TY - JOUR
T1 - A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation
AU - Simeone, Ester
AU - Scognamiglio, Giosuè
AU - Capone, Mariaelena
AU - Giannarelli, Diana
AU - Grimaldi, Antonio M.
AU - Mallardo, Domenico
AU - Madonna, Gabriele
AU - Curvietto, Marcello
AU - Esposito, Assunta
AU - Sandomenico, Fabio
AU - Sabbatino, Francesco
AU - Bayless, Nicholas L.
AU - Warren, Sarah
AU - Ong, Su Fey
AU - Botti, Gerardo
AU - Flaherty, Keith T.
AU - Ferrone, Soldano
AU - Ascierto, Paolo A.
N1 - Funding Information:
We thank the Data Safety Monitoring Committee and Clinical Research Technology S.r.l. for their contribution in the approval and conduction of the trial. A special thanks to the patients and their families for allowing the study to be conducted. Editorial assistance was provided by Laura Brogelli, M.D., Luca Giacomelli, PhD, and Aashni Shah (Polistudium SRL, Milan, Italy). This assistance was supported by internal funds.
Funding Information:
The study was supported by Roche S.p.a which provided fund and investigational drugs, and supported in part by providing the research drug from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The nCounter analysis was supported by NanoString Technologies, Seattle, WA. This work was also supported by Grants from Italian Ministry of Health (IT-MOH) through “Ricerca Corrente”. GS and GM have been funded by Institutional “Ricerca Corrente”.
Funding Information:
E. Simeone received honoraria from Bristol Myers Squibb, Novartis and Merck Sharp & Dohme. The other authors declare no potential competing interests. A.M.Grimaldi has/had an advisory and consultant role Bristol Myers Squibb, Merck Sharp & Dohme and Novartis. He received travel support from Bristol Myers Squibb, Merck Serono, Pierre Fabre, Roche-Genentech and Novartis. S Warren and S. Ong are/were employees and stockholders in NanoString Technologies. K.T. Flaherty served(s) on the Board of Directors of Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, and Loxo Oncology; Corporate Advisory Board of X4 Pharmaceuticals; Scientific Advisory Boards of PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, and consultant to Lilly, Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, and Debiopharm; as well as research funding from Novartis and Sanofi. P.A. Ascierto has/had a consultant/advisory role for Bristol Myer Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim. He also received research funds from Bristol Myers-Squibb, Roche-Genentech, Array, and travel support from MSD.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - Background: Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. Patients and methods: In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). Results: Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6–18.4 months) and a median overall survival of 31.0 months (range: 19.8–42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0–8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. Conclusion: Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. Trial registration: The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.
AB - Background: Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. Patients and methods: In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). Results: Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6–18.4 months) and a median overall survival of 31.0 months (range: 19.8–42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0–8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. Conclusion: Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. Trial registration: The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.
KW - BRAF inhibitor
KW - Interferon
KW - Malignant melanoma
KW - MAP kinase
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U2 - 10.1186/s12967-020-02680-7
DO - 10.1186/s12967-020-02680-7
M3 - Article
AN - SCOPUS:85098753878
VL - 19
JO - Journal of Translational Medicine
JF - Journal of Translational Medicine
SN - 1479-5876
IS - 1
M1 - 17
ER -