RIVER-mPDAC: A phase 2b/3 study of ponsegromab for the treatment of cachexia in patients with metastatic pancreatic ductal adenocarcinoma receiving first-line chemotherapy.

TPS791 Background: Ponsegromab is a humanized monoclonal antibody targeting growth differentiation factor 15 (GDF-15), a circulating cytokine linked to cancer cachexia. A phase 2 study showed that ponsegromab statistically significantly increased body weight and improved appetite and cachexia symptoms vs placebo, with a tolerable safety profile, in patients with non-small cell lung, colorectal, or pancreatic cancers (Groarke et al, N Engl J Med 2024). Methods: RIVER-mPDAC (NCT06989437) is a double-blind, placebo-controlled, randomized, phase 2b/3 study evaluating ponsegromab combined with first-line (1L) chemotherapy in patients with cachexia and metastatic pancreatic ductal adenocarcinoma (mPDAC). The study will enroll ≈1000 patients across the phase 2b and phase 3 parts of the study, with no interruption in enrollment between phases 2b and 3. Endpoints are detailed in the Table. Eligible patients are adults (≥18 years) with measurable mPDAC, cachexia (per Fearon criteria), and ECOG PS ≤1 who are receiving 1L chemotherapy (nab-paclitaxel + gemcitabine, or FOLFIRINOX modification allowed). Exclusion criteria include active reversible causes of decreased food intake, tube feedings or parenteral nutrition, and cachexia from other conditions. In phase 2b, patients will be randomized 1:1:1 to subcutaneous ponsegromab (200 or 400 mg) or matched subcutaneous placebo every 4 weeks, stratified by ECOG PS and chemotherapy regimen. The phase 3 ponsegromab dose will be determined based on the results of phase 2b. Phase 3 patients enrolled before dose selection will be randomized 1:1:1 per phase 2b doses, stratified by ECOG PS, chemotherapy regimen, and BMI-adjusted weight loss. Those enrolled after dose selection will be randomized 1:1 to ponsegromab or placebo every 4 weeks. The study also includes an optional open-label extension (≤1 year). Clinical trial information: NCT06989437 . Phase 2b Phase 3 Primary endpoints Percent change from BL in body weight at Week 12 Change from BL in appetite-related symptoms (FAACT-5IASS) Percent change from BL in body weight at Week 12 Change from BL in appetite-related symptoms (FAACT-5IASS) Key secondary endpoints Not applicable Change from BL in physical activity at Week 12 OS Other secondary endpoints Change from BL in physical activity at Week 12 OS Safety/tolerability PFS, ORR, DOR, DCR Change in body composition, body weight, physical function, and fatigue Safety/tolerability BL, baseline; FAACT-5IASS, Functional Assessment of Anorexia/Cachexia Therapy 5-item Anorexia Symptom Scale.