A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor

Abstract

Purpose: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST).

Patients and methods: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy.

Results: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed.

Conclusions: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

Figure 1.

Waterfall plot of the best percent change in sum of diameters from baseline in target lesions. Tumor shrinkage was observed in 7 patients, of which 4 patients had KIT/PDGFRA wild-type GIST (2 SDH deficient; 1 NF1 mutation; 1 SDH deficient and NF1 mutation).

Figure 2.

SDH-deficient patient with pathologic PR. A 29-year-old female patient with SDH-deficient GIST diagnosed in 2020 without any prior cancer systemic therapies, demonstrated a maximum 87% decrease in tumor size, following treatment with DS-6157a, at the MTD confirmed dose of 6.4 mg/kg. The target lesion, an abdominal mass, was 150 mm at baseline (A) which decreased to 33 mm in Cycle 3 and decreased further to 20 mm 4 weeks later (B). The patient discontinued from study to undergo a surgical resection of the remaining small lesion to become tumor-free. The resected tumor, showed a pathologic CR per the investigator's assessment.

Figure 3.

Kaplan–Meier curve of PFS. Median PFS, or the time from start of study treatment to first documented radiologic progression or death from any cause, was 4.2 months (95% CI, 1.6–6.9).

Figure 4.

Mean plasma concentrations over time of intact DS-6157a, DXd, and total anti-GPR20 antibody. Plasma concentrations and exposure of intact DS-6157a (left), DXd (middle), and total anti-GPR20 antibody (right) all demonstrated a dose-dependent profile.