Hauschild A, et al. - In the present exploratory analysis, researchers identified subgroups with distinct survival outcomes in patients with BRAF V600–mutated metastatic melanoma based on clinical and genomic characteristics. They also evaluated survival in identified prognostic subgroups across cohorts treated with dacarbazine, vemurafenib, or cobimetinib plus vemurafenib. In patients with BRAF V600–mutated metastatic melanoma treated with BRAF and/or MEK inhibitors, baseline lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS), disease burden, and gene signature seem to be what primarily determines survival outcomes. These outcomes were consistent with the survival benefits of cobimetinib plus vemurafenib over vemurafenib alone observed in the coBRIM study.

Methods

• Using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies, this retrospective and exploratory recursive partitioning analysis (RPA) modeled links between prespecified covariates and survival outcomes.
• Dacarbazine, vemurafenib, or cobimetinib plus vemurafenib were the assessed interventions.
• Main outcomes were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.

Results

• The RPA involved 1,365 subjects (783 men, 57.4%; 1,032 older than 65 years, 75.6%)
• Out of these, 310 received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine.
• Data reported that median follow-up was 14.1 months (interquartile range, 6.3-28.3 months).
• In the RPA that incorporated all patients, baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs) were significant prognostic factors for PFS: Median PFS was longest in subjects with lower LDH (≤2 × upper limit of normal [ULN]), ECOG PS 0, and shorter SLD (≤44 mm) (11.1 months; 95% CI, 7.0-18.4 months), and shortest in those with elevated LDH (>2 × ULN) (3.5 months; 95% CI, 3.0-3.8 months).
• The longest median OS (22.7 months; 95% CI, 20.3-27.2 months) was found in the subgroup with normal baseline LDH and no liver metastases.
• Findings revealed that similar PFS trends were observed when these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts.
• Significant prognostic factors for OS were baseline LDH, ECOG PS, and SLD: Median OS was longest in patients with normal LDH and shorter SLD (≤45 mm) (27.2 months; 95% CI, 22.1-32.1 months) and shortest in those with elevated LDH (>2 × ULN) (6.0 months; 95% CI, 5.3-6.8 months).
• It was observed that 3-year OS rates were 53.3% (95% CI, 39.5%-67.1%) in the cobimetinib plus vemurafenib cohort, 35.6% (95% CI, 27.4%-43.8%) in the vemurafenib cohort, and 35.6% (95% CI, 24.8%-46.4%) in the dacarbazine cohort among patients in the most favorable subgroup (normal LDH and SLD ≤45 mm).
• RPA identified gene signature as a significant prognostic factor for PFS in those with normal LDH; 3-year PFS rates were 21.9%, (95% CI, 15.4%-28.4%) and 8.8% (95% CI, 3.6%-14.1%) in immune and cell cycle signature, respectively among patients with available gene expression data.
• According to the RPA, gene signature was not significant factor for OS.