Nivolumab plus ipilimumab (N+I) in patients (pts) with colorectal cancer (CRC) with high tumor mutational burden (hTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

107 Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with hTMB treated with N+I are reported. Methods: Eligible pts had advanced CRC, no available standard treatment options, measurable disease, ECOG performance status (PS) 0-2, adequate organ function and no prior immune checkpoint inhibitor treatment. PDL-1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. hTMB was defined a priori as ≥9 mutations/megabase (Muts/Mb) reported by a FoundationOne test (n=7) or other tests (n=5) if approved by the Molecular Tumor Board. Pts received N 1 mg/kg IV every 3 weeks (wks) for 4 doses in combination with I 3 mg/kg every 3 wks for 4 doses. N was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response, or stable disease at 16+ wks (SD 16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, the study stops for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 12 pts (9 male) with CRC with hTMB in tissue biopsy were enrolled from February 2018 to May 2020; 2 pts were not evaluable and excluded from efficacy analyses. All pts were evaluated for toxicity. TMB ranged from 9 to 233 Muts/Mb (median 13). Demographics and outcomes are summarized in the table below. Tumor microsatellite (MS) status was reported stable for 11 pts and indeterminate for 1 pt. 1 PR (88.1 wks duration, tumor 11 Muts/Mb, MS stable, PDL-1 expression not reported, KRAS mutant) and 0 pts with SD16+ were observed for a DC and OR rate of 10% (95% CI: 0%, 45%); the null DC rate of 15% was not rejected (p=0.80) and the cohort closed due to futility. 4 pts had at least one grade 3-4 adverse or serious adverse event (AE/SAE) at least possibly related to N+I including myasthenia gravis, diarrhea, glucose intolerance, hyperglycemia, and small intestinal obstruction. Conclusions: Combination therapy with N+I does not have sufficient clinical activity in pts with MS stable, hTMB CRC for further evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Clinical trial information: NCT02693535. [Table: see text]

Duke Scholars

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics