As a reflection of 'on-target' effects, early on-treatment adverse events have been identified as predictors of therapeutic outcomes to several targeted medicines. This study aimed to explore the association between vemurafenib induced adverse events and response/survival in advanced melanoma patients.
A pooled secondary analysis of participants treated with first-line vemurafenib or vemurafenib plus cobimetinib in clinical trials BRIM3 (NCT01006980) and coBRIM (NCT01689519). Outcomes included overall survival (OS), progression free survival (PFS) and best overall response (BOR). Adverse effects evaluated included rash, arthralgia, photosensitivity, nausea and vomiting, diarrhoea, fatigue and pyrexia within the first four weeks of therapy. The association between early-onset adverse events and outcomes was evaluated by logistic regression for a BOR of complete or partial, and by Cox proportional hazards regression for survival outcomes. All analyses were stratified by study and treatment.
583 participants received vemurafenib monotherapy and 247 received vemurafenib plus cobimetinib. No association was apparent between the occurrence of rash, photosensitivity, nausea and vomiting, diarrhoea, fatigue and pyrexia with OS in the day 28 landmark analyses (P>0.05). Vemurafenib induced arthralgia occurring within the first 28 days of first-line vemurafenib or vemurafenib plus cobimetinib therapy was significantly associated with improved OS (HR [95%CI]: Grade 1 = 0.92 [0.73-1.16]; Grade 2+ = 0.67 [0.49-0.91]; P = 0.026), PFS (HR [95%CI]: Grade 1 = 0.80 [0.63-1.01]; Grade 2+ = 0.76 [0.57- 1.01]; P = 0.042) and BOR (OR [95%CI]: Grade 1 = 1.22 [0.83-1.80]; Grade 2+ = 1.78 [1.11-2.90]; P = 0.047).
For advanced melanoma patients treated with vemurafenib monotherapy or vemurafenib plus cobimetinib, early on-treatment arthralgia, particularly grade 2+, is associated with improved response and survival outcomes.