TY - JOUR
T1 - PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma
AU - Ribas, Antoni
AU - Algazi, Alain
AU - Ascierto, Paolo A.
AU - Butler, Marcus O.
AU - Chandra, Sunandana
AU - Gordon, Michael
AU - Hernandez-Aya, Leonel
AU - Lawrence, Donald
AU - Lutzky, Jose
AU - Miller, Wilson H.
AU - Campbell, Katie M.
AU - Delafont, Bruno
AU - Marshall, Shannon
AU - Mueller, Nancy
AU - Robert, Caroline
N1 - Funding Information:
The authors thank the patients and their families who participated in this study; Shaista Parveen and Shannon Morris of AstraZeneca for study support; and Keith Steele, Marlon Rebelatto, Nathan Standifer (AstraZeneca), Carla Prat Rojo (Definiens), and Melissa de los Reyes (AstraZeneca) for data analysis support. A. Ribas is funded by the Parker Institute for Cancer Immunotherapy and NIH grant R35 CA197. This study was sponsored by AstraZeneca, who contributed to the conception and design of the work, the data analysis and interpretation, and who were given the opportunity to review the article ahead of its final approval by the authors. Editorial support was provided by Daniel Johnson, PhD, Brad Imwalle, PhD, MBA, and Jackie Stone, PhD of SciMentum (Nucleus Global), London, UK, and by Rachel Cicchelli, PhD, of Ashfield Healthcare Communications, Macclesfield, UK, under the authors’ conceptual direction and based on feedback from the authors, and was funded by AstraZeneca. A.R. is supported by National Institutes of Health grants R35 CA197633, P01 CA244118, and P30 CA016042, The Parker Institute for Cancer Immunotherapy and The Ressler Family Fund. K.M.C. is supported by the UCLA Tumor Immunology Training Grant (NIH NCI T32CA009120) and the Cancer Research Institute Postdoctoral Irvington Postdoctoral Fellowship Program.
Funding Information:
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 Astra-Zenaca, personal fees paid to institution for conduction of clinical trials from BMS, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Poly-noma, 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 Gen-eoscopy 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.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097293812&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-19810-w
DO - 10.1038/s41467-020-19810-w
M3 - Article
C2 - 33288749
AN - SCOPUS:85097293812
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6262
ER -