Leap Therapeutics Shifts Focus to Colorectal Cancer After Mixed Phase 2b Trial Results

Leap Therapeutics has decided to redirect its efforts towards colorectal cancer following mixed results from a midstage trial of its anti-DKK1 antibody, sirexatamab.
The Massachusetts-based company reached this conclusion after analyzing data from two parts of its phase 2b study. The first segment evaluated sirexatamab in combination with bevacizumab and chemotherapy for colorectal cancer. The combination therapy demonstrated a response rate of 35%, outperforming the 23% observed in the control arm.
While early signs of improved progression-free survival (PFS) were noted in certain subgroups, these findings did not translate into a statistically significant difference. Across both arms, the number of PFS events was nearly identical, with 37 in the experimental group and 38 in the control group. Nevertheless, a larger proportion of patients—46 in the sirexatamab cohort compared to 36 in the control group—remain on treatment.

Leap views these results as promising enough to justify advancing sirexatamab into a phase 3 registrational trial for second-line colorectal cancer patients. The company plans to identify the most suitable patient population for this trial as additional data becomes available.
However, the second part of the phase 2b trial, which investigated sirexatamab in combination with tislelizumab (BeiGene’s anti-PD-1 antibody) and chemotherapy, painted a less optimistic picture for gastric cancer. While the combination showed improved response rates in certain subgroups of advanced gastroesophageal junction and gastric cancer patients, challenges emerged. Notably, discrepancies between investigator assessments and blinded independent central review (BICR) cast doubt on the reliability of the findings.
Leap anticipates that this portion of the trial will not meet its progression-free survival endpoints. As a result, the company has decided against pursuing a phase 3 trial for sirexatamab in gastric cancer. Instead, Leap intends to explore strategic partnerships to advance sirexatamab in combination with anti-PD-1 therapies for gastric cancer and other indications with high DKK1 expression.
Cynthia Sirard, M.D., Leap’s Chief Medical Officer, commented that the company would focus on the more promising colorectal cancer indication while keeping the door open for collaborations to further explore sirexatamab’s potential in other therapeutic areas.
During a December presentation at a Piper Sandler event, Leap CEO Douglas Onsi highlighted the differences between colorectal and gastric cancer opportunities. He described the colorectal cancer market as a robust and significant space in both the U.S. and Europe while acknowledging that interest in gastric cancer varies among pharmaceutical companies.

Onsi noted that gastric cancer is often viewed as an opportunity for combination therapies involving PD-1 inhibitors, with potential applications extending beyond gastric cancer to other cancers involving PD-1 pathways.
By prioritizing colorectal cancer, Leap aims to capitalize on a strong signal observed in its phase 2b trial while exploring external partnerships to address the complexities of gastric cancer treatment.