Phase 1/2 study of nivolumab and ipilimumab combined with gemcitabine, nab-paclitaxel, and adaptive stereotactic body radiotherapy in bordeline resectable, locally advanced or metastatic pancreatic cancer (LAPTOP).

4168 Background: This phase 1/2 study (NCT04247165) evaluated the safety and efficacy of combining nivolumab, ipilimumab, gemcitabine, nab-paclitaxel, and adaptive stereotactic body radiotherapy (SBRT) in patients with borderline resectable (BRPC), locally advanced (LAPC), or metastatic pancreatic cancer (mPC). Methods: Treatment-naïve patients with BRPC, LAPC or mPC received 28-day cycles of nivolumab (3 mg/kg), ipilimumab (1 mg/kg single dose), and gemcitabine (800 mg/m 2 ) with nab-paclitaxel (100 mg/m 2 on days 1, 8, and 15). Starting in cycle 3, patients underwent MRI or CT-guided adaptive SBRT (8 Gy x 3 fractions) targeting the primary pancreatic tumor. Primary endpoint: safety, defined by the incidence of treatment-related adverse events (TRAEs) leading to discontinuation, monitored via a Bayesian stopping rule for rates exceeding 30%. Secondary endpoints: OS, PFS, ORR, DCR, DOR, and resection rate. Exploratory endpoint: immunological changes. Results: A total of 55 patients received at least one treatment (BRPC: n=1, LAPC: n=23, mPC: n=31), with a median follow-up of 27.6 months (IQR 26.3-34.4) calculated via reverse Kaplan-Meier. Grade 3-4 TRAEs occurred in 70.8% of BRPC/LAPC and 71.0% of mPC patients. No grade 5 TRAEs were observed. Treatment discontinuation due to TRAEs occurred in 20.8% (BRPC/LAPC) and 9.7% (mPC). Median OS: 23.0 months (95% CI: 11.4–NR) for BRPC/LAPC and 11.2 months (6.8–15.8) for mPC. Median PFS: 14.9 months (8.7–24.2) for BRPC/LAPC and 6.1 months (3.8–8.4) for mPC. ORR: 33.3% (15.6–55.3) for BRPC/LAPC and 19.4% (7.5–37.4) for mPC. DCR: 75.0% (53.3–90.2) for BRPC/LAPC and 61.3% (42.2–78.2) for mPC. Median DOR: 8.9 months (4.0–12.7). Nine (37.5%) BRPC/LAPC patients and three (9.7%) mPC patients underwent resection. Preliminary analyses revealed treatment-induced T-cell activation, particularly after SBRT, with upregulation of activation and stemness markers in patients with durable clinical benefit. Conversely, an increase in senescence markers was observed in the rest of the cohort. Conclusions: The combination of nivolumab, ipilimumab, gemcitabine, nab-paclitaxel, and adaptive SBRT demonstrated an acceptable safety profile and efficacy supporting further investigation in BRPC, LAPC, and mPC patients. Clinical trial information: NCT04247165 .