Improves response rate and progression-free survival, while missing overall survival significance
Compass to hold further talks with FDA; Phase I/II first-line combination trial underway at MD Anderson
Tovestiga, a dual-antibody candidate developed by ABL Bio (298380), has demonstrated tumor response and disease progression delay in a Phase II second-line trial for biliary tract cancer. However, the drug failed to secure a statistically significant difference in overall survival, raising questions over how to prove a survival benefit during the U.S. approval process.
Compass Therapeutics, ABL Bio’s U.S. partner, announced on the 24th (local time) that the results of the "COMPANION-002" Phase II/III trial were published in the Journal of Clinical Oncology (JCO) and presented at the European Society for Medical Oncology (ESMO) congress. The clinical trial involved 168 patients with advanced biliary tract cancer who had undergone one prior line of systemic therapy. Patients were randomized into two cohorts: 111 in the tovestiga-paclitaxel combination arm and 57 in the paclitaxel monotherapy control arm.
The objective response rate was recorded at 18.0% for the patient group receiving tovestiga, compared to 5.3% for the paclitaxel-only group. Progression-free survival, which measures the time to disease progression or death, had a median of 4.7 months for the combination arm and 2.6 months for the control arm. Improvements in both response rate and progression-free survival were statistically significant. Treatment-related adverse events of Grade 3 or higher were reported more frequently in the combination arm at 93.5%, compared to 64.2% in the control arm.
Cross-over treatment acted as a variable in the interpretation of overall survival. Thirty-one out of the 57 patients in the control group switched to the tovestiga combination therapy following disease progression, which the company explained affected the comparative survival outcome between the two arms. However, post-hoc analyses adjusted for cross-over included in the publication also failed to secure statistical significance. The hazard ratio for overall survival was 0.85, with a 95% confidence interval of 0.59 to 1.26 and a p-value of 0.53.
Demonstrating a survival benefit remains a core issue in regulatory discussions with the U.S. Food and Drug Administration (FDA). Feedback from the FDA, disclosed by Compass on September 22, included a recommendation to conduct a trial proving survival benefit prior to filing a Biologics License Application (BLA). Compass maintains that, given the urgent unmet medical needs of biliary tract cancer patients and previous clinical outcomes, an additional pre-filing trial is unnecessary. The company stated it will continue preparing for the BLA submission while discussing the regulatory pathway with the FDA.
While negotiating the second-line approval pathway, Compass is also evaluating the potential of using tovestiga in the first-line setting for biliary tract cancer. A Phase I/II clinical trial led by the MD Anderson Cancer Center is evaluating the addition of tovestiga to the standard first-line regimen of gemcitabine, cisplatin, and durvalumab. Both the patient demographic and drug combination differ from COMPANION-002, which paired tovestiga with paclitaxel.
The first-line trial is designed to enroll approximately 50 patients. Following an initial safety evaluation in a lead-in cohort, the target population will be expanded to assess the maximum tolerated dose of tovestiga in combination and progression-free survival at six months. Compass announced the dosing of the first patient in April of last year, prior to the disclosure of the FDA's recommendation. In an August business update, the company projected that the trial is ongoing and that participating sites would expand. MD Anderson is currently actively recruiting patients for the study.
