DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish

Abstract

Purpose: The outcomes of anti-PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study.

Patients and methods: Patients had untreated human epidermal growth factor receptor 2-negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m² once every 3 weeks, and capecitabine 1,000 mg/m² twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS).

Results: Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%.

Conclusion: 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).

FIG 1.

Overall study flow for part A of the DisTinGuish trial. AE, adverse event; ITT, intention-to-treat; mITT, modified intention-to-treat; PD, progressive disease; WD, consent withdrawn by patient.

FIG 2.

Changes in tumor burden in the mITT population (n = 21). (A) Maximal percentage change in tumor from baseline, colored by DKK1 expression level, (B) percentage change from baseline over time colored by DKK1 expression level, (C) maximal percentage change in tumor from baseline, colored by PD-L1 expression level, (D) percentage change from baseline over time colored by PD-L1 expression level. Includes patients from the mITT Population with evaluable postbaseline assessments. One patient had only baseline tumor measurement data and was not included. CR, complete response; GC, gastric cancer; GEJ, gastroesophageal junction; mITT, modified intention-to-treat; NE, not evaluable; PR, partial response; SD, stable disease; vCPS, visual combined positive score.

FIG 3.

Survival in the ITT population (N = 25). (A) PFS and (B) OS. ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival.

FIG A1.

Survival by DKK1 and PD-L1 in the overall population. PFS by (A) DKK1 and (B) PD-L1 expression in the overall population. OS by (C) PD-L1 and (D) DKK1 expression level. ITT, intention-to-treat; NA, not applicable; OS, overall survival; PFS, progression-free survival; vCPS, visual combined positive score.

FIG A2.

DKK1 and PD-L1 expression level are not correlated in the overall population (Spearman correlation r = 0.06). CR, complete response; NE, not evaluable; PR, partial response; SD, stable disease; vCPS, visual combined positive score.