Pancreatic Cancer: Extended Release siRNA Implant Targeting KRAS Shows Promising Improvement Trends in Survival and Response in Select Patients

Pancreatic Cancer: Extended Release siRNA Implant Targeting KRAS Shows Promising Improvement Trends in Survival and Response in Select Patients

A small interfering RNA (siRNA) implant targeting KRAS G12D/G12V mutations has shown a promising trend toward improved overall survival (OS) and objective response rate (ORR) in patients with locally advanced pancreatic cancer (LAPC) with these mutations, according to results of a multisite, international phase 2 clinical trial led by Memorial Sloan Kettering Cancer Center (MSK). The study findings, published January 13, 2026 in Clinical Cancer Research, (1) indicate that this innovative treatment approach warrants further investigation.

SiG12D-LODER is an extended-release siRNA implant that is injected directly into the tumor using a standard-gauge endoscopic ultrasound (EUS) biopsy needle. The trial (NCT01676529) evaluated the safety, efficacy, and tolerability of siG12D-LODER in combination with chemotherapy in patients with LAPC, regardless of KRAS mutational status, in two cohorts. In cohort 1, patients with unresectable LAPC were randomized to receive siGD12-LODER plus gemcitabine/nab-paclitaxel (GnP) or GnP alone. In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (FOLFIRINOX or GnP) in a single arm. (1)

In the modified intent-to-treat (mITT) population in cohort 1, there was no significant difference in overall survival (OS) between patients treated with siG12D-LODER plus GnP and those treated with GnP alone: OS results were 22.7 months versus 21.9 months, respectively (p > 0.05). (1)

Notably, an exploratory analysis among patients with KRAS G12D/G12V mutations found that OS trended toward improvement in the siG12D-LODER plus GnP arm, with an OS of 22.7 months compared to 13.4 months for the GnP arm (hazard ratio (HR) 0.59, p = 0.39. In cohort 2, the ORR overall was 31.6%, with a higher rate of 57.1% in patients with KRAS G12D/G12V mutations, similar to the 63.6% observed in cohort 1 patients with these mutations. (1)

“The use of an endoscopic platform to deliver therapy directly into the tumor is a very exciting and novel approach for treating pancreatic cancer,” said co-principal investigator gastroenterologist Mark Schattner, MD, FASGE, AGAF, Chief of the Gastroenterology, Hepatology and Nutrition Service. “We anticipate this approach will continue to expand in the future, allowing us to provide patients with more treatment options to battle this disease.”

“It’s exciting to see progress with this targeted local treatment approach. Patients with locally advanced pancreatic cancer experience high rates of morbidity and mortality, and there are few treatment options. Insights from this phase 2 trial are now informing the design of a phase 3 study,” said co-principal investigator gastrointestinal medical oncologist Eileen O’Reilly, MD, Winthrop Rockefeller Endowed Chair of Medical Oncology, Co-Director Medical of the David M. Rubenstein Center for Pancreatic Cancer Research, and Section Head of the Hepatopancreatobiliary Service at MSK. 

At MSK, hepatopancreatobiliary surgeons operate on about 350 people with pancreatic cancer annually, and oncologists and subspecialists treat about 850 patients annually, among the highest number of pancreatic cases in New York City and the nation. MSK is a National Pancreas Foundation Center of Excellence.

Internationally renowned physicians and clinicians at MSK’s David M. Rubenstein Center for Pancreatic Cancer Research conduct bold, innovative, multidisciplinary research aimed at improving the lives of people with pancreatic cancer. Learn more.

Pancreatic Cancer and KRAS Mutations

Pancreatic cancer is usually detected at an advanced stage, with most patients presenting with locally advanced (about 30%) or metastatic disease (about 50%). (2) (3)The current treatment for patients with LAPC is induction chemotherapy with or without radiation. However, only a small percentage of patients respond sufficiently to make surgical resection feasible. (4) For many patients, systemic treatment is associated with high failure rates characterized by local progression, substantial morbidity, and the development of metastatic disease.

Oncogenic missense mutations in KRAS are present in more than 90% of pancreatic ductal adenocarcinoma, with the majority, about 70% to 75%, being G12D or G12V mutations. (5) Active KRAS mutations promote cell proliferation, tumor growth, and therapy resistance. 

Two KRAS G12C-selective inhibitors (note the “C”), adagrasib and sotorasib, are FDA-approved for treating KRAS G12C-mutant advanced non-small cell lung cancer and colorectal cancer. However, various mechanisms can lead to the emergence of resistance to these drugs. (6) (7) (8) (9) While adagrabsib and sotorasib are included in the National Comprehensive Cancer Network guidelines for patients with PDAC and KRAS G12C mutations, these mutations are found in only about 1% of PDAC patients.

Recent studies have suggested that subtypes of pancreatic cancer cells may respond differently to KRAS inhibition, and combination therapy may be needed to improve the durability of response. (10) (11)

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RNA Silencing Therapy with SiG12D-LODER

RNA silencing therapy suppresses gene expression that encodes a mutant protein. Preclinical models of PDAC have shown that SiRNAs targeting KRAS can silence its expression by degrading messenger RNA, leading to decreased cellular proliferation and impaired tumor growth. (12) (13) (14)

The manufacturer Silexion Therapeutics (Modiin, Israel; previously Silenseed) developed the LODER™ delivery platform, which consists of an anti-KRAS G12D siRNA encased in a biodegradable polymer matrix. SiG12D-LODER is injected directly into the tumor using a preloaded standard EUS biopsy needle. (14) (15) This local delivery approach aims to overcome issues associated with systemic therapies, such as peripheral degradation, off-target effects, and immune activation. (16)

Preclinical studies have suggested that siG12D-LODER can inhibit KRAS G12D/G12V alleles in vivo and in wild-type KRAS in vivo. (14) (15) (16) (17) Further, a phase 1/2a clinical trial in combination with chemotherapy in patients with LAPC demonstrated that siG12D-LODER was safe and tolerable with no dose-limiting toxicities observed, with a promising median OS of 15 months, and most patients (76%) achieved stable disease. (17)

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Study Design

The MSK research team included co-first authors Brinda Alagesan, MD, PhD, a fourth-year fellow in the Department of Medicine, and gastrointestinal medical oncologist and principal investigator of the trial, Anna Varghese, MD.

The open-label trial was conducted at nine cancer centers in the United States and Israel. Adult patients were enrolled in cohort 1 from 2018 to 2019 and subsequently in cohort 2 from 2020 to 2023. All patients in both cohorts were enrolled irrespective of KRAS mutation status. (1)

Cohort 1 assessed the efficacy, safety, and tolerability of siG12D-LODER plus GnP versus GnP alone. To facilitate enrollment, the investigators added cohort 2 as a single-arm to assess the safety, tolerability, and efficacy of siG12D-LODER plus standard chemotherapy, either modified FOLFIRINOX or GnP. Cohort 1 included patients with unresectable LAPC, and cohort 2 included patients with LAPC or borderline resectable pancreatic cancer. Eligibility criteria for both cohorts included measurable disease with a target tumor accessible by EUS. (1)

In cohort 1, siG12D-LODER was inserted into the pancreatic tumor once every 12 weeks. Each dose consisted of eight 2.8 mg units administered in two insertions. Patients in arm 1 began systemic therapy within 7 days of the first siG12D-LODER insertion. Patients in both arms of cohort 1 received intravenous GnP on days 1, 8, and 15 of a four-week schedule. (1)

In cohort 2, patients received siG12D-LODER as described above, along with standard chemotherapy beginning up to 7 days after the first siG12D-LODER insertion. Patients were assigned to GnP or FOLFIRINOX/mFOLFIRINOX at the investigator’s discretion. (1)

The primary endpoints were OS in cohort 1 and ORR in cohort 2, defined as the proportion of patients with a confirmed complete or partial response. Additional study endpoints included progression-free survival (PFS), duration of response (DoR), OS for cohort 2, and ORR for cohort 1. Safety evaluations included vital signs, physical examinations, Eastern Cooperative Oncology Group Performance Status, pain assessments, clinical laboratory assessments, and adverse events. Exploratory endpoints included primary endpoints analyzed by KRAS mutational status. (1)

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Study Results

A total of 59 patients with pancreatic cancer were enrolled in both cohorts of the study. Overall, 38 patients were treated with siG12D-LODER. (1)

Cohort 1 Results

Cohort 1 enrolled 37 patients, with 19 patients randomized to receive siG12D-LODER plus GnP (arm 1) and 18 patients randomized to receive GnP (arm 2). The mITT group included 18 patients in arm 1 and 11 patients in arm 2. (1)

In the mITT group, median OS was 22.7 months in arm 1 compared with 21.9 months in arm 2 (HR 1.47, p = 0.361). (1)

The secondary endpoint of ORR was 44.4% in arm 1 compared to 27.3% in arm 2 (odds ratio 2.13, p = 0.36). No patients in either study arm achieved a complete response. There was no significant difference between arms for the PFS or DoR secondary endpoints. (1)

The investigators performed an exploratory analysis of results for patients with an available KRAS mutational status. The analysis revealed a promising trend toward improved survival among cohort 1 patients with KRAS G12D/G12V mutations: the median OS was 22.7 months in 11 patients in arm 1, compared with 13.4 months in 5 patients in arm 2 (HR 0.59, p = 0.39). Additionally, in patients with KRAS G12D/G12V-mutated disease, the secondary endpoint of ORR trended higher to 63.6% in arm 1 versus 20% in arm 2 (p > 0.05). (1)

Cohort 2 Results

Following completion of cohort 1, 22 patients enrolled in cohort 2, and 20 of them received treatment and had at least one post-baseline tumor assessment. The primary efficacy endpoint of ORR in the mITT population was 31.6% overall. The secondary endpoint of OS was 22.1 months. (1)

The exploratory analysis showed that the ORR was 57.1% for cohort 2 patients with KRAS G12D/G12V mutations, similar to the 63.6% rate observed in cohort 1, arm 1. (1)

Safety Results Across Both Cohorts

The combination of siG12D-LODER and standard chemotherapy was generally well-tolerated with toxicities in line with previous data. (17)All patients experienced at least one treatment-emergent adverse event (TEAE), with the most common events of any grade being gastrointestinal disorders, blood disorders, fatigue, fever, and chills. (1)

A total of 27 patients reported serious TEAEs (24 received siG12D-LODER plus GnP, 3 received GnP). Sepsis, the most frequently reported event, occurred in five patients. However, only one case was possibly related to siG12D-LODER treatment and all other events occurred more than a month after study treatment. Two deaths occurred in the siG12D-LODER population, which the safety review board determined were caused by recognized complications of unresectable pancreatic ductal adenocarcinoma and unrelated to siG12D-LODER. (1)

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Next Steps

“While the present study did not meet its primary endpoint in the overall patient population, the directional findings among patients with KRAS G12D/G12V-mutated disease are encouraging and are informing the design of a future phase 2/ 3 trial,” said Dr. O’Reilly, who is Chair of the new trial in development.

In their paper, the authors noted that the manufacturer has developed a next-generation siRNA product, SIL-204, with increased stability and broader silencing activity across a range of KRAS mutations (G12x, Q61H, and G13D). (1)

“SIL-204 is currently in late-stage preclinical development,” Dr. O’Reilly said. “At MSK, we look forward to continuing to advance groundbreaking treatment approaches that hold promising potential for improving outcomes for patients with pancreatic cancer.”

Learn more about MSK clinical trials for patients with pancreatic cancer.

The study was sponsored by Silexion Therapeutics (Israel). The study was supported by funding from the National Institutes of Health/National Cancer Institute MSK Cancer Center Support Grant/Core Grant P30 CA008748 and P50 CA257881-01A1. Access disclosures for Dr. O’Reilly. For disclosures for other study authors, refer to the paper.

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