Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study

Abstract

Cobimetinib combined with vemurafenib was available in France in 2015 through a ‘Temporary Authorization for Use’ program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5–20.7). Brain metastasis (P < 0.001), ECOG index ≥2 (P = 0.007), and hepatic impairment (P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2–8.4). ECOG index ≥2 (P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Long-Term Real-World Outcomes and Safety of Vemurafenib and Vemurafenib + Cobimetinib Therapy in Patients with BRAF-Mutated Melanoma

“…Our data confirmed previous observations from the pooled analysis of BRIM-2, BRIM-3, BRIM-7, and coBRIM clinical trials on the prognostic significance of LDH level and performance status (ECOG) for OS and data from the real-world MELANIS study, where in addition to the above-mentioned, OS was influenced by the presence of brain metastases [ 12 , 18 ]. Performing multivariate Cox analysis, we identified clinical baseline parameters which predict therapy outcomes.…”

“…The mOS of non-co-BRIM-like patients was shorter than that of co-BRIM-like patients (14.7 months vs 25.4 months, respectively), but there were practically no differences in mPFS (7.2 months vs 7.7 months). However, the small size of the co-BRIM-like group (47 patients) and the heterogeneity of the population (51.4% received previous systemic treatment) make it impossible to clearly interpret the results of this study [ 12 ]. Likewise, Ismail et al, in a large analysis (435 patients) conducted on a real-world Dutch population treated with first-line BRAFi and MEKi (D+T 86% and V + C 14%), divided patients according to the inclusion criteria for the COMBI-d study into trial eligible and ineligible.…”

“…Whereas in the MELANIS early access program group of patients treated with V + C, differences in achieved PFS and OS were observed depending on the presence or absence of brain metastases, normal versus elevated LDH, and ECOG PS < 2 versus ECOG PS 2. However, the independent negative prognostic factors for OS were the presence of brain metastases, ECOG PS 2 status, and liver impairment, while for PFS only the ECOG PS ≥ 2 was relevant [ 12 ]. At the same time, the Dermatologic Cooperative Oncology Group conducted a multicenter retrospective study to identify patient and pretreatment characteristics associated with the results of vemurafenib therapy.…”

“…Also, 95% confidence intervals (CI) were reported. Differences were considered statistically significant if the p -values were < 0.05 [ 12 ]. Analysis was performed with Statistica software version 13.3.…”

COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma

“…For reports on dabrafenib plus trametinib, we identified a French phase IIIB early access program (EAP) in 856 patients [ 23 ], a Dutch population study using data from a prospectively planned registry describing outcomes of 435 first-line patients [ 24 ], and a small Japanese post-marketing surveillance study [ 25 ]. For the combination of vemurafenib plus cobimetinib, only one completely published non-retrospective real-world study report from France was identified [ 26 ]. Apart from these prospective non-interventional studies, a number of retrospective studies and case series were published; however, due to the known constraints of retrospective studies, we refer in this discussion to the few published real-world and the previously cited confirmative trials on BRAF/MEK inhibition.…”