1137P Incidence and time course of adverse events (AEs) with atezolizumab (A) in combination with vemurafenib (V) and cobimetinib (C) in the phase III IMspire150 study

Abstract

The phase III IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line A vs placebo (P) combined with V+C in patients (pts) with BRAFV600 mutation–positive advanced melanoma. Safety profiles of A and V+C partially overlap. Here we report incidence, time course, and outcomes of select AEs of special interest (AESIs) in IMspire150. 514 pts were randomized 1:1 to A+V+C or P+V+C. Pts received V+C from cycle 1; A or P was added from cycle 2 onward. Incidence (overall and by cycle), time to onset/resolution, and recurrence of select AESIs were evaluated in the safety population (A+V+C, n=230; P+V+C, n=281). Rash and hepatitis were analyzed as overall combined medical concepts. Median follow-up was 18.9 mo. AESI rates were numerically higher with A+V+C vs P+V+C (rash, 81% vs 77%; elevated creatine phosphokinase [eCPK], 53% vs 47%; pyrexia, 49% vs 35%; and hepatitis [clinical diagnosis and asymptomatic lab abnormalities], 53% vs 38%), excepting diarrhea (50% vs 56%). Incidences of diarrhea, rash, and eCPK were highest in cycle 1 and decreased thereafter. Incidences of pyrexia and hepatitis peaked in cycle 2 after addition of A in the A+V+C arm then similarly declined. Median time to onset was similar with A+V+C vs P+V+C for diarrhea (0.4 vs 0.4 mo) and rash (0.5 vs 0.4 mo), but was numerically longer with A+V+C for eCPK (1.4 vs 0.7 mo), pyrexia (1.2 vs 0.7 mo), and hepatitis (1.6 vs 1.2 mo). Median time to resolution was similar between arms (diarrhea, 0.3 vs 0.2 mo; rash, 0.8 vs 0.8 mo; eCPK, 0.5 vs 0.5 mo; pyrexia, 0.1 vs 0.1 mo; hepatitis, 0.7 vs 0.7 mo). In pts who had first occurrence of an AESI with A+V+C vs P+V+C, incidences of recurrent AESIs were diarrhea (58/115 vs 64/157), rash (65/187 vs 62/215), eCPK (62/121 vs 61/133), pyrexia (53/112 vs 29/98), and hepatitis (38/122 vs 25/107). Recurrent AESIs were generally grade 1/2 with median times to recurrence of 0.8-1.5 mo. These data indicate that key AESIs with A+V+C occur early during treatment; are manageable, with resolution times similar to those with V+C; and have low to moderate risk of recurrence. Recurrent AESIs are generally mild to moderate in severity with no evidence of cumulative effect.