LODER Plus SOC Chemotherapy Elicits Responses, Boosts OS in KRAS+ Unresectable, Locally Advanced Pancreatic Cancer

Ilan Hadar

The addition of siG12D LODER to standard-of-care (SOC) chemotherapy generated responses and improved overall survival (OS) compared with chemotherapy alone in patients with unresectable, locally advanced pancreatic cancer harboring KRAS G12D/V mutations, according to updated data from the phase 2 PROTACT trial (NCT01676259).¹

Findings announced by Silexion Therapeutics showed that patients harboring a KRAS G12D or G12V mutation treated with LODER plus chemotherapy (n = 18) experienced an objective response rate (ORR) of 56% compared with 20% for those given chemotherapy alone (n = 5). Patients treated with LODER and chemotherapy achieved a 9.3-month improvement in OS. Furthermore, the ORR was 67% in patients treated with LODER plus chemotherapy whose disease became resectable.

“We are very encouraged by these new findings, which demonstrate LODER's ability to significantly improve tumor resectability in patients with non-resectable pancreatic cancer, and the improved profile of SIL-204,” Ilan Hadar, chairman and CEO of Silexion Therapeutics, stated in a news release. “As we advance our broader pipeline to address KRAS-driven cancers, this data further validates our oncogene silencing approach.”

LODER is a proprietary, miniature biodegradable polymeric matrix that features small-interfering RNAs (siG12D) for KRAS G12D mutations. After being injected intratumorally, siG12D is released locally with the goal of preventing translation of KRAS proteins and inhibiting growth of tumor cells with KRAS overexpression.²

The prospective, multinational, multicenter, open-label PROTACT trial enrolled patients at least 18 years of age with histologically or cytologically confirmed, locally advanced, stage III adenocarcinoma of the pancreas who were allocated to receive first-line treatment with gemcitabine plus nab-paclitaxel (Abraxane), FOLFIRINOX, or modified FOLFIRIONOX. Key inclusion criteria consisted of an accessible target tumor for intratumoral administration of LODER by endoscopic ultrasound; measurable disease per RECIST 1.1 criteria; an ECOG performance status of 0 or 1; and adequate organ function.³

Patients were excluded if they had resectable pancreatic cancer; had evidence of metastatic disease; had any evidence of ascites; had bulky celiac adenopathy of at least 2.5 cm or non-adenocarcinoma histology; had a history of clinically significant coagulopathy; underwent major surgery, except for diagnostic surgery, within 4 weeks of enrollment; had New York Heart Association class III or IV cardiac disease, myocardial infarction within 4 months to the first dose of chemotherapy, or unstable arrhythmia or symptomatic peripheral arterial vascular disease; or active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.

The study also excluded patients who received any prior therapy for the treatment of pancreatic cancer, including chemotherapy, immunotherapy, vaccines, monoclonal antibodies, major surgery, or irradiation. Prior therapy with any hypoxia-targeting drugs was not allowed.

In clinical trial sites in the United States and Israel, patients in cohort 1 (n = 29) were randomly assigned 1:1 to receive LODER plus SOC chemotherapy or chemotherapy alone; 16 patients in this cohort had confirmed KRAS G12D or G12V mutations. In cohort 2 (n = 19), patients with unresectable, locally advanced or borderline resectable pancreatic cancer received LODER plus chemotherapy; 7 patients in this group harbored KRAS G12D or G12V mutations.¹

The primary end point in cohort 1 was OS. ORR and safety were primary end points for cohort 2.

The next-generation product, SIL-204, is being developed by Silexion Therapeutics with the goal of building upon the efficacy LODER.SIL-204 is intended to target a wider range of KRAS mutations, included pan-G12x and G13D.

References

1. Silexion Therapeutics announces significant new data from phase 2 trial of LODER in non-resectable pancreatic cancer. News release. Silexion Therapeutics. September 24, 2024. Accessed September 24, 2024. https://silexion.com/wp-content/uploads/2024/09/SLXN-FINAL-PR-_-240924.pdf
2. siG12D LODER. National Cancer Institute. Accessed September 24, 2024. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/sig12d-loder
3. A phase 2 study of siG12D LODER in combination with chemotherapy in patients with locally advanced pancreatic cancer (PROTACT). ClinicalTrials.gov. Updated July 2, 2021. Accessed September 24, 2024. https://clinicaltrials.gov/study/NCT01676259