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), amplifications, fusions, and mutations occur in many tumor types. SRC is a key downstream MET effector while CSF1R modulates tumor associated macrophages. Inhibition of SRC and CSF1R can potentially improve the durability of response compared to inhibition of MET alone. Currently there are no approved targeted therapies after progression on a MET TKI. The Phase 1 SHIELD-1 trial (NCT03993873) is evaluating the safety, pharmacokinetics (PK), and preliminary activity of elzovantinib in patients with advanced solid tumors harboring genetic MET alterations. A previous interim analysis included 15 efficacy evaluable patients. Among 10 MET TKI-naïve patients, 5 had achieved PRs (3 confirmed), including 3 gastric/GE junction, 1 CRC, and 1 NSCLC. Of the 5 MET TKI-pretreated NSCLC patients, 3 had stable disease (Hong et al. EORTC-NCI-AACR 2020, Abstract nr LBA-01). Here we report updated data from the SHIELD-1 trial. Patients and methods: Adults with advanced solid tumors harboring genetic MET alterations were enrolled using a 3+3 dose-escalation design. Expansion was allowed at doses where clinical activity was observed. Elzovantinib was given orally in continuous 28-day cycles. Results: As of 13 May 2021, 52 patients have been enrolled across 7 dose levels, including 30 NSCLC patients (20 Δex14, 8 amplifications, 2 mutations), 9 gastric cancer patients (8 amplifications, 1 fusion), and 13 patients who had other cancers with MET alterations. Median age was 63 (33-84) years. Median number of prior therapies was 2 (range 0-6). 34 of 52 patients (65%: 13 NSCLC; 9 gastric; 12 others) had not received a prior MET TKI and 18 (35%: 17 NSCLC; 1 liver) had a prior MET TKI. The most common adverse events (AEs) were dizziness (65%), lipase increase (33%), anemia (29%), constipation (29%), and fatigue (29%). Most AEs were Grade 1 or 2 with 94% 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. Two dose-limiting toxicities (Grade 2 dizziness; Grade 3 vertigo) occurred at the highest tested dose of 120 mg QD. Systemic exposure increased in a dose-dependent manner. The steady state trough concentrations were consistently above the IC₉₅ for inhibition of MET phosphorylation across all cohorts with a terminal half-life of 13-17 hours. Evaluation of the recommended Phase 2 dose (RP2D) is ongoing and further efficacy analysis will be available for presentation. Conclusions: Elzovantinib is a novel MET/SRC/CSF1R inhibitor with a favorable PK profile. Elzovantinib was generally well tolerated with primarily low-grade dizziness, and no high-grade edema reported. 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 patients with MET-altered tumors is planned. Citation Format: David S. Hong, Daniel Catenacci, Lyudmila Bazhenova, Byoung Chul Cho, Mariano Ponz-Sarvise, Rebecca Heist, Victor Moreno, Gerald Falchook, Viola W. Zhu, Aurélie Swalduz, Benjamin Besse, Dong-Wan Kim, Shinkyo Yoon, Xiuning Le, Tingting Zhao, Alysha Kadva, Zachary Zimmerman, Jeeyun Lee. 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 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P225.