Probes for DKK1

Background Despite recent approval of anti-PD-1 antibodies as 1L therapy in advanced GEA, benefit is largely limited to PD-L1 combined positive scores (CPS) ≥5 patients (pts); novel therapeutic approaches are needed. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated activity in GEA pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Methods Phase IIa single arm trial investigating DKN-01 300 mg (D) + tislelizumab (TS) + CAPOX as 1L therapy in advanced HER2(-) GEA regardless of DKK1 status. Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Primary endpoint was ORR in modified intent to treat (mITT) population (>1 dose D); secondary endpoints included PFS and OS in intent to treat (ITT) population overall and by DKK1 expression: high (H-score ≥35) vs low. Results 25 pts enrolled (01 Sept 2020 - 08 Apr 2021). Median age 61 years (22, 80); 17 pts gastroesophageal junction adenocarcinoma; 8 pts gastric cancer. 21 GEA pts had RNAscope DKK1 expression; 57% were DKK1-high. 22 of 25 pts had vCPS: 73% were vCPS

Background Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody, in combination with an anti-PD1 antibody, has demonstrated safety and clinical activity in advanced previously treated DKK1-high GEA. We report response and survival outcomes in GEA patients (pts) treated with D + tislelizumab (T) + capecitabine/oxaliplatin (CAPOX) as a first line therapy. Methods We enrolled advanced GEA pts in a phase IIa study of D + T + CAPOX (NCT04363801). Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Objective response rate (ORR) [primary efficacy objective], duration of response (DoR), disease control rate (DCR), and progression free survival (PFS) were evaluated in a modified intent to treat (mITT) population (completed ≥ 1 cycle) as well as compared between DKK1 high (H-score ≥35) and low groups. Results Twenty-five GEA pts were enrolled. Median age was 61 (22, 80); 19 males, 6 females. 17 pts (68%) had gastroesophageal junction (GEJ) adenocarcinoma; 8 pts (32%) had gastric cancer (GC). 18 GEA pts had RNAscope DKK1 expression available; 9 pts DKK1-high [5 GEJ, 4 GC) and 9 pts DKK1-low [7 GEJ, 2 GC]. Mean duration of treatment 3 mos, longest duration to date on study 7 mos, 19 pts remain on therapy. Most common D + T + CAPOX regimen related TEAEs were G1/2: anemia, thrombocytopenia, fatigue, diarrhea, nausea each in 3 pts. No related G3/4 toxicities; overall four G5 events; 1 related event pulmonary embolism. mITT analysis included 22 pts. Preliminary ORR in response evaluable (RE) mITT was 68% (13 PR, 6 SD, 1 NE, 2 pending first scan) and DCR 100%. In RE DKK1 high pts (n=7) there was an ORR of 100% (6 PR, 1 NE) compared with DKK1 low pts (n=9) ORR of 56% (5 PR, 4 SD). Median DoR and PFS were not reached. Conclusions D + T + CAPOX was well tolerated and has encouraging early activity as first line treatment for advanced GEA (unselected for PD-L1), with a preliminary ORR of 68% and DCR of 100%. Higher ORR in biomarker RE population: DKK1 high compared with DKK1 low (ORR 100% vs 56%). Updated ORR, DoR, PFS and PD-L1 expression will be reported.

292 Background: Despite recent approval of anti-PD-1 antibodies as 1L therapy in HER2(-) advanced GEA, benefit remains modest and limited largely to PD-L1(+) patients (pts), primarily those with combined positive scores (CPS) ≥5. Thus novel therapeutic approaches are needed for this pt population. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated improved clinical outcomes in pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Methods: DisTinGuish (NCT04363801) is a Phase 2a single arm 2-part trial; Part A investigated DKN-01 (D) + tislelizumab (TS) + CAPOX as 1L therapy for pts with advanced HER2(-) GEA regardless of DKK1 status; Part B investigated two dosing cohorts of D (300 mg and 600 mg) + TS as 2L therapy for DKK1-high advanced GEA pts. Primary objective was to examine safety and tolerability and secondary objectives evaluated multiple efficacy endpoints including overall response rate (ORR) in a modified intent to treat (mITT) population (>1 dose D). Results: Forty-nine pts enrolled between 01 Sept 2020 and 15 Sept 2021; 25 pts in Part A and 24 pts in Part B (D-300 mg). Key clinicopathologic features and efficacy outcomes are shown in Table. The most common D-related AEs were low grade (G1/2) fatigue, nausea, and diarrhea. Nine pts had D-related ≥G3 toxicities, elevated AST/ALT, elevated alkaline phosphatase, hypophosphatemia, hyponatremia, lymphopenia, neutropenia, diarrhea, vomiting, fatigue all occurring in 1 pt and pulmonary embolism in 2 pts (one G5 event). No new safety signals were observed in Part A or B1. Duration of response (DoR), median PFS and median OS have not been reached for Part A. Last pt enrolled in Part B1 on 15 Sept 2021. Conclusions: The combination of D/TS + CAPOX represents a well-tolerated, active 1L combination, particularly for DKK1-high patients consistent with the proposed mechanism of action. Activity appears to be independent of PD-L1 status. Part B1 is aligned with biomarker enrichment and efficacy and biomarker data will be presented along with updated Part A efficacy data. Clinical trial information: NCT04363801. [Table: see text]