In the phase II TRICOTEL study reported in The Lancet Oncology, Reinhard Dummer, MD, and colleagues found that the combination of atezolizumab plus vemurafenib and cobimetinib produced durable intracranial responses in patients with BRAF V600–mutated melanoma and central nervous system (CNS) metastases. 

Reinhard Dummer, MD

Study Details

In the trial, patients from sites in seven countries were enrolled between December 2018 and December 2020 into either a BRAF V600 wild-type cohort or a BRAF V600 mutation–positive cohort. The wild-type cohort received atezolizumab at 840 mg on days 1 and 15 of each 28-day cycle plus cobimetinib at 60 mg once daily on days 1 to 21. The mutation-positive cohort received atezolizumab at the same dosage, vemurafenib at 720 mg twice daily, and cobimetinib at the same dosage in 28-day cycles, with atezolizumab withheld in cycle 1.

The wild-type cohort was closed after enrollment of 15 patients following primary analysis of the phase III IMspire170 study; the study showed no improvement in progression-free survival with atezolizumab/cobimetinib vs pembrolizumab in BRAF V600 wild-type advanced melanoma. A total of 65 patients were enrolled in the mutation-positive cohort (5 did not receive atezolizumab).

The primary endpoint was intracranial objective response rate on independent review committee (IRC) assessment confirmed by assessments at least 4 weeks apart. Due to closure of the wild-type cohort, responses were per investigator assessment.  

Intracranial Response Rates

Median follow-up was 9.7 months (interquartile range [IQR] = 6.3–15.0 months) in the mutation-positive cohort and 6.2 months (IQR = 3.5–23.0 months) in the wild-type cohort.

Intracranial objective response on IRC assessment was observed in 27 (42%, 95% confidence interval [CI] = 29%–54%) of 65 patients in the mutation-positive cohort, with complete response seen in 4 patients (6%). An additional 18 patients (28%) had stable disease. Median duration of intracranial response was 7.4 months (95% CI = 5.7–11.0 months). Median intracranial progression-free survival was 5.3 months (95% CI = 3.8–7.2 months).

Objective response on investigator assessment was observed in 4 (27%, 95% CI = 8%–55%) of 15 patients in the wild-type cohort. Median intracranial progression-free survival was 2.2 months (95% CI = 1.7–8.0 months).

Adverse Events

In the mutation-positive cohort, five patients did not receive atezolizumab. Among the 60 receiving all three drugs, treatment-related grade ≥ 3 adverse events occurred in 41 patients (68%), most commonly increased lipase (25%) and increased blood creatine phosphokinase (17%). Grade ≥ 3 adverse events of special interest occurred in 58%, most commonly pancreatitis (28%), hepatitis (20%), creatine phosphokinase elevation (17%), and rash (15%).

Serous retinopathy of any grade occurred in 28%. Treatment-related serious adverse events occurred in 23%, with none occurring in more than one patient. Treatment-related adverse events led to discontinuation of any study treatment in 27%. One treatment-related death was reported (due to limbic encephalitis).

The investigators concluded, “Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAF V600–mutated melanoma with CNS metastases.”

Dr. Dummer, of the Skin Cancer Center, University Hospital Zurich, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit thelancet.com.