Safety and efficacy of a DKK1 inhibitor (DKN-01) in combination with pembrolizumab (P) in patients (Pts) with advanced gastroesophageal (GE) malignancies

Abstract

Background: Dickkopf-1 (DKK1) is a modulator of the Wnt and PI3K/AKT signaling pathways and contributes to an immunosuppressive tumor microenvironment by activating MDSCs and Tregs. DKN-01 (D), an mAb against DKK1, acts on innate immune cells, and in preclinical studies demonstrates upregulation of both PD-L1 and IFNcrelated chemokines, suggesting a role for immune checkpoint combination. Anti-PD-1 plus DKN-01 shows additive antitumor effects in the B16 syngeneic mouse model; clinical studies are underway. GE cancers commonly overexpress DKK1 and harborWnt pathway alterations. Methods: Phase 1b study to evaluate dose, safety and efficacy of D (150 mg or 300 mg on Days 1 & 15) plus P (200 mg on Day 1) of each 21-day cycle in pts with advanced GE cancer. Safety, efficacy, and correlative analyses (cytokines, PBMC immunophenotyping, tumor genomics and intra-tumoral DKK1/PD-L1) are ongoing. Results: Pts enrolled in 2 cohorts: D (150 mg [n=2] or 300 mg [n=11]) + P. All 13 pts had adenocarcinomas (4 pts: EC, 6 pts: GEJ, 3 pts: GC). Three pts (23%) were refractory to prior checkpoint inhibitor, and only 1 pt was known to be PD-L1+ at study entry. No DLTs or treatment related SAEs were observed. Most TEAE were Grade 1/2 and commonly gastrointestinal disorders.≥ Grade 3 TEAE included hyponatremia & anorexia (each 2 pts), lymphopenia, transfusion reaction, GI bleed, abdominal pain, dehydration, weight loss, thrombotic event & weakness (each 1 pt); only lymphopenia felt related to D. Among 9 evaluable patients there was one confirmed PR, SD in 5 pts (including one IO-refractory pt with minor response) and PD in 3 pts. The 6-week disease control rate was 75%; 6 pts remain on therapy. Most PR/SD pts have had downward trend of peripheral MDSC; more evident in pt with PR. Complete cohort details and correlative work will be presented. Conclusions: Preliminary results demonstrate that D +P is well tolerated with no new safety signals and shows encouraging early efficacy signals in advanced GE cancer. A subset of pts with features typically associated with lower response to single agent anti- PD-1 therapy (KRAS amp, PD-L1 neg, and MSS) exhibited prolonged clinical benefit and warrant further study. Expansion to confirm efficacy is ongoing.