Triple Combination Active Against CNS Metastases of BRAFV600-Mutated Melanoma

Patients receiving chemotherapy
Patients receiving chemotherapy
The 3-drug strategy combines targeted therapy against BRAF (vemurafenib) and MEK (cobimetinib), and immunotherapy (atezolizumab).

The combination of atezolizumab and cobimetinib with vemurafenib has good intracranial activity in patients with BRAFV600 mutation-positive melanoma with central nervous system (CNS) metastases, according to research presented at the 2022 ASCO Annual Meeting.

Investigators reported primary results from cohort 2 of the phase 2 TRICOTEL trial ( Identifier: NCT03625141). This cohort evaluated the 3-drug combination in adult patients with stage IV BRAFV600-mutated melanoma having magnetic resonance imaging-confirmed CNS metastases that measured at least 5 mm in at least 1 dimension, including those receiving corticosteroids and/or having symptoms. To enroll, the patients could not have received any previous systemic treatment for metastatic disease.

The 3-drug strategy combines targeted therapy against BRAF (vemurafenib) and MEK (cobimetinib), and immunotherapy (atezolizumab). The patients received vemurafenib (720 mg twice daily), cobimetinib (60 mg once daily, 21 days on, 7 days off), and atezolizumab (840 mg on days 1 and 15 of each 28-day cycle from cycle 2 onward). The primary outcome was intracranial objective response rate (ORR), confirmed with assessments at least 4 weeks apart, as assessed by an independent review committee (IRC).

A total of 65 patients (median age, 55 years; 63% male) were included in cohort 2, of whom 37% were receiving corticosteroids and/or were symptomatic at baseline. The median follow-up was 9.7 months for all patients, 10.0 months for those initially receiving corticosteroids and/or symptomatic, and 9.7 months for those who were asymptomatic.

The intracranial ORR was 42% (95% CI, 29-54) as assessed by the IRC and 51% (95% CI, 38-63) as assessed by the investigator. The median intracranial duration of response (DOR) was 7.4 months (95% CI, 5.7-11.0) and 7.4 months (95% CI, 5.6-10.2), respectively.

The median intracranial progression-free survival (PFS) for all patients was 5.3 months (95% CI, 3.8-7.2) according to the IRC and 5.8 months (95% CI, 5.4-7.4) per the investigator. The 6-month intracranial PFS rate was 41% (95% CI, 28-53) and 48% (95% CI, 36-61), respectively.

Patients who were receiving corticosteroids and/or were symptomatic had an intracranial ORR of 46% (95% CI, 26-67) and a median DOR of 9.9 months (95% CI, 4.8-12.7) according to the IRC. They had an intracranial ORR of 58% (95% CI, 37-78), a median DOR of 10.2 months (95% CI, 5.6-not estimable), a median PFS of 7.2 months (95% CI, 3.8-12.0), and a 6-month PFS rate of 57% (95% CI, 36-77) per the investigator.

Among patients who were asymptomatic, the intracranial ORR was 39% (95% CI, 24-56) and the median DOR was 7.4 months (95% CI, 3.9-11.0) according to the IRC, compared with an intracranial ORR of 46% (95% CI, 31-63) and median DOR of 5.7 months (95% CI, 5.5-7.6) according to the investigator.

In the cohort as a whole, the extracranial median PFS was 9.4 months (95% CI, 6.9-13.7), and the extracranial 6-month PFS rate was 70% (95% CI, 59-82) according to the investigator. The overall median PFS was 5.5 months (95% CI, 5.1-7.6), and the 6-month PFS rate was 45% (95% CI, 33-58) per the investigator.

The full cohort’s median overall survival was 13.7 months (95% CI, 9.7-19.8), with a 6-month overall survival rate of 82% (95% CI, 72-91).

Grade 3 and 4 adverse events occurred in 42 (70%) of the 60 patients who received all 3 drugs. Adverse events led to discontinuation of any study treatment in 27% of patients.

“Particularly promising intracranial activity and durable clinical benefit were seen in symptomatic patients, a population with high unmet need,” stated the researchers. “Vemurafenib plus cobimetinib run-in may reduce need for corticosteroid use, thereby increasing benefit from subsequent addition of atezolizumab.”

Disclosure: This research was supported by F. Hoffmann-La Roche Ltd. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Dummer R, Queirolo P, Guijarro AMA, et al. Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation-positive melanoma with central nervous system (CNS) metastases (mets): primary results from phase 2 Tricotel study. Presented at ASCO 2022; June 3-7, 2022. Abstract 9515.

This article originally appeared on Cancer Therapy Advisor