Atezolizumab, Vemurafenib, and Cobimetinib in Melanoma With CNS Metastases

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1. Intracranial objective response rate was 42% in the BRAF V600 mutation-positive cohort and 27% in the BRAFV600 wild-type cohort.

2. Treatment-related grade ≥ 3 adverse events occurred in 68% of the BRAF V600 mutation-positive cohort (most common being lipase increased creatine phosphokinase increased) and 53% in the BRAFV600 wild-type cohort (anemia and dermatitis acneiform).

Evidence Rating Level: 2 (Good)

Study Rundown: BRAF inhibitors, MEK inhibitors, and immune checkpoint inhibitors (ICIs) have all individually demonstrated significant response rates in patients with melanoma and central nervous system (CNS) metastases. Recent studies have suggested beneficial immunomodulatory effects with BRAF/MEK inhibition in addition to ICIs. This study assessed the safety and effectiveness of atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in melanoma patients with CNS metastases. The primary endpoint was intracranial objective response rate (ORR) and secondary endpoints included extracranial ORR, overall ORR, overall duration of response (DoR), overall progression-free survival (PFS), overall survival (OS), and safety. For the first cohort, the median follow-up was 6.2 months. The intracranial ORR was 27%, median intracranial PFS was 2.2 months. Treatment-related grade ≥3 adverse events occurred in 53% of patients, most commonly anemia (13%) and dermatitis acneiform (13%). For the second cohort, the median follow-up duration was 9.7 months. The intracranial ORR was 42%, the median intracranial DoR was 7.4 months, and the median intracranial PFS was 5.3 months. It is important to note that some patients in this cohort had symptomatic CNS metastasis which in part was treated with corticosteroids (≤8mg dexamethasone equivalent), and on post-hoc analysis both symptomatic and asymptomatic patients had similar endpoint results. Median extracranial PFS was 9.4 months, median overall PFS was 5.5, and median OS was 13.7 months. Treatment-related grade ≥3 adverse events occurred in 68% of patients with the most common being lipase increase (25%) and creatine phosphokinase increase (18%). The strength of this study included the two-cohort approach and the limitation included a lack of a control group treated with just targeted therapy. Overall, this study found that the combination of ICIs (atezolizumab) with targeted therapy (cobimetinib ± vemurafenib) demonstrated intracranial activity in patients with BRAF V600-mutated melanoma and CNS metastases and will require additional studies for confirmation.

Click to read the study in Lancet

Relevant Reading: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.

In-Depth [prospective cohort]: This multicenter, open-label, single-arm, phase 2 study investigated 2 cohorts; one cohort evaluated atezolizumab plus cobimetinib in BRAF V600 wild-type melanoma with CNS metastases (15 patients) and the other cohort evaluated atezolizumab plus vemurafenib plus cobimetinib in BRAF V600 mutation-positive melanoma with CNS metastases (65 patients). For the first cohort, the median follow-up was 6.2 months. The intracranial ORR was 27% (95%CI, 8-55), median intracranial PFS was 2.2 months (95%CI, 1.7-8.0). Treatment-related grade ≥3 adverse events occurred in 53% of patients, most commonly anemia (13%) and dermatitis acneiform (13%). For the second cohort, the median follow-up duration was 9.7 months. The intracranial ORR was 42% (95%CI, 29-54), the median intracranial DoR was 7.4 months (95%CI, 5.7-11.0), and the median intracranial PFS was 5.3 months (95%CI, 3.8-7.2). It is important to note that some patients in this cohort had symptomatic CNS metastasis which in part was treated with corticosteroids (≤8mg dexamethasone equivalent), and on post-hoc analysis both symptomatic and asymptomatic patients had similar endpoint results. Median extracranial PFS was 9.4 months (95%CI, 6.9-13.7), median overall PFS was 5.5 (95%CI, 5.1-7.4), and median OS was 13.7 months (95%CI, 9.7-19.8). Treatment-related grade ≥3 adverse events occurred in 68% of patients with the most common being lipase increase (25%) and creatine phosphokinase increase (18%). Overall, this study found that the combination of ICIs (atezolizumab) with targeted therapy (cobimetinib ± vemurafenib) demonstrated intracranial activity in patients with BRAF V600-mutated melanoma and CNS metastases which will require phase 3 data to confirm efficacy.

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