A phase 1 study of HWK-007, a next-generation, protein tyrosine kinase 7 (PTK7)–targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors.

Abstract

TPS3156 Background: PTK7 is a pseudokinase expressed during embryogenesis and downregulated in normal adult tissue. Aberrant overexpression of PTK7 has been reported in up to 70% of solid tumors and is associated with tumor progression, metastasis, chemoresistance, and poor prognosis. A previous analysis demonstrated particularly high PTK7 expression in non-small cell lung cancer (NSCLC), endometrial carcinoma (EC), and ovarian cancer (OC), across histologic subtypes and disease stages, making PTK7 an attractive therapeutic target with cross-indication applicability (Matulonis et al. AACR-NCI-EORTC 2025, Poster C040). Results from early clinical trials of cofetuzumab pelidotin, a PTK7-targeted, auristatin-based ADC, showed promising clinical activity. HWK-007 is a next-generation, PTK7-targeted ADC comprising an Fc effector-attenuated IgG1 antibody conjugated to the DNA topoisomerase I inhibitor (TOP1i) CPT116. It was designed using novel bioconjugation and advanced linker–payload technologies that enhance intracellular delivery and minimize systemic release of unconjugated TOP1i. This first-in-human, phase 1 trial evaluates HWK-007 in patients with advanced or metastatic solid tumors. Methods: This multicenter, open-label, single-arm, phase 1 dose-escalation (a)/expansion (b) trial is enrolling patients aged ≥18 years with advanced or metastatic NSCLC (non-squamous, epidermal growth factor receptor–wild-type [ EGFR wt]), EC (all histologies), or epithelial OC (all histologies). Patients with NSCLC or EC must have prior treatment with platinum-based chemotherapy and a PD-(L)1 inhibitor, if eligible. Patients with OC must have platinum-resistant disease and prior treatment with standard-of-care therapy. All patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (except in the OC dose-escalation cohorts in which patients with non-target lesions per RECIST and CA125 ≥2 times ULN are permitted), Eastern Cooperative Oncology Group performance status 0 or 1, and no prior treatment with a TOP1i-containing ADC. Patients with clinically active brain metastases or a history of pneumonitis/interstitial lung disease are ineligible. In phase 1a, patients are sequentially assigned to HWK-007 dose levels (DLs; administered intravenously, once every three weeks) using a Bayesian Optimal Interval design (toxicity threshold, 25%), with potential backfill. Backfill cohorts are enriched for patients with EGFR wt NSCLC. Primary endpoints are safety, maximum tolerated dose, and recommended dose for expansion cohorts (phase 1a); and safety and objective response rate (phase 1b). Secondary endpoints include pharmacokinetics and preliminary efficacy outcomes. Recruitment is underway; planned enrollment is up to 226 patients. Clinical trial information: NCT07444814 .