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 (ClinicalTrials.gov 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.