A revised report of findings from the phase II TRICOTEL study of atezolizumab, vemurafenib, and cobimetinib in patients with melanoma and central nervous system (CNS) metastases was published in The Lancet Oncology by Reinhard Dummer, MD, and colleagues. The first version of trial findings, published online in August 2022, was retracted. In the modified report, the study continued to show that the triplet demonstrated intracranial activity in this patient population.
As stated by the editors of The Lancet Oncology, “[We] republish a corrected version along with a revised appendix, in which the findings have changed—for example, the intracranial response rate for patients with symptomatic CNS metastases, a post-hoc subgroup analysis, is lower than previously reported and thus the combination of atezolizumab, vemurafenib, and cobimetinib no longer appears to provide substantially improved efficacy over targeted therapy alone in this subset of patients. Of note, however, the primary endpoint has not changed and the overall message of the paper is broadly similar to the previous version.”
Reinhard Dummer, MD
Study Details
In the trial, previously untreated patients with metastatic melanoma and brain metastases of ≥ 5 mm in at least one dimension were enrolled from sites in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland between December 2018 and December 2020. A total of 65 patients were enrolled in a BRAF V600 mutation–positive cohort; a BRAF V600 wild-type cohort was closed early after enrollment of 15 patients (following primary analysis of the phase III IMspire170 study of cobimetinib plus atezolizumab in BRAF V600 wild-type melanoma).
Patients in the BRAF V600 mutation–positive cohort received atezolizumab at 840 mg on days 1 and 15 of each 28-day cycle (withheld in cycle 1) plus vemurafenib at 720 mg twice daily and cobimetinib at 60 mg once daily on days 1 to 21. Patients in the BRAF V600 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.
Treatment was continued until disease progression or unacceptable toxicity. The primary outcome measure was intracranial objective response rate on independent review committee (IRC) assessment in the BRAF V600 mutation–positive cohort and on investigator assessment in the BRAF V600 wild-type cohort.
Key Findings
Median follow-up was 9.7 months (interquartile range [IQR] = 6.3–15.0 months) in the BRAF V600 mutation–positive cohort. Intracranial objective response was observed in 27 patients (42%, 95% confidence interval [CI] = 29%–54%) by IRC assessment, including complete response in 4 (6%). Median duration of response was 7.4 months (95% CI = 5.7–11.0 months). In post hoc analysis including 26 patients with symptomatic CNS metastases, intracranial objective response was observed in 9 (35%, 95% CI = 17%–56%). Median intracranial progression-free survival was 5.3 months (95% CI = 3.8–7.2 months).
Median follow-up was 6.2 months (IQR = 3.5–23.0 months) in the BRAF V600 wild-type cohort. Intracranial objective response on investigator assessment was observed in four patients (27%, 95% CI = 8%–55%). Median intracranial progression-free survival was 2.2 months (95% CI = 1.7–8.0 months).
Treatment-related grade ≥ 3 adverse events occurred in 68% of patients in the BRAF V600 mutation–positive cohort, most commonly increased lipase (25%) and increased creatine phosphokinase (18%), and in 53% of patients in the BRAF V600 wild-type cohort, most commonly anemia (13%) and dermatitis acneiform (13%). Treatment-related serious adverse events occurred in 23% and 13% of patients. No treatment-related deaths were observed.
The investigators concluded, “Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAF V600-mutated melanoma with CNS metastases.”
Dr. Dummer, of the Department of Dermatology, 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.
