DKN-01 and atezolizumab as second- or third-line therapy in advanced oesophagogastric adenocarcinoma: the WAKING trial.

BACKGROUND: Survival for patients with advanced oesophagogastric adenocarcinoma (OGA) is poor. Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in mismatch repair proficient (MMRp) OGA. Dickkopf-1 modulates Wnt/β-catenin signalling and promotes an immunosuppressive tumour microenvironment potentially enhancing ICI activity. PATIENTS AND METHODS: This multicentre, single-arm phase II trial occurred in two phases: dose escalation (IIA) and dose expansion (IIB). Phase IIA established the recommended phase II dose of DKN-01. Phase IIB evaluated DKN-01 600 mg i.v. plus atezolizumab 840 mg i.v. administered two-weekly in patients with previously treated MMRp advanced OGA. The primary endpoint was objective response rate (ORR) per RECIST v1.1 (target ORR 25% in 40 patients). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). RESULTS: Between June 2022 and May 2024, 61 patients were enrolled; 47 started treatment (5 phase IIA, 42 phase IIB). No dose-limiting toxicities occurred. Forty patients were assessable for the primary endpoint. ORR was 7.5% (3/40) [one-sided 95% lower confidence interval (CI) 2.1], median duration of response 8.6 months (range 2.7-19.4); 13/40 (32.5%; 95% CI 18.6-49.1) had disease control. Baseline programmed death-ligand 1 combined positive score (CPS) in responders was 1, 2, and 85; the patient with CPS 85 remained alive 3 years postprogression. Median PFS was 1.8 months, and median OS was 5.9 months, with a median follow-up of 39.3 months. Grade ≥3 adverse events occurred in 60% of patients. CONCLUSIONS: DKN-01/atezolizumab was well tolerated. However, efficacy in MMRp/microsatellite stable OGA in an otherwise biomarker-unselected population did not meet the primary efficacy endpoint.