Preliminary interim data of elzovantinib (TPX-0022), a novel inhibitor of MET/SRC/CSF1R, in patients with advanced solid tumors harboring genetic alterations in MET: Update from the Phase 1 SHIELD-1 trial

Background: Elzovantinib is a novel, type I tyrosine kinase inhibitor (TKI) that targets MET, SRC, and CSF1R. Genetic alterations in MET, including exon 14 skipping (Δex14) mutations and other oncogenic mutations, amplifications, and fusions are present in many tumor types. The Phase 1 SHIELD-1 trial (NCT03993873) is evaluating safety, pharmacokinetics (PK), and preliminary activity of elzovantinib in patients (pts) with advanced solid tumors harboring genetic MET alterations. An early analysis included 46 efficacy evaluable pts. Among 32 TKI-naïve pts, 8 had confirmed PRs, including 4 NSCLC, 3 gastric/GE junction adenocarcinomas, and 1 colorectal cancer (Hong DS, et al. EORTC-NCI-AACR 2021, Poster nr P225). Here we report updated data from SHIELD-1. Patients and methods: Adults with advanced solid tumors harboring genetic MET alterations were enrolled using a 3+3 dose-escalation design with additional pt enrollment at doses where clinical activity was observed. Dose expansion at the preliminary RP2D of 40 mg QD to BID titration dose is enrolling pts and results from this portion of the study will be available for presentation. Elzovantinib was given orally in continuous 28-day cycles. Results: As of 13 May 2022, 59 pts have been enrolled across 8 dose levels in the dose-escalation phase, including 33 NSCLC pts (21 Δex14, 9 amplifications, 3 mutations), 9 gastric cancer pts (8 amplifications, 1 fusion), and 17 pts who had other cancers with MET alterations. Median age was 63 (33–84) years. Median number of prior therapies was 2 (range 0–7). 39 of 59 pts (66%: 15 NSCLC; 9 gastric; 15 others) had not received a prior MET therapy and 20 (34%: 18 NSCLC; 1 liver; 1 pancreatic) had prior MET therapy. The most common adverse events (AEs) were dizziness (68%), fatigue (41%), anemia (36%), constipation (34%), lipase increase (32%). Most AEs were low-grade, with 95% of dizziness AEs being Grade 1 or 2. No events of interstitial lung disease/pneumonitis, Grade 3/4 edema, or treatment-related Grade 3/4 ALT/AST elevation were reported. Systemic exposure increased in a dose-dependent manner. Evaluation of the recommended Phase 2 dose (RP2D) is ongoing and updated safety and efficacy analyses will be available for presentation. Conclusions: Elzovantinib, a novel MET/SRC/CSF1R inhibitor, was generally well tolerated with primarily low-grade dizziness, no high-grade edema, and a favorable PK profile. The RP2D is currently under evaluation and updated safety and efficacy data will be available for presentation. A global multi-cohort Phase 2 trial of pts with MET-altered tumors is planned. Conflict of interest: Advisory Board: Drs. Bazhenova and Falchook: Turning Point Therapeutics, Inc. Corporate-sponsored Research: Drs. Hong, Shergill, Heist, Moreno, Falchook, Besse, Kim: Turning Point Therapeutics, Inc. Other Substantive Relationships: Ms. Zhao, Drs. Atwal, Park: Employment, Stock ownership – Turning Point Therapeutics, Inc.