The phase 3 study of DKN-01 in combination with tislelizumab vs chemotherapy (DisTinGuish; NCT04363801) for the treatment of patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (gastric/GEJ) is advancing to part C, according to an announcement by Leap Therapeutics, Inc.1
Part C will include 160 patients who have received no prior therapy for unresectable, locally advanced, or metastatic disease, have measurable disease per RECIST v1.1 criteria, and are HER2-negative. The patients will be randomized 1:1 to receive DKN-01 plus tislelizumab and standard-of-care (SOC) chemotherapy, or tislelizumab and SOC chemotherapy.1,2
About the DisTinGuish Study
Trial Name: A Phase 2a, Multicenter, Open-Label Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients With Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (DisTinGuish)
ClinicalTrials.gov Indentifier: NCT04363801
Completion Date: June 2023
Recruitment Status: Recruiting
Sponsor: Leap Therapeutics, Inc.
Recruitment Contact: Cynthia Sirard, MD617-714-0357 CSirard@leaptx.com
Elizabeth Parker Eparker@leaptx.com
Stratified by DKK1 expression based on a score of either ≥ 20% or < 20% and PD-L1 expression of ≥ 5% or < 5%, the study will assess the primary end point of progression-free survival (PFS) in the DKK1-high population. The secondary end points of the study will include PFS in all patients, overall survival (OS) in the DKK1-high and overall populations, and objective response rate (ORR) in the DKK1-high and overall populations.
Earlier findings from the DisTinGuish study showed that adding DKN-01 to tislelizumab can achieve anti-tumor activity in patients with gastric/GEJ adenocarcinoma who are treated in either the first-line or second-line setting.2
In part A of the study, 25 patients with DKK1 expression were assessed for ORR, PFS, duration of response, and safety. The ORR observed in the intent-to-treat population of part A was 68.2%, which consisted of 1 complete response and 14 partial responses. When patients were evaluated according to their DKK1 expression level, the ORR was 90% in the DKK1-high population.
The median PFS in part A was 10.7 months, which was a 7.7-month improved compared with CheckMate-649 (NCT02872116) results from the combination of nivolumab (Opdivo) plus chemotherapy. In the DKK1-high cohort, the median PFS was 11.9 months. The median OS was not reached in part A compared with 13.8 months with the CheckMate-649 combination.
When ORR was assessed according to patients’ PD-L1 expression, it was notable that the PD-L1-low population achieved an ORR of 79%.
All 25 patients were evaluable for safety. Treatment-emergent adverse events (TEAEs) leading to death within 30 days of the last dose occurred in 12% of patients. Any-grade AEs were observed in 100% of patients, and grade 3 or higher AEs were seen in 56%. Twenty percent of the any-grade AEs were related to DKN-01 treatment.
Serious AEs occurred in 40% of patients, with 8% of those directly related to DKN-01. Events led to dose reduction in 4% of patients.
In terms of other drug-related AEs in the study, 56% were DKN-01 related, 68% were related tislelizumab, 96% were capecitabine-related, 100% were oxaliplatin related, and 100% were regimen-related.
So far, these data from DisTinGuish indicate that enhanced clinical responses and survival benefit are associated with high tumoral DKK1 expression but irrespective of PD-L1 expression.
“AI would say that DKK1 appears to be an important emerging target in gastroesophageal adenocarcinoma. It is associated with an aggressive biology, shorter response to 5-FU, and shorter survival. [This suggests] that this a relatively aggressive population and perhaps suggest that the results from part A are even more encouraging,” Samuel Klempner, MD, medical oncologist at Massachusetts General Cancer Center, during a presentation of the data on a conference call.
DKN-01 is a humanized monoclonal antibody. As a single agent, DKN-01 has been granted orphan drug designation by the FDA for the treatment of gastric/GEJ adenocarcinoma. Also, DKN-01 in combination tislelizumab has an FDA fast track designation for the treatment of gastric/GEJ adenocarcinoma in patients whose tumors express high DKK1 protein, following progression on fluoropyrimidine- and platinum- containing chemotherapy.
Upcoming data from part C of DisTinGuish will further confirm the benefit and safety of DKN-01 in this patient population, according to Klempner.
1. Leap Therapeutics announces initiation of new DKN-01 clinical trials in gastric cancer, colorectal cancer and endometrial cancer. News release. July 12, 2022. Accessed July 13, 2022. https://bit.ly/3nYmu5N
2. DKN-01 R&D Day. July 12, 2022. Leap Therapeutics website. Accessed July 13, 2022.