Leap Therapeutics announced initial clinical data from Part B of the DeFianCe study and Part C of the DisTinGuish study, evaluating sirexatamab in advanced cancers. The DeFianCe study demonstrated promising results in second-line colorectal cancer (CRC), while the DisTinGuish study did not meet the necessary signal to advance into Phase 3 for gastric cancer.
DeFianCe Study: Sirexatamab in Second-Line Colorectal Cancer
The DeFianCe study (NCT05480306) is a Phase 2, open-label, global study evaluating sirexatamab in combination with bevacizumab and chemotherapy in patients with advanced microsatellite stable (MSS) CRC who have received one prior systemic therapy. Part B of the study is a 188-patient randomized controlled trial, with the primary objective being progression-free survival (PFS). Key secondary objectives include objective response rate (ORR) and overall survival.
Across the intent-to-treat (ITT) population with second-line MSS CRC (n=188), patients treated with sirexatamab plus bevacizumab and chemotherapy (n=94) had an ORR of 35% and a disease control rate (DCR) of 86%, compared to an ORR of 23% and a DCR of 84% in patients treated with bevacizumab and chemotherapy alone (n=94).
"Data from Part B of the DeFianCe study closely mirror the findings from Part A, and together they demonstrate the potential of sirexatamab to provide a compelling treatment option for second-line CRC patients who do not benefit from current standard of care," said Cynthia Sirard, M.D., Chief Medical Officer of Leap.
In patients with left-sided primary tumors (n=144), the experimental arm (n=71) had an ORR of 38%, compared to 25% in the control arm (n=73). Plasma DKK1 levels were highly correlated with clinical activity. Patients in the experimental arm with DKK1 levels above the median (n=49) had an ORR of 39%, compared to 22% in the control arm (n=36). Patients in the upper quartile of DKK1 levels in the experimental arm (n=25) had an ORR of 48%, compared to 11% in the control arm (n=18).
Key patient subgroups also demonstrated higher ORRs in the experimental arm:
- No prior anti-VEGF therapy: 51% vs 29%
- Prior anti-EGFR therapy: 54% vs 27%
- RAS wildtype tumors: 43% vs 32%
With only 3 months of follow-up on the final patients enrolled and a mean duration on study of approximately 6 months, PFS data is not yet mature. However, early separation in the Kaplan-Meier PFS curves is being observed in key patient subgroups. Sirexatamab plus bevacizumab and chemotherapy was well-tolerated, without additive toxicity.
Leap plans to initiate a registrational Phase 3 clinical trial to evaluate sirexatamab plus bevacizumab and chemotherapy in second-line MSS CRC patients with high unmet need, subject to regulatory discussions. Potential Phase 3 patient populations include DKK1 biomarker-selected, anti-VEGF naïve, anti-EGFR experienced, or RAS-wt patients.
DisTinGuish Study: Sirexatamab in Gastric Cancer
Leap also reported data from Part C of the DisTinGuish study (NCT0436380) evaluating sirexatamab in combination with tislelizumab and chemotherapy in first-line patients with advanced GEJ and gastric cancer. While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer.
Across the ITT population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (n=85) had a confirmed ORR of 52% by both investigator assessment (IA) and Blinded Independent Central Review (BICR), while patients treated with tislelizumab and chemotherapy alone (n=85) had a confirmed ORR of 56% by IA and 42% by BICR.
Based on BICR, patients in the experimental arm with DKK1-high tumors (n=22) had a confirmed ORR of 59%, compared to 36% in the control arm (n=22). Patients in the experimental arm with PD-L1-negative tumors (n=18) had a confirmed ORR of 44%, compared to 32% in the control arm (n=19).
In the ITT population, preliminary median PFS in the experimental arm was 9.72 months by BICR and 7.66 months by IA, compared to 11.99 months by BICR and 10.41 months by IA in the control arm. In the DKK1-high population, preliminary median PFS in the experimental arm was 7.72 months by BICR and 7.43 months by IA, compared to 7.79 months by BICR and 11.14 months by IA in the control arm. The hazard ratio for PFS by BICR was 0.68, representing a trend in favor of the experimental arm.
"Sirexatamab plus tislelizumab and chemotherapy demonstrated improved confirmed response rates compared to the control arm in the ITT, DKK1 -high, and PD-L1 negative patients by Blinded Independent Central Review (BICR). However, gastric cancer is a difficult tumor to assess radiologically, and unfortunately, there was a high level of discordance between investigator assessment (IA) and BICR," said Dr. Sirard. Leap will focus on advancing sirexatamab in CRC and explore strategic partnership opportunities to advance sirexatamab plus anti-PD-1 antibodies in gastric cancer and other indications where there is high DKK1 expression.
