Baum, Jason

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/m 2 once every 3 weeks, and capecitabine 1,000 mg/m 2 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 ).

4027 Background: DKN-01 is an anti-DKK1 mAb which has demonstrated anti-tumor activity in patients with advanced GEA with low tumor PD-L1 expression, a subset with very limited therapeutic options. DKN-01 has immunomodulatory activity, stimulates a pro-inflammatory tumor microenvironment, and upregulates PD-L1 levels. Here we present 2-year survival data for 1L advanced GEA patients who received combination treatment with DKN-01, the Fc-optimized anti-PD-1 tislelizumab, and CAPOX chemotherapy. The ORR was previously reported (68% in ITT and 79% in PD-L1-low populations). Methods: This Phase 2, multi-center, single arm Part A of the DisTinGuish (NCT04363801) study investigated DKN-01 + tislelizumab + CAPOX as 1L therapy in advanced HER2(-) GEA, regardless of DKK1 and PD-L1 expression levels. Tumor DKK1 and PD-L1 were assessed by central laboratories. The primary endpoint was ORR in a modified intent to treat population (>1 dose DKN-01); secondary endpoints included PFS and OS in the ITT population. Results: Twenty-five patients were enrolled from September 2020 to April 2021. As of 23 January 2023: Median age was 61 years (22, 80); 17 patients had GEJ adenocarcinoma; 8 had gastric cancer. Twenty-one patients had tumors with evaluable DKK1 expression. Twenty-two patients had tumors with evaluable PD-L1 expression; the majority (73%) were low expressors (vCPS <5%). Median (m) duration on treatment is 11.3 months (mo). Seven patients remain on study, with 4 on-treatment beyond 2 years. The mPFS is 11.3 mo in the overall ITT population and 10.7 mo in patients with low tumor PD-L1 expression. The mOS is 19.5 mo in the overall ITT population and 18.7 mo in the patients with low tumor PD-L1 expression. Treatment related adverse events (TRAEs) were mild with most G1/2. The most common AEs related to the study drug regimen were nausea (72%), diarrhea (64%) and fatigue (60%). Five patients experienced G3 DKN-01-TRAEs including decreased neutrophil count (1), diarrhea (1), vomiting (1), hypophosphatemia (2), and pulmonary embolism (1). Conclusions: At 2-years of follow-up, 1L treatment of advanced GEA patients with DKN-01 in combination with tislelizumab and CAPOX resulted in a prolongation of PFS and OS compared with the modern SOC regimen of nivolumab plus chemotherapy, both in the overall population (mPFS 11.3 vs 7.7 mo; mOS 19.5 vs 13.8 mo) and in the PD-L1 low subgroup (mPFS 10.7 vs 7.5 mo; mOS 18.7 vs 12.4 mo), alongside a manageable safety profile. The prolonged PFS and OS observed in the current study are notable, especially in our trial population dominated by patients with tumors of low PD-L1 expression, where the known benefit of anti-PD-1 therapy is limited. The ongoing Part C of this study is evaluating mFOLFOX6/CAPOX plus tislelizumab with or without DKN-01 in the same 1L GEA patient population. Further evaluation of biomarkers is also ongoing. Clinical trial information: NCT04363801 .

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]