Atezolizumab Combination Improved Intracranial Activity in BRAF V600–Mutated Melanoma with CNS Metastases

Improved intracranial activity was observed in patients with BRAF V600–mutated melanoma with central nervous system (CNS) metastases when atezolizumab (Tecentriq) was added to a combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic), according to results from a phase 2 study (NCT03625141) published in The Lancet Oncology.

In the BRAF V600 mutation–positive cohort, the intracranial objective response rate was 42% (95% CI, 29%-54%) vs 27% (95% CI, 8%-55%) in the BRAF V600 wild-type cohort. The median follow-up was 9.7 months in the BRAF-mutant cohort and 6.2 months in the wild-type cohort.

A total of 80 patients enrolled on the trial and were given at least 1 dose of treatment, all of whom were included in the efficacy and safety analyses. A total of 65 patients were included in the BRAF-mutant cohort, 24 of whom received corticosteroids at baseline and 11 had symptomatic CNS metastases, or both. Symptomatic patients had a higher tumor burden than asymptomatic patients. Additionally, the median sum of longest intracranial target lesion diameter was 27.5 mm in the BRAF mutation cohort vs 18.0 mm in the wild-type cohort.

Investigators noted that intracranial objective response rate by independent review committee (IRC) was consistent across all subgroups. The median intracranial duration of response (DOR) was 7.4 months (95% CI, 5.7-11.0) via IRC and 7.4 months (95% CI, 5.6-10.2) by investigator assessment. Within the BRAF mutation cohort, 78% of patients had intracranial disease or death by IRC compared with 74% by investigator assessment. Additionally, the median intracranial progression-free survival (PFS) by IRC was 5.3 months (95% CI, 3.8-7.2) compared with 5.8 months (95% CI, 5.4-7.4) by investigator assessment. At baseline, those who received corticosteroids, had symptomatic metastases, or both had a median follow-up of 10.0 months vs 9.7 months for those who were asymptomatic.

For patients in the wild-type cohort, the median follow-up was 6.2 months. Progressive disease or death occurred in 80% of patients by investigator assessment and the median intracranial PFS was 2.2 months (95% CI, 1.7-8.0). The median DOR with atezolizumab was 2.0 months and 1.9 months with cobimetinib.

A total of 60% of patients in the BRAF-mutant population developed extracranial progressive disease or death, and overall disease progression or death occurred in 75%. The median extracranial PFS was 9.4 months (95% CI, 6.9-13.7) and the overall median PFS was 5.5 months (95% CI, 5.1-7.6). Death occurred in 57% of patients in the BRAF-mutant group, and the median overall survival (OS) was 13.7 months (95% CI, 9.7-19.8). Of the 24 patients who received corticosteroids or with or without symptomatic metastases at baseline, 58% died and the median OS was 16.6 months (95% CI, 9-22.7).

Among patients who received a dose of dexamethasone exceeding more than 2 mg per day (n = 11) or an equivalent corticosteroid, 6 discontinued or tapered steroid treatment during cycle 1, with 5 patients remaining on treatment during the beginning of cycle 2 at a dose of more than 2 mg per day of dexamethasone or equivalent upon starting atezolizumab.

Treatment-emergent adverse effects (AEs) of any grade occurred in 60 patients treated with the triplet regimen. Grade 3 or higher treatment-related AEs (TRAEs) occurred in 68% of patients, and the most common were lipase increase (25%), and blood creatine phosphokinase increase (17%). AEs of special interest that were grade 3 or higher commonly included pancreatitis (28%), hepatitis (20%), creatine phosphokinase elevation (17%), and rash (15%). Treatment-related serious AEs occurred in 23% of patients, with 1 treatment-related death being reported from limbic encephalitis which was related to treatment with atezolizumab. TRAEs led to discontinuation in 27% of patients, with 3% discontinuing atezolizumab because of infusion-related reactions. AEs that led to dose modifications or interruptions occurred in 87% of patients.

TRAEs of grade 3 or higher occurred in 8 patients and included anemia (13%) and dermatitis acneiform (13%). Two patients had treatment-related serious AEs, and no treatment-related deaths were reported. TRAEs led to discontinuation of treatments in 5 patients, and 2 patients discontinued cobimetinib because of dermatitis acneiform. In 12 patients, AEs led to dose modifications or interruptions.

Reference

Dummer R, Queirolo P, Abajo Guijarro AM, 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. Published online August 5, 2022. doi:10.1016/S1470-2045(22)00452-1