KRASG12D-LODER: brief review of its R&D progress and the clinical result in 2023 ESMO

Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancer (PC). LAPC incurs high mortality. On October 20, 2023, a novel extended-release siRNA targeting KRASG12D/V (G12D/V) mutations (Loder) in combination with standard chemotherapy was reported at the ESMO Congress.

KRASG12D-LODER's R&D Progress

The drug KRASG12D-LODER is a small interfering RNA (siRNA) that targets the KRAS G12D gene. It is being developed for the treatment of pancreatic cancer, a type of neoplasm that affects the digestive system. Additionally, it has potential therapeutic applications in the fields of endocrinology and metabolic diseases.

According to the Patsnap Synapse, KRASG12D-LODER is currently in Phase 2, which is the second highest phase in the drug development process. And the clinical trial areas for KRASG12D-LODER are primarily in the United States and Israel. The key indication is Pancreatic Ductal Adenocarcinoma and Locally Advanced Pancreatic Adenocarcinoma.

Detailed Clinical Result of KRASG12D-LODER

The two-cohort, phase II multicenter, open-label trial (NCT01676259) was conducted in pancreatic cancer patients. 

In this study, cohort 1: Patients (pts) with LAPC randomized to: Loder + gemcitabine/nab-paclitaxel (GnP); or GnP. Cohort 2: pts with Borderline Resectable (BR) PC or LAPC single arm, Loder + (modified)FOLFIRINOX ((m)FFX) or GnP. The Loder was inserted into primary tumor via endoscopic ultrasound (EUS 19G needle) q3 mo. for 2-3 doses. mITT, all patients ≥ 1 treatment. Key study endpoints: overall survival (OS), safety.

The result showed that N= 49 pts in mITT (6 BRPC, 43 LAPC, Loder n=38, control n=11). KRAS known for n=35: G12V, n=12; G12D, n=11; G12R, n=7; Q61R, n=2; wild-type, n=1. For mITT: no difference in OS for Loder + chemo vs. chemo (OS=21.1 vs. 22.2 mo.). However, in pts with G12D/V a non-statistically significant numerical advantage was seen in Loder + (m)FFX or GnP arm (n=18, Cohorts 1,2) median OS = 19.4 mo. vs. 13.8 mo.

It can be concluded that loder with chemotherapy is feasible, safe, and shows a promising signal in KRASG12D/V BR, LAPC. Further evaluation is warranted.

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