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DisTinGuish Part A Trial of DKN-01 plus Tislelizumab and CAPOX Results Indicate Early Activity in Patients with Advanced DKK1-High Gastroesophageal Adenocarcinoma

2021 Year in Review - Gastrointestinal Cancer

DKN-01 plus tislelizumab and CAPOX combination demonstrates promising response rates and safety data in phase 2a study.

Dickkopf-1 (DKK1) is secreted by cancer cells, and promotes tumor angiogenesis, proliferation, and metastasis.1 DKK1 also modulates Wnt signaling, promotes Akt signaling activation, downregulates natural killer cell function, and enhances myeloid-derived suppressor cell activity.1 Increased DKK1 is an indicator of poor prognosis in patients with cancer.1 Preclinical study models found that DKN-01 is a monoclonal antibody that binds to DKK1 and blocks its activity, leading to activation of an innate immune response.1 It has also demonstrated the ability to downregulate Akt activity along with upregulating tumor PD-L1 expression.1 When combined with pembrolizumab for treatment of patients with advanced DKK1-high gastroesophageal adenocarcinoma (GEA), it demonstrated clinical activity and acceptable safety.1

Klempner and colleagues presented the results of the phase 2 DisTinGuish part A trial combining DKN-01 with tislelizumab and capecitabine/oxaliplatin (CAPOX) chemotherapy as first-line therapy at the European Society for Medical Oncology Congress 2021. Tislelizumab is an anti–PD-1 monoclonal antibody that was developed to minimize binding to the FcγR receptor on macrophages to prevent antibody-dependent phagocytosis.1 Twenty-five patients with GEA were evaluated during this study. Response rates and survival rates were evaluated in a modified intent-to-treat (mITT) population who completed ≥1 treatment cycles. The primary efficacy end point was objective response rate (ORR) and secondary end points were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival. Patient tumor DKK1 mRNA expression was determined and assigned an H-score ranging from 0 to 300. Response rates and survival rates were also compared between those patients with a DKK1 H-score ≥35 (high) and those with low DKK1 H-scores.

The median patient age was 61 years and there were 19 male and 6 female participants. Gastroesophageal junction (GEJ) adenocarcinoma was the diagnosis for 17 patients, and 8 patients had a gastric cancer diagnosis. When the DKK1 H-scores were determined, 8 patients with GEJ adenocarcinoma had a high score and 7 had a low DKK1 score.1 DKK1 high scores were found in 4 patients with gastric cancer and 2 had low DKK1 scores.1 The mean duration of treatment was 5 months and the longest duration of treatment was 10 months.1 There were 16 patients remaining on treatment at the time of the study presentation.1 The mITT response evaluable population was 21 patients, with 15 having a partial response and 6 having stable disease.1 The ORR in the mITT patients was 68.2% and the DCR was 96%.1 Analysis of the DKK1-high mITT patients found an ORR of 90%, with 7 of 9 patients remaining on therapy.1 The ORR was 55.6% for the DKK1-low mITT patients, with 4 of the 5 patients still on therapy.1 Treatment-related adverse events were mostly grade 1 or 2. Anemia, diarrhea, fatigue, nausea, and thrombocytopenia occurred each in 3 patients. Grade 5 events occurred in 4 patients, with 1 pulmonary embolism reported.1

Although the mean DOR and PFS were not reached in this study, the therapy was well-tolerated and had promising early activity.

Source: Klempner SJ, Sirard C, Chao J, et al. DKN-01 in combination with tislelizumab and chemotherapy as a first-line therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial. Ann Oncol. 2021;32(suppl_5):S1040-S1075.

Reference

  1. Klempner SJ, Sirard C, Chao J, et al. DKN-01 in combination with tislelizumab and chemotherapy as a first-line therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial. Poster presented at ESMO Congress 2021; September 16, 2021.
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