Cobimetinib plus vemurafenib (C+V) in patients (Pts) with solid tumors with BRAF V600E/d/k/R mutation: Results from the targeted agent and profiling utilization registry (TAPUR) study.
Authors: Meric-Bernstam Funda , Rothe Michael , Garrett-Mayer Elizabeth , Gutierrez Rodolfo , Ahn Eugene R , Cannon Timothy Lewis , Powell Steven Francis , Krauss John C. , Reynolds Christopher M. , von Mehren Margaret , Behl Deepti , Calfa Carmen Julia , Duvivier Herbert Leon , Kaplan Henry G. , Livingston Michael B. , Sharma Manish , Urba Walter John , O'Lone Raegan , Halabi Susan , Schilsky Richard L. 
Published: June 2022

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Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with solid tumors with BRAF V600E/D/K/R mutation (mut) treated with C+V are reported. Methods: Eligible pts had advanced solid tumors, no standard treatment (tx) options, measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts matched to C+V had various solid tumors with BRAF V600E/D/K/R mut, or other BRAF mut if approved by the Molecular Tumor Board, and no MAP2K1/2, MEK1/2, NRAS mut. Recommended dosing was C, 60 mg orally daily for 21 days, 7 days off and V, 960 mg orally every 12 hours. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease at 16+ wks (SD 16+) (RECIST v1.1). Low accruing histology-specific cohorts with the same genomic target and tx were collapsed into a single histology-pooled cohort for this analysis. For histology-pooled cohorts with sample size of 28, the results are evaluated based on a one-sided exact binomial test with a null DC rate of 15% vs. 35% (power = 0.84; α = 0.10) and one-sided 90% confidence interval (CI). Other efficacy endpoint estimates are presented with two-sided 95% CIs. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 31 pts with solid tumors (13 histologies; 6/31 ovarian cancer) with BRAF muts were enrolled from Dec 2016 to Jan 2021 and collapsed into one histology pooled cohort for analysis. 3 pts were not evaluable due to lack of post-baseline tumor evaluation and excluded from efficacy analyses. Demographics and outcomes are summarized in the Table. Pts had tumors with BRAF V600E mut (N = 26), G469V mut (N = 1), K601E mut (N = 2), N581I (N = 1) and T599_V600insT (N = 1). 2 CR (breast and ovarian cancer; V600E), 14 PR (13 V600E, 1 N581I), and 3 SD16+ (2 V600E, 1 T599_V600insT) were observed for a DC rate of 68% (90% CI: 54%, 100%) and an objective response (OR) rate of 57% (95% CI: 37%, 76%). CR durations were 5.1 (ovarian cancer) and 108.9 wks (breast cancer) and median duration of PR was 20.5 wks (range: 8.0, 176.0). 19 pts experienced ≥1 Grade 1-5 AE/SAE at least possibly related to tx including 1 death attributed to tx-related kidney injury. Conclusions: C+V demonstrated evidence of anti-tumor activity in pts with advanced solid tumors with BRAF V600E and other muts . Clinical trial information: NCT02693535. [Table: see text]