A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation
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 therapeuti...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-01-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-020-02680-7 |
| _version_ | 1818411116505595904 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ester Simeone |
| collection | DOAJ |
| description | 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://clinicaltrials.gov/ct2/show/NCT01959633 |
| first_indexed | 2024-12-14T10:26:18Z |
| format | Article |
| id | doaj.art-86e55258d57a4fdc9a2470824a69f5e9 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-14T10:26:18Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-86e55258d57a4fdc9a2470824a69f5e92022-12-21T23:06:19ZengBMCJournal of Translational Medicine1479-58762021-01-0119111010.1186/s12967-020-02680-7A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutationEster Simeone0Giosuè Scognamiglio1Mariaelena Capone2Diana Giannarelli3Antonio M. Grimaldi4Domenico Mallardo5Gabriele Madonna6Marcello Curvietto7Assunta Esposito8Fabio Sandomenico9Francesco Sabbatino10Nicholas L. Bayless11Sarah Warren12SuFey Ong13Gerardo Botti14Keith T. Flaherty15Soldano Ferrone16Paolo A. Ascierto17Istituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori Regina Elena, IRCCSIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleOncology Unit, AOU San Giovanni Di Dio E Ruggi D’AragonaParker Institute for Cancer ImmunotherapyNanoString TechnologiesNanoString TechnologiesIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleMassachusetts General Hospital Cancer CenterMassachusetts General Hospital Cancer CenterIstituto Nazionale Tumori–IRCCS–Fondazione G PascaleAbstract 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/NCT01959633https://doi.org/10.1186/s12967-020-02680-7Malignant melanomaBRAF inhibitorMAP kinaseInterferon |
| spellingShingle | 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 A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation Journal of Translational Medicine Malignant melanoma BRAF inhibitor MAP kinase Interferon |
| title | A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation |
| title_full | A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation |
| title_fullStr | A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation |
| title_full_unstemmed | A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation |
| title_short | A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation |
| title_sort | monocentric phase i study of vemurafenib plus cobimetinib plus peg interferon vemuplint in advanced melanoma patients harboring the v600braf mutation |
| topic | Malignant melanoma BRAF inhibitor MAP kinase Interferon |
| url | https://doi.org/10.1186/s12967-020-02680-7 |
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