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.

9515 Background: Despite recent advances in the treatment of melanoma, there remains an urgent need to improve outcomes in pts with CNS mets. To date, studies evaluating intracranial activity of immunotherapies and targeted therapies have included limited numbers of pts with symptomatic CNS mets. Cohort 2 of the phase 2 Tricotel study evaluated the safety and efficacy of A + C + V in BRAFV600-mutated melanoma with CNS mets, including symptomatic pts receiving corticosteroids. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Primary outcome was intracranial objective response rate (ORR; confirmed by assessments ≥4 wk apart per independent review committee [IRC]). Secondary end points were investigator-assessed intracranial ORR, extracranial ORR, overall ORR, duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Prespecified subgroup analyses were performed in pts receiving corticosteroids (>2 mg/d dexamethasone) and/or with CNS-related symptoms at baseline vs asymptomatic pts. Results: This study enrolled 65 pts (median age, 55 y; 63% male). At baseline, 37% were on corticosteroids and/or were symptomatic; 49% had elevated lactate dehydrogenase. Median follow-up was 9.7 mo for all pts, 10.0 mo for pts on corticosteroids and/or symptomatic at baseline (n = 24), and 9.7 mo for asymptomatic pts (n = 41). Intracranial ORR was 42% by IRC and 51% by investigator (BOR concordance: 68%). Intracranial DOR and PFS are listed in the Table. In pts on corticosteroids and/or symptomatic at baseline, ORR was 58%, DOR was 10.2 mo, and PFS was 7.2 mo by investigator; in asymptomatic pts, ORR was 46%, DOR was 5.7 mo, and PFS was 5.5 mo. Additional secondary efficacy end points will be presented. In 60 pts who received A + C + V, grade 3/4 adverse events (AEs) occurred in 70% of pts; most commonly lipase increased (27%) and blood CPK increased (17%). Serious AEs occurred in 30% of pts. AEs led to discontinuation of any study treatment in 27% of pts. Conclusions: Addition of A to C + V provides promising intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets, particularly in those receiving corticosteroids and/or in symptomatic pts. The safety profile of A + C + V is consistent with that observed in the IMspire150 study. Clinical trial information: NCT03625141. [Table: see text]