First-in-Human Study of the PARP Inhibitor HWH340 in Advanced Solid Tumors with Enrichment for Homologous Recombination Repair Gene Mutations.

HWH340 is a novel, orally administered poly(ADP-ribose) polymerase inhibitor (PARPi) developed for the treatment of solid tumors with homologous recombination repair (HRR) deficiency. It features a distinct chemical structure that has shown high selectivity and favorable PARP inhibitory and anti-tumor activities in preclinical studies. In this study, we evaluated the safety, tolerability, pharmacokinetics, and clinical profiles of HWH340 tablets in patients with advanced solid tumors to determine the recommended Phase 2 dose (RP2D). This Phase 1, open-label, multicenter study (25 centers across China) consisted of three stages: dose-escalation (n=21; 3+3 design; 20-520 mg single doses), multiple-dose escalation (n=14; 3+3 design; 100/140/200/260 mg BID), and dose-expansion (n=42; 140/200 mg BID; 28-day cycles). The dose-expansion study enrolled two cohorts: 50% of patients with germline/systemic BRCA1/2 mutations and 50% of patients with non-BRCA1/2 HRR gene mutations. No dose-limiting toxicities were detected, and the maximum tolerated dose was not reached. The most common treatment-related severe adverse events of grades ≥3 were neutropenia (14.3%), anemia (14.3%), vomiting (11.9%), leukopenia (9.5%), thrombocytopenia (4.8%), and elevated γ-glutamyl transferase (4.8%). Among the 41 patients in the dose-expansion study with evaluable preliminary anti-tumor activity, the objective response rate (ORR) was 19.5%, and the disease control rate (DCR) was 56.1%, with a median duration of response of 4.68 months. Patients with BRCA1/2 mutations in the 200 mg group showed better outcomes, achieving an ORR of 41.7% and a DCR of 75.0%. Breast cancer patients with BRCA1/2 mutations in the 200 mg cohort achieved an ORR of 50%. HWH340 was well-tolerated and demonstrated promising preliminary anti-tumor activity in cancer patients with HRR-mutated advanced solid tumors. An integrated assessment of safety, preliminary efficacy, and pharmacokinetic profiles established 200 mg BID as the RP2D, balancing anti-tumor activity with acceptable tolerability. Given the small sample size and patient heterogeneity, these preliminary efficacy data need further confirmation by subsequent studies with larger sample sizes. This study is registered with ClinicalTrials.gov, NCT03415659.