguyen et al. Nat Rev Immunol 2015, 15:45; Woo et al. Cancer Res 2012, 72:

16 Anti-LAG3 and Nivolumab Ascierto et al ESMO 2017

17 CA Phase 3: Anti-LAG3 and Nivolumab Screening Period Stratification Treatment Assignment On Treatment Phase 2 N=400 Phase 3 N=700 Previously untreated for unresectable or metastatic melanoma Tissue available for biomarker analyses Stratify by: PD-L1 status LAG-3 status BRAF status AJCC M stage Rand a 1:1 BMS b IV Q4W Nivolumab c IV Q4W Enrollme nt Pause BMS b IV Q4W Nivolumab c IV Q4W n=200 Interim Analysis Population n=200 Remaining Phase 2 Population Interim Analysis Decision Point n=300 Additional a A safety lead-in evaluation will be performed on the first (up to) 18 participants. b BMS is the fixed-dose combination relatlimab/nivolumab at a 1:3 ratio. For adults, dosing is relatlimab 160 mg/nivolumab 480 mg. Adolescents > 40 kg will receive adult dosing; for adolescents < 40 kg, dosing is relatlimab 2 mg/kg/nivolumab 6 mg/kg. c Nivolumab monotherapy dosing for adults is 480 mg. Adolescents > 40 kg will receive adult dosing; for adolescents < 40 kg, dosing is 6 mg/kg.

18 Dual MAPK pathway inhibition changes the tumour environment, making tumours more susceptible to cancer immunotherapy MAPKi-induced changes MEKi ERK MEK Melanoma cell ETS p21 PUMA CDKN2A CDK4 CCND1 p53 MDM4 Increased melanoma antigen expression Decreased immunosuppressive cytokine production Increased CD8+ T-cell infiltration Increased T-cell clonality Increased PD-L1 expression Class I MHC upregulation BRA Fi BRAF NRAS RTK 50% S6K 4EBP1 MHC P13K AKT PTEN mtor PD- L1 TCR PDL-1 Enhanced tumour cell death T cells are activated and live longer Tumour cells are more visible T lymphocyte Anti PD-1/PD-L1 Tumours are more susceptible to cancer immunotherapy McArthur and Ribas, J Clin Oncol, 2014; Frederick et al. Clin Cancer Res 2013; Ebert et al. Immunity 2016

19 Change in sum of longest diameters from baseline (%) Triple therapy shows promising anti-tumour activity in BRAF V600 mutant melanoma Phase Ib Atezolizumab + cobimetinib + vemurafenib Tumour CD8 + T cells before and after cobimetinib + vemurafenib run-in Unconfirmed ORR=81.6%* Time on study (days) Numbers in each panel represent the percentage of CD8+ cells in the tumour center, 40x magnification. *25 responses confirmed as of data cutoff: January 17, 2017 CR, complete response; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Sullivan RJ. ASCO poster 2017

20 Phase II-III clinical trials BRAF/MEKi + Anti-PD-1/PDL-1

21 MEK and PD-L1 inhibition increase CD8+ T-cell infiltration and MHC I expression Phase I Cobi + Atezolizumab in metastatic melanoma Treatment with cobimetinib increased intra-tumoural CD8+ T-cell infiltration and MHC I expression in a patient with clear-cell sarcoma who achieved a partial response BRAFmut (n=10) ORR=40% DCR=70% BRAFwt (n=10) ORR=50% DCR=80% Additional atezolizumab further enhanced the CD8+ T- cell infiltration Miller et al. ASCO. 2017

22 IMspire170: phase III study of atezolizumab + cobimetinib in BRAF wild-type melanoma First patient in: December 2017 Previously untreated advanced melanoma Stage IIIc or IV BRAFwt Non-ocular Measurable disease by RECIST v1.1 Archival tissue or fresh biopsy Adjuvant treatment with ipilimumab allowed N 450 R Cobimetinib 60 mg PO D Atezolizumab 840 mg Q2W Pembrolizumab 200 mg Q3W Primary endpoint: IRC-assessed PFS Secondary endpoints: Investigator-assessed PFS, OS, ORR, DOR, safety, QoL Stratification factors: PD-L1 status LDH status Geographic region NCT Infante J et al. SMR presentation. 2016

23 Patients with BRAF wild-type metastatic melanoma who have progressed on PD-1 inhibitors First patient in: June 2017 Advanced BRAFwt melanoma verified by approved BRAF tests Progressed on anti PD1 prior to enrolment Primary resistance Secondary resistance ECOG PS 0 or 1 Available pretreatment biopsy samples Cohort A: anti-pd1 progressors (n=90) Cobimetinib 60 mg QD D atezolizumab 840 mg Q2W Cohort B*: biopsy cohort Primary resistance (n=6) Secondary resistance (n=6) Cobimetinib 60 mg QD D atezolizumab 840 mg Q2W (starting C1D15) Treat until loss of clinical benefit Treatment beyond RECISTdetermined PD is allowed Primary endpoint: ORR Disease control (CR, PR, or SD) at 12 weeks Secondary endpoints: DOR PFS (RECIST) OS Safety *Participants in cohort B will undergo tumour biopsies before and during treatment Cohort C (not shown) - anti-pd1 therapy naïve patients (n=50) will receive atezolizumab 840 mg Q2W CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate: OS, overall survival; PD, progressive disease; PD-1. programmed death ligand 1; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease NCT

24 Phase II: Pembro + Ipi 1mg/kg immediately following progression on Anti_PD-1 N=31 PD during treatment with an anti-pd1/l1 Ab as the treatment regimen immediately prior to accrual or disease progression within 6 m of adjuvant anti-pd1 antibody ORR 10/22= 45% Olson et al ASCO 2018 abstr 9514

25 New combinations in development following anti-pd-1 progression?

26 SD-101 and Pembrolizumab ORR 40-70% IMO2125 and ipilimumab Ribas et al. ASCO 2018; Diab et al ASCO 2018 abs9515

27 NKTR214 and Nivolumab Phase I-II PIVOT Diab et al ASCO 2018 abs 3006

28 Entinostat and Pembrolizumab Phase II ENCORE 601 N=34 Entinostat 5 mg QW PO + pembrolizumab 200 mg Q3W IV in 21-day cycles ORR 18% Agarwala et al ASCO 2018 abstr 9530

29 Final Remarks Ipilimumab and Nivolumab is the first combination approved in melanoma Immune checkpoints are actively being investigated in combination with a wide spectrum of agents Continuing to incorporate the emerging knowledge from mechanistic basic-science studies is critical to achieve greater therapeutic success.

30 Muchas Gracias