Atezolizumab Triplet Induces Intracranial Responses in BRAF V600-Mutated Metastatic Melanoma

In patients with BRAF V600-mutated melanoma and central nervous system metastases, treatment with atezolizumab to vemurafenib plus cobimetinib achieved a good intracranial overall response rate. Responses were all achieved with the combination in patients with BRAF wild-type tumors.

The addition of atezolizumab (Tecentriq) to vemurafenib (Zelboraf) plus cobimetinib (Cotellic) for the treatment of patients with BRAF V600-mutated melanoma demonstrated promising intracranial activity in the phase 2 TRICOTEL clinical trial (NCT03625141).

At a median follow-up of 9.7 months (interquartile range, 6.3-15.0 months) the intracranial objective response rate shown in the 65 patients who were BRAF V600 mutation-positive was 42% (95% CI, 29%-54%) by independent review committee (IRC). In the BRAF V600 wild-type cohort of 15 patients, the intracranial ORR was 27% (95% CI, 8%-55%).

“Results of our study showed promising intracranial activity with atezolizumab plus vemurafenib plus cobimetinib in patients with BRAF V600-mutated melanoma with CNS metastases under daily practice co-medications. To our knowledge, TRICOTEL is the first study to report intracranial activity with combined immunotherapy and targeted therapy in patients who were receiving corticosteroids, had symptomatic CNS metastases, or both,” wrote the study author led by Reinhard Dummer, MD, vice director, Department of Dermatology, director CCCZ Clinical Trials Comprehensive Cancer Center Zurich, head of Skin tumour centre, and Chair Expert Group on Immunoncology at Universitats Spitla Zurich.

TRICOTEL was a multicenter, open-label, single-arm, study of patients 18 years of age or older with previously untreated metastatic melanoma, a central nervous system (CNS) metastases that were 5 mm or larger, and an ECOG performance status of previously untreated metastatic melanoma, CNS 2 or lower.

Patients were assigned to a treatment arm based on their mutational status. Patients with a BRAF V600 mutation-positive tumor received atezolizumab administered intravenously (IV) at 840 mg on days 1 and 15 of each 28-day cycle in combination with oral vemurafenib at 720 mg twice daily plus oral cobimetinib at 60 mg once daily on days 1-21. Atezolizumab was withheld during cycle 1 for the BRAF V600 mutation-positive group. In the BRAF V600 wild-type group, patients received IV atezolizumab at 840 mg on days 1 and 15 of each 28-day cycle plus oral cobimetinib at 60 mg once daily on days 1-21. All treatment in the study was continued until disease progression, toxicity, or death.

The TRICOTEL trial assessed the primary end point of intracranial ORR. The secondary efficacy end points evaluated were extracranial ORR, overall ORR, progression-free survival, duration of response, disease control rate (DCR), and overall survival. Time to cognitive symptom deterioration, time to symptom and function deterioration, duration of stable/improved health-related quality of life, occurrence and severity of adverse event, the number of patients with a change from baseline in targeted vital signs, and the number of patients reporting change from baseline in targeted lab values were analyzed as secondary safety end points.

At baseline, the study population had a median age of 55 years (range 45-65 years) in the BRAF V600 mutation-positive cohort and 63 years (range 51-72 years) in the BRAF wild-type cohort. Patients in the BRAF V600 mutation-positive cohort were predominantly male (63%). In the BRAF wild-type cohort, patients were predominantly female. The majority of patients were White.

The BRAF wild-type cohort was discontinued after 15 patients were evaluated for intracranial ORR.

Intracranial ORR by IRC in the BRAF V600 mutation-positive cohort included complete response in 6% of patients, partial response in 35%, stable disease in 28%, non-complete response or progressive disease in 5%, and progressive disease in 20%. The DCR at 16 weeks was 38% (95% CI, 27%-61%). The median DOR was 7.4 months (95% CI, 5.7-11.0 months).

Regarding secondary end points in the study, DFS, and DOR were consistent between the 2 cohorts. However, there was a difference between the cohort in terms of extracranial progressive disease or death. Extracranial progressive was observed in 60% of the 65 patients with progressive disease in overall disease or death. The median intracranial PFS was 5.8 months (95% CI, 5.4-7.4 months), and the median extracranial PFS was 9.4 months (95% CI, 6.9-13.7 months). The median overall PFS was 5.5 months (95% CI, 5.1-7.6 months).

Safety-wise, treatment-related grade 3 or higher adverse events occurred in (68%) of those treated with atezolizumab plus vemurafenib plus cobimetinib in the BRAF V600 mutation-positive cohort. The most common TRAEs were in the cohort were lipase increased (25%) and blood creatine phosphokinase increased (17%). In the BRAF wild-type arm, the most common TRAEs were anemia (13%) and dermatitis acneiform (13%). Serious TRAE were observed in 23% of the BRAF V600 mutation-positive cohort compared with 13% of the BRAF wild-type arm. There was 1 death in the BRAF V600 mutation-positive cohort that resulted from limbic encephalitis associated with atezolizumab treatment.

“Triplet combination therapy with atezolizumab plus vemurafenib plus cobimetinib provided clinically meaningful intracranial activity in patients with BRAFV600-mutated melanoma and symptomatic CNS metastases, suggesting that the combination is beneficial in this population who have limited clinical benefit with currently available treatment options. Randomized studies are needed to determine the benefit of triplet combination over targeted therapy alone,” wrote Dummer et al.

REFERENCE:

Dummer R, Querirolo P, Guijarro A, et al. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2022;23(9):1145-1155. doi: 10.1016/S1470-2045(22)00452-1