In a phase IIa study (DisTinGuish) reported in the Journal of Clinical Oncology, Klempner et al found that use of the DKK1-neutralizing antibody DKN-01 in combination with tislelizumab and chemotherapy showed activity in the first-line treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma.
In the U.S. multicenter trial, 25 patients enrolled between September 2020 and April 2021 received intravenous DKN-01 at 300 mg once every 2 weeks, tislelizumab at 200 mg once every 3 weeks, oxaliplatin at 130 mg/m2 once every 3 weeks, and capecitabine at 1,000 mg/m2 twice daily on days 1 to 15 of each 21-day cycle.
Key Findings
Among 22 patients evaluable for response, the objective response rate was 73% (95% confidence interval [CI] = 49.8%–89.3%), with a disease control rate of 95%. Among 21 patients with known tumor DKK1 status, the objective response rates were 90% (95% CI = 55.5%–99.7%) among 12 patients with DKK1-high tumors and 67% (95% CI = 29.9%–92.5%) among 9 patients with DKK1-low tumors. Objective response rates were 86% (95% CI = 57.2%–98.2%) among 16 patients with a PD-L1 combined positive score < 5 and 67% (95% CI = 22.3%–95.7%) among 6 patients with a combined positive score ≥ 5.
Among all 25 patients, median progression-free survival was 11.3 months (95% CI = 5.8–12.0 months), with a 12-month rate of 33%. Median overall survival was 19.5 months (95% CI = 15.2–24.4 months), with 12- and 18-month rates of 76% and 55%.
Grade ≥ 3 adverse events were observed in 60% of patients, most commonly diarrhea (20%), decreased potassium (16%), and decreased hemoglobin (12%). One treatment-related death was reported (from pulmonary embolism). The most common adverse events of any grade considered related to DKN-01 were fatigue (28%), diarrhea (28%), decreased neutrophils (28%), and nausea (24%).
The investigators concluded: “DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier NCT04363801).”
Samuel J. Klempner, MD, of the Division of Hematology-Oncology, Massachusetts General Hospital, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Leap Therapeutics, Inc. For full disclosures of the study authors, visit ascopubs.org.
