Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management

Abstract

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenibþbinimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. R e s u l t s : T h e s a f e t y p o p u l a t i o n i n c l u d e d a t o t a l o f 5 7 0 p a t i e n t s (encorafenibþbinimetinib Z 192; encorafenib Z 192; vemurafenib Z 186). Median duration of exposure was longer with encorafenibþbinimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenibþbinimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenibþbinimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenibþbinimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenibþbinimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenibþbinimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenibþbinimetinib because of this event. Conclusion: Encorafenibþbinimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

Severe pyrexia from nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib

“…Among the AE, the largest difference between these combined therapies was observed for pyrexia. Indeed, the incidence of pyrexia was lower with E + B combined therapy than with D + T combined therapy (18% vs 52%) 1,2 . Notably, except for one patient, a clinical study on E + B combined therapy did not include patients who were pretreated with anti‐PD‐1 antibody, 2 suggesting the different immunological background in advanced melanoma patients between a clinical study and the actual clinical setting.…”

“…As several clinical studies have suggested, the subtypes of serious AE differed between BRAF inhibitor monotherapy and BRAF plus MEK inhibitor combined therapy 1,2,4,11 . The incidence of severe pyrexia, chills, diarrhea and vomiting that may be caused by MEK inhibitors was higher with combined therapy than with BRAF inhibitor monotherapy 11 .…”

“…The incidence of severe pyrexia, chills, diarrhea and vomiting that may be caused by MEK inhibitors was higher with combined therapy than with BRAF inhibitor monotherapy 11 . Moreover, the subtypes of AE differed between D + T and E + B combined therapies 1,2 . Among the AE, the largest difference between these combined therapies was observed for pyrexia.…”

“…Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen‐activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors 1,2 . For example, the incidence of pyrexia was higher in dabrafenib plus trametinib combined therapy (D + T) (52%) 2 than in encorafenib plus binimetinib (E + B) combined therapy (18%), 1 whereas a high frequency of serous retinitis was observed in patients on E + B combination therapy 1 . Previous reports have suggested that the differences in the AE among the BRAF/MEK inhibitors were, at least in part, caused by immunomodulatory effects 3 …”

Case of inflammatory arthritis induced by encorafenib and binimetinib in a patient with melanoma

“…Although arthralgia is a common adverse event associated with encorafenib and binimetinib, arthritis has yet to be reported. 1 I describe a case of inflammatory arthritis induced by encorafenib and binimetinib, which has not been observed with other BRAF/MEK inhibitors (dabrafenib and trametinib).…”