Efficacy and safety of ponsegromab in patients with colorectal cancer and cachexia: A subgroup analysis of the PROACC-1 phase 2 study.

110 Background: Ponsegromab is a monoclonal antibody that inhibits growth differentiation factor 15 (GDF-15), a circulating cytokine implicated in cachexia. Here, we report the body weight and safety findings from the subset of participants with colorectal cancer (CRC) in a phase 2, randomized, double-blind trial of ponsegromab versus placebo in patients with cancer cachexia (PROACC-1; NCT05546476). Methods: Patients with cancer, cachexia, and elevated serum GDF-15 (≥1500 pg/mL) (n=187) were randomized 1:1:1:1 to subcutaneous ponsegromab (100, 200, 400 mg) or matching placebo every 4 weeks for 12 weeks. The primary endpoint was a change from baseline (CFB) in body weight at 12 weeks. Safety and tolerability were key secondary endpoints. Results: Overall, 54 participants (28.9% of the overall study population) had CRC (mean age 65.1±11.9 years; 61.1% male; 81.5% stage IV). Baseline mean body weight was 56.5±13.3 kg; 51.9% and 48.1% had a body mass index <20 kg/m 2 and body weight loss over prior 6 months of ≥10%, respectively. Overall, the median GDF-15 level was 6468 (interquartile range 4106, 10052) pg/mL. Dose-responsive increases in body weight were observed at 12 weeks in ponsegromab groups relative to placebo, reaching statistical significance in the 200- and 400-mg ponsegromab groups (Table). All-causality and treatment-related adverse events (AEs) occurred in 60.5% and 5.3% of ponsegromab-treated patients and 81.3% and 6.3% of placebo-treated patients, respectively. Gastrointestinal-related all-causality AEs occurred less frequently in ponsegromab-treated versus placebo participants (34.2% vs 62.5%), including nausea (0% vs 18.8%), vomiting (2.6% vs 25.0%), and diarrhea (5.3% vs 18.8%). Conclusions: Among patients with CRC, cachexia, and elevated GDF-15 levels, GDF-15 inhibition with ponsegromab through 12 weeks resulted in body weight gain and was generally well tolerated. Clinical trial information: NCT05546476 . Change from baseline in body weight at Week 12, kg N n Observed Mean (SD) LS Mean* (90% CI) LS Mean* Difference from Placebo (90% CI) 1-sided p -value a Placebo 16 12 -1.24 (1.98) -1.59(-3.26, 0.07) - - Ponsegromab 100 mg 13 11 +0.54 (3.78) -0.29(-1.96, 1.39) +1.31(-1.05, 3.67) 0.1804 Ponsegromab 200 mg 10 8 +0.88 (4.80) +1.55(-0.48, 3.57) +3.14(0.50, 5.77) 0.0253 Ponsegromab 400 mg 15 8 +4.51 (4.66) +3.37(1.51, 5.23) +4.96(2.46, 7.46) 0.0006 N: number of participants at baseline. n: number of participants with change from baseline values at Week 12. a Modeled LS means, differences and confidence intervals are from a mixed model repeated measures analysis. CI, confidence interval; LS, least squares; SD, standard deviation.