Arcus Biosciences, Inc.

Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5-71.6%), median progression-free survival was 12.9 months (90% CI 9.8-14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1-77.1%) and 69% (90% CI 45.2-86.8%), median progression-free survival was 13.2 months (90% CI 11.3-15.2 months) and 14.5 months (90% CI 11.3 months-NE), and median overall survival was 26.7 months (90% CI 19.5 months-NE) and not reached (90% CI 17.4 months-NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 .

AXL receptor tyrosine kinase (AXL), a transmembrane protein highly expressed in a variety of cancers, has been implicated in the development of resistance to various forms of therapy and poor patient outcomes. Although several strategies have been postulated to limit AXL signaling and thus tumor growth, further refinement is possible. In this Drug Annotation, we report the structure-based design, SAR-driven optimization, preclinical pharmacokinetics (PK), and synthetic chemistry which enabled the discovery of AB801. AB801 is a novel, highly potent, selective, and orally bioavailable AXL inhibitor. In addition to its characterization in a variety of in vitro assays and in vivo studies, AB801 was recently dosed in healthy volunteers and is currently being evaluated clinically as a single agent in advanced solid tumors and in combination with chemotherapy for the treatment of nonsmall cell lung cancer (NSCLC).

High expression of the membrane-bound receptor tyrosine kinase AXL is linked to poor patient outcomes and therapeutic resistance in a variety of cancers. Selective inhibition of AXL is a promising approach to overcome mechanisms of resistance to standard of care therapies, but it is unclear if reported inhibitors have achieved an appropriate therapeutic window to effectively block AXL signaling in tumors. Herein, we report the initial design and structure-activity relationship (SAR)-driven optimization of a novel series of 7-azaindazole AXL inhibitors. These efforts identified a suitable tool compound for in vivo studies that demonstrated a significant reduction in tumor volume in combination with standard-of-care therapies. Further optimization culminated in the discovery of lead compound 68, a molecule with favorable potency, kinome selectivity, oral bioavailability, and safety. SAR insights gained from this campaign helped guide subsequent optimization efforts that ultimately led to the identification of clinical development candidate AB801.