Hauschild A, et al. - Researchers assessed subgroups with distinct survival outcomes 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, the key determinants of survival outcomes included baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS) score, disease burden, and gene signature. Findings suggested consistency of these results with survival benefits of cobimetinib plus vemurafenib vs vemurafenib alone.

Methods

• In this retrospective and exploratory recursive partitioning analysis (RPA), authors modeled correlations between prespecified covariates and survival outcomes using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies.
• The interventions included dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.
• Main outcomes and measures included the progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.

Results

• A total of 1,365 patients (783 men; 57.4%) were included in the RPA.
• Of these patients, 1,032 (75.6%) were older than 65 years of age; 310 received cobimetinib plus vemurafenib; 717 received vemurafenib monotherapy; and 338 received dacarbazine.
• The median follow-up was 14.1 months.
• In the RPA that included all patients, significant prognostic factors for PFS were baseline LDH level, ECOG PS score, presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs).
• Median PFS was longest in those with lower LDH levels, an ECOG PS score of 0, and a shorter SLD; median PFS was shortest in those with elevated LDH levels.
• The longest median OS (22.7 months) was observed in the subgroup with normal baseline LDH levels and no liver metastases.
• When these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts, similar PFS trends were observed.
• The significant prognostic factors for OS were baseline LDH level, ECOG PS score, and SLD.
• Median OS was longest in patients with normal LDH levels and shorter SLD, and shortest in those with elevated LDH levels.
• Findings suggested that, among patients in the most favorable subgroup (normal LDH and SLD ≤ 45 mm), 3-year OS rates were 53.3% in the cobimetinib plus vemurafenib cohort, 35.6% in the vemurafenib cohort, and 35.6% in the dacarbazine cohort.
• Among patients with available gene expression data, in those with normal LDH, gene signature was identified by RPA as a significant prognostic factor for PFS; 3-year PFS rates were 21.9% and 8.8% in immune and cell cycle signature, respectively.
• Gene signature was not identified as a significant factor by RPA for OS.