On September 4, 2022 Leap Therapeutics, Inc. (NASDAQ: LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported the Company will be presenting data in first-line patients with advanced gastroesophageal adenocarcinoma (GEA) from the DisTinGuish study, a Phase 2a clinical trial evaluating Leap’s anti-Dickkopf-1 (DKK1) antibody, DKN-01, in combination with tislelizumab, BeiGene’s anti-PD-1 antibody, and chemotherapy, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 being held on September 9-12 (Press release, Leap Therapeutics, SEP 4, 2022, View Source [SID1234618975]). Safety and early efficacy data will be presented from the WAKING study, a multicenter Phase 2 non-randomized trial evaluating DKN-01 plus Tecentriq (atezolizumab), Roche’s anti-PD-L1 antibody, in patients with advanced oesophagogastric adenocarcinoma (OGA).

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"Data from the DisTinGuish study continue to demonstrate promising results with the combination of DKN-01 plus tislelizumab and standard chemotherapy as a first-line treatment in patients with advanced gastroesophageal adenocarcinomas," said Samuel Klempner, MD, Associate Professor at Harvard Medical School. "The mature median progression-free survival of 11.3 months compares favorably with recent benchmarks in this patient group. The outcomes in the aggressive DKK1-high and the less checkpoint-inhibitor sensitive PD-L1-low (CPS < 5) subgroups are notable and encouraging. As the last patient enrolled in early April 2021, the overall survival results are also on track to show an increase over current standards. Gastroesophageal cancer patients and physicians want new biomarker-directed therapies to improve the standard of care in first-line treatment, and we are enthusiastic about the upcoming randomized clinical trial involving this encouraging DKN-01 combination."

"Early results from the WAKING study show the promise of boosting anti-tumor activity by targeting the Wnt signaling pathway and DKK1-driven tumor microenvironment modulation with a DKN-01 plus atezolizumab combination therapy strategy in patients with advanced OGA," said Fiona Turkes, MD, Clinical Research Fellow at The Royal Marsden Hospital. "We look forward to continuing to enroll patients and studying the biological mechanisms of this unique chemotherapy-free combination therapy, especially in those patients whose tumors express high levels of DKK1."

Key Findings DisTinGuish
DKN-01 and tislelizumab plus CAPOX was well tolerated in first-line treatment for advanced GEA patients, with a safety profile consistent with previous reports
Overall median progression-free-survival (PFS) of 11.3 months exceeds benchmark results in unselected patients and in all four important biomarker-directed subgroups
11.3 months PFS in DKK1-high and 12.0 months in DKK1-low
10.7 months PFS in PD-L1-low (CPS < 5) and 11.6 months in PD-L1-high (CPS > 5)
Median overall survival (OS) is not mature with only 44% of patients deceased as of the data cut (June 30, 2022), with a median duration on study of 15.7 months and last patient enrolled in early April 2021
High and durable overall response rate (ORR) in unselected and aggressive subgroups (DKK1-high and PD-L1-low) (mITT): 68% (1 CR, 14 PR) overall
DKK1-high: 90% ORR (9 PR)
DKK1-low: 56% ORR (1 CR; 4 PR)
PD-L1-low expression: 79% (11 PR)
100% (6/6) ORR in DKK1-high, PD-L1-low patients
PD-L1-high expression: 67% (1 CR; 3 PR)
75% (3/4) ORR in DKK1-high, PD-L1-high patients
Key Findings WAKING
DKN-01 up to 600mg every 2 weeks in combination with atezolizumab was considered safe
3 patients with the longest time on treatment received the 600mg dose level
At time of data cut off (August 16, 2022), 18 patients were enrolled in the study
12 patients were treated in initial phase
10 patients were response evaluable at the time of data cut-off
1 patient had a PR and DKK1 expression of 81% tumor percentage score (TPS)
Disease control rate: 50% (1 PR, 4 SD, 5 PD)
Elevated baseline DKK1 expression (TPS > 20%) may be associated with clinical response
4 DKK1-high patients: Best ORR 25% (1 PR, 1 SD, 1 PD, 1 NE)
Translational analyses and assessment of PD-L1 status are ongoing
Safety
No dose-limiting toxicity (DLT) was observed, and no formal maximum tolerated dose (MTD) was reached
No treatment-related deaths occurred, and no dose reductions were required
Leap Poster Details:
Title: DKN-01 and Tislelizumab + Chemotherapy as First-line (1L) Investigational Therapy in Advanced Gastroesophageal Adenocarcinoma (GEA): DisTinGuish Trial
First Author: Samuel J. Klempner, Harvard Medical School
Session Category: Poster Session
Session title: Oesophagogastric cancer
Date and time: Monday, September 12, 2022, at 12:00 CET
Poster Number: 1213

Title: Safety and efficacy of Wnt inhibition with a DKK1 inhibitor, DKN-01, in combination with atezolizumab in patients with advanced oesophagogastric adenocarcinoma (OGA): Phase IIa results of the WAKING trial
First Author: Fiona Turkes, The Royal Marsden NHS Foundation Trust
Session Category: Poster Session
Session title: Oesophagogastric cancer
Date and time: Monday, September 12, 2022, at 12:00 CET
Poster Number: 1253

About the DisTinGuish Study
The DisTinGuish study (NCT04363801) is a Phase 2a study of DKN-01 in combination with tislelizumab, an anti-PD-1 antibody, with or without chemotherapy as first-line or second-line therapy in patients with inoperable, locally advanced, G/GEJ adenocarcinoma. The study is being conducted in two parts in the United States and the Republic of Korea. Enrollment of Part A has been completed with 25 first-line HER2- G/GEJ cancer patients whose tumors express either high levels of DKK1 (DKK1-high) or low levels of DKK1 (DKK1-low). Part B of the study has completed enrollment patients with second-line DKK1-high G/GEJ cancer. Part C of the study will be a randomized controlled trial of DKN-01 in combination with tislelizumab and chemotherapy compared to tislelizumab and chemotherapy. Leap is conducting this combination study as part of an exclusive option and license agreement with BeiGene.

About the WAKING Study
The WAKING study (NCT04166721) is a Phase IIa/b nonrandomized, open-label, multicenter study to be conducted concurrently in 2 Parts. Approximately 52 patients aged 18 years or older with inoperable, histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease (RECIST v1.1) requiring therapy will be enrolled in the study. Both parts are designed to evaluate safety, tolerability, and efficacy of the combination therapy of DKN-01 and atezolizumab in immunotherapy naïve, PD-L1 unselected G/GEJ adenocarcinoma patients. Treatment continues in repeating 14-day cycles until patient meets criteria for discontinuation or is no longer deriving clinical benefit. The WAKING study is being led by the Royal Marsden Hospital in the United Kingdom with financial support from Roche.