Abstract
BackgroundWe sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.MethodsRecursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.ResultsRPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3–16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8–2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.ConclusionA combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment.Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).
Highlights
We sought to identify patient subgroups with distinct postprogression overall survival outcomes and investigate the impact of original treatment assignment and initial postprogression treatment on ppOS
Recent analyses suggest that lactate dehydrogenase (LDH) remains the most important prognostic factor for survival in patients treated with BRAF inhibitor (BRAFi) and/or MEK inhibitor (MEKi) or immunotherapy, with poor outcomes being observed in patients with LDH elevated > 2 × upper limit of normal (ULN) [15,16,17,18]
ECOG Eastern Cooperative Oncology Group performance status (PS) at the time of progressive disease (PD) was prognostic for ppOS among patients with normal baseline LDH, baseline disease stage M1c, and initial Postprogression treatment (ppRx) other than immune/targeted therapy
Summary
We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS. Extended follow-up of clinical studies evaluating BRAF inhibitor (BRAFi) monotherapy or combined BRAFi and MEK inhibitor (MEKi) shows a plateau in overall survival (OS) curves after approximately 3 years [8,9,10,11]. A similar plateau in OS is observed with ipilimumab [12] These observations suggest that a subgroup of patients with metastatic melanoma have good long-term survival prognosis. The impact on survival outcomes of clinical and disease-related variables and treatment following progression are poorly understood. Insight into the impact of clinical characteristics and subsequent treatment on survival following progressive disease (PD) may inform treatment decisions in the management of patients with metastatic melanoma
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