PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

Antoni Ribas, Alain Algazi, Paolo A Ascierto, Marcus O Butler, Sunandana Chandra, Michael Gordon, Leonel Hernandez-Aya, Donald Lawrence, Jose Lutzky, Wilson H Miller Jr, Katie M Campbell, Bruno Delafont, Shannon Marshall, Nancy Mueller, Caroline Robert, Antoni Ribas, Alain Algazi, Paolo A Ascierto, Marcus O Butler, Sunandana Chandra, Michael Gordon, Leonel Hernandez-Aya, Donald Lawrence, Jose Lutzky, Wilson H Miller Jr, Katie M Campbell, Bruno Delafont, Shannon Marshall, Nancy Mueller, Caroline Robert

Abstract

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

Conflict of interest statement

A.R. has received honoraria from consulting with Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche and Sanofi, is/has been a member of the scientific advisory board and holds stock in Advaxis, Apricity, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, IsoPlexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics, and has received research funding from Agilent and BMS through SU2C. A.A. reports grants from AstraZeneca, GSK and Novartis, during the conduct of the study, consulting fees, travel support and stock options from OncoSec, stock options for consulting from Valitor, honoraria and research funding to UCSF from Regeneron, honoraria from Array, and grants in the form of research funding to UCSF from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, Pfizer, Sensei, Tessa. P.A.A. reports grants or personal fees for advisory/consultancy work and research funding from BMS, Roche-Genentech and Array, personal fees for advisory/consultancy work and travel support from MSD, personal fees for advisory/consultancy work from Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, and Nektar, and personal fees for consultancy work from Italfarmaco. M.B. reports he is contracted by his institute to complete work on this study for AstraZeneca, along with personal fees and honoraria for consultancy work from Merck, BMS, Novartis, Sanofi, Pfizer, Immunocore, Adaptimmune, and EMD Serono. S.C. has received honoraria from consulting with and/or has been a member of the scientific advisory board of BMS, Novartis, Array BioPharma, Regeneron, Sanofi-Genzyme, and Exicure. M.G. reports institutional research support from Medimmune, Merck, BMS, Amgen, Tesaro, Beigene, ABBVIE, Aeglea, Arcus, Astex, BluePrint, Calithera, CellDex, Corcept, Clovis, Eli Lilly, Endocyte, Five Prime, Genocea, Neon, Plexxicon, Revolution Medicine, Seattle Genetics, Serono, SynDevRx, and Tolero, and personal fees and institutional research support from Agenus, Imaging Endpoints, Tracon, Deciphera, and Salarius. L.H.-A. reports personal fees for study-related fees to institution from AstraZenaca, personal fees paid to institution for conduction of clinical trials from BMS, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, Genentech. J.L. reports personal fees for advisory board consultancy/attendance from Castle, Array Pharmaceuticals and Kimera and personal fees for advisory board and speaker bureau work from Regeneron Pharmaceuticals. W.H.M. reports consultancy fees from BMS, Merck, Roche, Novartis, Amgen, and GSK. KMC is a shareholder in Geneoscopy LLC. B.D., S.M., and N.M. are all employees of AstraZeneca. C.R. has received honoraria from consulting with Amgen, BMS, MSD, Novartis, Roche, CureVac, Biother, Sanofi, Pierre Fabre, and Merck.

Figures

Fig. 1. Best percentage change from baseline…
Fig. 1. Best percentage change from baseline in tumor diameter (as-treated population).
Longitudinal tumor size was analyzed using a non-linear mixed-effects model to determine tumor growth rate constants and time to growth. Cohort A, n = 26; Cohort B, n = 20; Cohort C, n = 22. CR/PR, complete response/partial response.
Fig. 2. Duration of response (as-treated population).
Fig. 2. Duration of response (as-treated population).
Vertical lines indicate planned 12 months of treatment with durvalumab. Cohort A, n = 26; Cohort B, n = 20; Cohort C, n = 22.
Fig. 3. RNA-sequenced gene expression profiling, CD8+…
Fig. 3. RNA-sequenced gene expression profiling, CD8+ T-cell infiltration by IHC, and IFNγ levels in circulating blood.
Cohort A, n = 13; Cohort B, n = 12; Cohort C, n = 5. CR complete response, IHC immunohistochemistry, IFN-γ interferon-gamma, PR partial response, PD progressive disease, SD stable disease, TIL tumor-infiltrating lymphocyte.

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