Efficacy and safety of surufatinib (S) plus KN046 (K) and chemotherapy in first line (1L) advanced pancreatic cancer (PC): A single-arm, phase 1b/2 trial.

4157 Background: Gemcitabine (G) and nab-paclitaxel (nP) are standard 1L regimen for patients (pts) with unresectable PC, yet the efficacy remains unsatisfactory. K is a humanized bispecific antibody targeting PD-L1/CTLA-4, while S is a kinase inhibitor of VEGFR1-3, FGFR1 and CSF-1R with immune-regulatory potential. It is hypothesized the add-on of S and K to GnP chemotherapy would provide improved efficacy. Methods: This single-arm, phase 1b/2 trial enrolled pts with unresectable locally advanced or metastatic PC who were eligible for 1L treatment. The phase 1b part was designed in a "3+3" algorithm to determine the recommended phase 2 dose (RP2D) of S for dose expansion in phase 2 part. Pts received oral S at escalating dose starting from 200 mg qd, plus intravenous K at 5 mg/kg on day 1, and GnP chemotherapy on days 1 and 8 at 21-day cycles. The primary endpoint was dose-limiting toxicities (DLTs) within the first 28 days for phase 1b, and ORR per RECIST 1.1 for phase 2. Secondary endpoints included DCR, PFS, OS, safety, and efficacy-related biomarkers. Results: As of Dec 19th, 2024, 18 pts were enrolled with a median age of 54 (range: 41-74), predominantly male (16/18) and metastatic disease (15/18). Of the 16 pts with genetic testing, KRAS (15/16) and TP53 (11/16) mutations were common, followed by DNA damage response (DDR) -related mutations (7/16) including ARID1A , ATM , CHEK2 , etc., while TMB-H (1/16) is rare, and none had MSI-H or dMMR status. Within the 9 pts from phase 1b part (3 in S 200 mg cohort, 6 in S 250 mg cohort), no DLTs occurred thus the RP2D of S was determined as 250mg qd. In the 16 evaluable pts, the best overall responses were 1 CR, 10 PRs and 5 SDs. The ORR was 68.8% and the DCR was 100%. 2 pts received R0 resection after 6 cycles' treatment. With a median follow up of 7.43 months, the estimated median PFS was 8.25 (95% CI: 4.57-NR) months and the 6-month PFS rate was 72.9%. Estimated median OS was 11.14 (95% CI: 5.52-NR) months and the 6-month OS rate was 82.5%. In the exploratory analysis, DDR-related mutations seemed predictive for better ORR (85.7% vs 55.6%, P = 0.308), PFS (6-month PFS rate:100% vs 53.3%, log-rank P = 0.519), and OS (6-month OS rate:100% vs 62.5%, log-rank P = 0.116). Treatment-related adverse events (TRAEs) occurred in 14 (77.8%) pts, and most common TRAEs (≥20%) included leucopenia (44.4%), hypertension (38.9%), and thrombocytopenia (22.2%). TRAEs of grade ≥3 included leucopenia, neutropenia, thrombocytopenia, and hypertension (n = 2 [11.1%] for each). There were no treatment-related deaths. Conclusions: These preliminary results showed encouraging anti-tumor efficacy and an acceptable safety profile of S plus K and GnP chemotherapy as 1L treatment for advanced PC. Clinical trial information: NCT05832892 .