Durable Response to Vemurafenib and Cobimetinib for the Treatment of BRAF-Mutated Metastatic Melanoma in Routine Clinical Practice

Abstract

Background:The combination of BRAF and MEK inhibitors delays the onset of resistance and provides more sustained and dramatic responses in comparison with a BRAF inhibitor in monotherapy. The objective of the study was to evaluate the effectiveness of the combination therapy with vemurafenib/cobimetinib in terms of durability, and to describe differential characteristics in patients associated to durable responses in real-world settings. Patients and Methods: Retrospective, observational, cross-sectional, multicenter study involving 41 patients with advanced melanoma harboring a BRAF V600 mutation who initiated a combination therapy with vemurafenib/cobimetinib between May 2018 and March 2019. Participants were differentiated regarding the durability of the response: durable (complete response, CR, or a partial response, PR, for at least 12 months) and non-durable (stable disease, SD, progressive disease, PD, or CR/PR <12 months). Secondary endpoints included treatment adherence, labor productivity, anxiety/depression, and safety profile. Results: During the combination therapy, 12 patients (29.3%) had a CR, 19 a PR (46.3%), 5 showed SD (12.2%), and 5 had PD. A total of 12 patients (29.3%) were considered as achieving a durable response and 29 (70.7%) as a non-durable one. Practically all sociodemographic and clinical characteristics were similar between patients. Body mass index was the only differential factor (with higher body mass index achieving a non-durable response). The treatment adherence was 100% in patients with durable response and 66.7% in those with non-durable. Conclusion:The combination treatment with vemurafenib/cobimetinib results in an important impact on long-term survival, leading to a steady CR in one-third of the patients.

Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches

“…A total of 12 patients (29.3%) were thought to have received a durable response, while 29 patients (70.7%) received a non-durable response. One-third of the participants experienced a stable complete response as a result of using cobimetinib and vemurafenib in combination, which has a significant influence on long-term survival [291].…”

The future of targeted kinase inhibitors in melanoma

“…Although most patients respond to BRAF inhibitor plus MEK inhibitor combination therapy upfront (~70% objective response rates), long-term PFS following treatment only occurs in a subset of patients (5-year PFS rates are 14% with vemurafenib plus cobimetinib, 19% with dabrafenib plus trametinib, and 22.9% with encorafenib plus binimetinib) ( Ascierto et al, 2021 ; Dummer et al, 2021 ; Robert et al, 2019 ), and tumors often recur within months ( Álamo et al, 2021 ). In particular, worse PFS and OS on combined BRAF inhibitor plus MEK inhibitor therapy is associated with a high baseline lactate dehydrogenase serum level and an increased number of metastatic tumor sites ( Dummer et al, 2021 ; Hauschild et al, 2018 ; Saiag et al, 2021 ).…”

Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma

“…One main reason for the high death rate associated with melanoma is its highly aggressive and metastatic nature ( Shain and Bastian 2016 ). Current therapeutic options for stage III and IV metastatic melanoma consist of immunotherapy (anti-PD-1 alone or in combination with anti-CTLA-4) or, for BRAF mutated melanomas, BRAF inhibitors (BRAFis) combined with MEK inhibitors (MEKis) ( Álamo et al 2021 ; Garbe et al 2022 ). Although the 5-yr overall survival rate has improved thanks to these therapies, a significant number of patients do not benefit from them due to innate or acquired resistance ( Czarnecka et al 2020 ), generating a dire need for new treatments.…”