A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation

Ester Simeone, Giosuè Scognamiglio, Mariaelena Capone, Diana Giannarelli, Antonio M Grimaldi, Domenico Mallardo, Gabriele Madonna, Marcello Curvietto, Assunta Esposito, Fabio Sandomenico, Francesco Sabbatino, Nicholas L Bayless, Sarah Warren, SuFey Ong, Gerardo Botti, Keith T Flaherty, Soldano Ferrone, Paolo A Ascierto, Ester Simeone, Giosuè Scognamiglio, Mariaelena Capone, Diana Giannarelli, Antonio M Grimaldi, Domenico Mallardo, Gabriele Madonna, Marcello Curvietto, Assunta Esposito, Fabio Sandomenico, Francesco Sabbatino, Nicholas L Bayless, Sarah Warren, SuFey Ong, Gerardo Botti, Keith T Flaherty, Soldano Ferrone, Paolo A Ascierto

Abstract

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://ichgcp.net/clinical-trials-registry/NCT01959633.

Keywords: BRAF inhibitor; Interferon; MAP kinase; Malignant melanoma.

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Patient disposition. Group A: patients who received vemurafenib plus PEG-IFN-α-2b, group B: patients who received vemurafenib + cobimetinib + PEG-IFN-α-2b
Fig. 2
Fig. 2
Change in tumor size during the study. Group A: patients who received vemurafenib plus PEG-IFN-α-2b, group B: patients who received vemurafenib + cobimetinib + PEG-IFN-α-2b
Fig. 3
Fig. 3
Tumor response during study treatment according to baseline staging. a patients who received vemurafenib plus PEG-IFN-α-2b (patients 1 and 3 had durable response); b patients who received vemurafenib + cobimetinib + PEG-IFN-α-2b (patient 1 had durable response). CR: complete response, DP: disease progression, PR: partial response, SD: stable disease
Fig. 4
Fig. 4
Proportion of IFNAR1-positive cells in tumor samples, in the immunohistochemical analysis
Fig. 5
Fig. 5
PFS (a) and OS (b) according to the proportion of IFNAR1-positive cells in pretreatment specimens
Fig. 6
Fig. 6
Differential gene expression by Nanostring. a Pretreatment: Responders vs. non-responders. b Post-treatment vs. pretreatment in responders

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