Modeled Prognostic Subgroups for Survival and Treatment Outcomes in BRAF V600–Mutated Metastatic Melanoma
August 13, 2018
Key Points
Question What are the clinical and genomic factors associated with survival outcomes in patients with BRAF V600–mutated metastatic melanoma treated with BRAF and/or MEK inhibitors?
Findings In this exploratory recursive partitioning analysis, which modeled associations between prespecified covariates and survival outcomes in 1365 patients, baseline lactate dehydrogenase level, performance status, disease burden, and gene signature were associated with survival outcomes in BRAF V600–mutated metastatic melanoma. Cobimetinib plus vemurafenib provided survival advantages over vemurafenib monotherapy across all prognostic subgroups.
Meaning The results of this analysis provide a framework that may be used to compare treatment outcomes for patients with metastatic melanoma across trials and regimens and may aid in clinical decision making for individual patients.
Abstract
Importance Prognostic models may provide insight into clinical trial results and inform the clinical management of patients with BRAF V600–mutated metastatic melanoma.
Objective To identify subgroups with distinct survival outcomes based on clinical and genomic characteristics and to assess survival in identified prognostic subgroups across cohorts treated with dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.
Design, Setting, and Participants This retrospective and exploratory recursive partitioning analysis (RPA) modeled associations between prespecified covariates and survival outcomes using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies.
Interventions Dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.
Main Outcomes and Measures Progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.
Results The RPA included 1365 patients (783 men; 57.4%). Of these, 1032 (75.6%) were older than 65 years; 310 received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine. Median follow-up was 14.1 months (interquartile range, 6.3-28.3 months). In the RPA that included 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 patients 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 subgroup with normal baseline LDH and no liver metastases had the longest median OS (22.7 months; 95% CI, 20.3-27.2 months). Similar PFS trends were observed when these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts. Baseline LDH, ECOG PS, and SLD were significant prognostic factors for OS: 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). Among patients in the most favorable subgroup (normal LDH and SLD ≤45 mm), 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 with available gene expression data, 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. The RPA for OS did not identify gene signature as a significant factor.
Conclusions and Relevance Baseline LDH, ECOG PS, disease burden, and gene signature appear to be key determinants of survival outcomes in patients with BRAF V600–mutated metastatic melanoma treated with BRAF and/or MEK inhibitors. These results are consistent with survival benefits of cobimetinib plus vemurafenib over vemurafenib alone observed in the coBRIM study.
Source:
Hauschild A, Larkin J, Ribas A, et al. Modeled Prognostic Subgroups for Survival and Treatment Outcomes in BRAF V600–Mutated Metastatic MelanomaPooled Analysis of 4 Randomized Clinical Trials. JAMA Oncol. Published online August 02, 2018. doi:10.1001/jamaoncol.2018.2668