Efficacy and safety of cafelkibart (LM-108), an anti-CCR8 monoclonal antibody, in combination with anti-PD-1 therapy in patients with pancreatic cancer: Results from phase 1/2 studies.

4010 Background: Targeting tumor-infiltrating Tregs presents a promising strategy to overcome resistance to immunotherapy in cancer treatment. LM-108 is a novel Fc-optimized anti-CCR8 monoclonal antibody designed to selectively deplete tumor-infiltrating Tregs while sparing peripheral Tregs. This pooled analysis of two phase 1/2 trials assesses the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with pancreatic cancer. Methods: Eligible patients (pts) with pancreatic cancer who had progressed on or after at least one prior line of systemic therapy were included. Treatment regimens included LM-108 at doses of 3 mg/kg Q3W, 3 mg/kg Q2W, 10 mg/kg Q3W, or 10 mg/kg Q2W, in combination with pembrolizumab (400 mg Q6W) or toripalimab (240 mg Q3W). The primary endpoint was ORR. Secondary endpoints were DCR, PFS, OS, DoR, safety, and biomarkers analysis. Data cutoff: December 2, 2024. Results: A total of 80 pts (median age: 63 years; 58.8% male) from China and Australia were treated. Of these, 48 pts had progressed on or after 1 prior line of therapy, and 32 pts had ≥2 lines. Eighteen pts (22.5%) had prior anti-PD-1 therapy, and 52 pts (65.0%) had liver metastases at baseline. TRAEs were reported in 76 pts (95.0%). Common TRAEs (≥25%) included increased AST, increased ALT, anemia, rash, pyrexia, decreased platelet count and increased conjugated bilirubin. Grade ≥3 TRAEs occurred in 42 pts (52.5%), the most common events (≥5%) were lipase elevation (7.5%), increased ALT (6.3%), increased AST (5.0%), immune-mediated enterocolitis (5.0%), hypokalemia (5.0%), and rash (5.0%). Median follow-up was 10.48 months (95% CI 7.20-12.65). Among 74 efficacy-evaluable pts, ORR was 20.3% (95% CI 11.8-31.2%) and DCR was 62.2% (95% CI 50.1-73.2%). Median DoR was 5.49 months (95% CI 3.02-8.87), PFS was 3.12 months (95% CI 1.61-4.86), and OS was 10.02 months (95% CI 6.41-13.11). Among 45 pts who had progressed on or after one prior line of therapy, ORR was 24.4% (95% CI 12.9-39.5%) and DCR was 71.1% (95% CI 55.7-83.6%), with a median DoR of 6.93 months (95% CI 3.02-NA), PFS of 4.86 months (95% CI 2.79-6.90), and OS not reached. The 12-month OS rate was 51.6% (95% CI 31.4-68.5%). Among these, 9 pts with high CCR8 expression (7 with baseline liver metastases) showed ORR of 33.3% (95% CI 7.5-70.1%) and DCR of 77.8% (95% CI 40.0-97.2%). Median PFS was 6.90 months (95% CI 1.22-NA), and OS was 9.15 months (95% CI 3.61-NA). Conclusions: LM-108 in combination with anti-PD-1 therapy demonstrated encouraging antitumor activity and a manageable safety profile in patients with pancreatic cancer who had progressed on or after prior systemic therapies. These findings support further investigation of LM-108 in combination with anti-PD-1 therapy as a potential treatment option for pancreatic cancer. Clinical trial information: NCT05199753 ; NCT05518045 .