Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. Our objective was to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in melanoma patients with CNS metastases.
BRAFV600 the mutation-positive cohort received atezolizumab intravenously (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus cobimetinib intravenously. oral (60 mg once daily, days 1-21); atezolizumab was discontinued in cycle 1. Treatment continued until progression, toxicity, or death. The primary endpoint was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by an Independent Review Committee (IRC) using the modified response in solid tumors version 1.1. Due to the early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not performed in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analyzed in all patients who received at least one dose of study drug. This trial is closed to registration and is registered with ClinicalTrials.gov, NCT03625141.
Between December 13, 2018 and December 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 the wild-type cohort was closed early after recruiting 15 patients. The median follow-up was 9 7 months (IQR 6 3–15 0) for the BRAFV600 mutation-positive cohort and 6 2 months (3 5–23 0) for BRAFV600 wild-type cohort. The objective intracranial response rate was 42% (95% CI 29-54) as assessed by IRC in the BRAFV600 cohort of positive mutations and 27% (95% CI 8 to 55) according to the investigator’s assessment in the
BRAFV600 wild-type cohort. Grade 3 or worse treatment-related adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 cohort of positive mutations, the most common of which were increased lipase (15 [25%]
of 60 patients) and increase in blood creatine phosphokinase (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in BRAFV600 the wild-type cohort experienced grade 3 or worse treatment-related adverse events, most commonly anemia (two [13%]) and acneiform dermatitis (two [13%]). Serious treatment-related adverse events occurred in 14 (23%) of 60 patients in the BRAFV600 cohort of positive mutations and two (13%) of the 15 in the BRAFV600 wild-type cohort. A death in the BRAFV600 positive cohort for the mutation (limbic encephalitis) was considered related to atezolizumab treatment.
Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAFV600– mutated melanoma with CNS metastases.
F Hoffmann-La Roche.