Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
A Phase II Trial of an Extended-Release siRNA Implant Targeting KRASG12D/V in Locally Advanced Pancreatic Cancer.
СтатьяКлиническое исследование II фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Alagesan Brinda, Varghese Anna M, Ang Celina, Gutierrez Martin, Kamar Moshe, Passhak Maria, Geva Ravit, Yarom Nirit, Lahav Maor, Ligresti Rosario, Khamaysi Iyad, Bhutani Manoop S, Phillips Adam, Matalon Shay, Pollack-Shragai Orit, Rom Dror, Shirvan Mitchell, Javle Milind M, Park Wungki, Yu Kenneth, Schwartz Carly, Golan Talia, Schattner Mark, O'Reilly Eileen M
Аннотация
PURPOSE: Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRASG12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC.
PATIENTS AND METHODS: This two-cohort, phase II multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, regardless of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (arm 1) or gemcitabine/nab-paclitaxel alone (arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, nonrandomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival, duration of response, OS (cohort 2), and ORR (cohort 1).
RESULTS: Across two cohorts, 59 patients were enrolled. In cohort 1, the median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (P > 0.05). Among patients with KRASG12D/V mutations, OS was 22.7 versus 13.5 months [HR, 0.59; 95% confidence interval (CI), 0.18-1.96; P = 0.39]. In cohort 2, ORR was 31.6% (95% CI, 0.13-0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. Treatment-emergent adverse events were mainly procedure related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm.
CONCLUSIONS: siG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRASG12D/V-mutant LAPC.
PATIENTS AND METHODS: This two-cohort, phase II multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, regardless of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (arm 1) or gemcitabine/nab-paclitaxel alone (arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, nonrandomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival, duration of response, OS (cohort 2), and ORR (cohort 1).
RESULTS: Across two cohorts, 59 patients were enrolled. In cohort 1, the median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (P > 0.05). Among patients with KRASG12D/V mutations, OS was 22.7 versus 13.5 months [HR, 0.59; 95% confidence interval (CI), 0.18-1.96; P = 0.39]. In cohort 2, ORR was 31.6% (95% CI, 0.13-0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. Treatment-emergent adverse events were mainly procedure related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm.
CONCLUSIONS: siG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRASG12D/V-mutant LAPC.