1626P - A novel endoscopic ultrasound guided extended-release siRNA implant targeting KRASG12D/V in localized pancreatic cancer

Background

Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancer (PC). LAPC incurs high mortality. We evaluated a novel extended-release siRNA targeting KRAS^G12D/V (G12D/V) mutations (Loder) in combination with standard chemotherapy.

Methods

A two-cohort, phase II multicenter, open-label trial was conducted. 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.

Results

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. GnP arm.

Table: 1626P

Loder treatment was well tolerated. Safety events were primarily related to procedure, mainly reversible abdominal pain. Four Grade 5 events (visceral arterial ischemia, sepsis; 2 progression of disease), assessed as unrelated.

Conclusions

Loder with chemotherapy is feasible, safe, and shows a promising signal in KRASG12D/V BR, LAPC. Further evaluation is warranted.

Clinical trial identification

NCT01676259.

Editorial acknowledgement

Legal entity responsible for the study

Silenseed Ltd.

Funding

Silenseed Ltd.

Disclosure

A.M. Varghese: Financial Interests, Institutional, Local PI, Institutional PI of multi-institution clinical trial: Bristol Myers Squibb, GSK, Lilly Oncology, OBI Pharma, Inc, Silenseed Ltd. T. Golan: Financial Interests, Personal, Advisory Board: AstraZeneca, AbbVie, Teva, Merck MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Grant: AstraZeneca; Financial Interests, Institutional, Other, grant: Merck MSD. M. Schattner: Financial Interests, Personal, Advisory Board: Boston scientific; Financial Interests, Personal, Advisory Board, data safety monitoring board: Novo Nordisk. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Other, Consultant: Merck; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Local PI: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Sereno, Fate Therapeutics, GSK, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta. M. Passhak: Financial Interests, Personal, Invited Speaker: Medison, Roche, Merk. R. Geva: Financial Interests, Personal, Other, Honoraria: Roche, MSD, Merck, Medison, Janssen, Pfizer, BMS; Financial Interests, Personal, Advisory Board, 07/2022: AstraZeneca; Financial Interests, Personal, Advisory Board, Ended 3/2022: BOL Pharma; Financial Interests, Personal, Advisory Board: Roche, Ranium, JNJ, Bayer, Oncotest; Financial Interests, Personal, Advisory Board, 06/2022: MSD; Financial Interests, Personal, Other, Travel/Accommodations/Expenses 01/2022: Takeda; Financial Interests, Personal, Other, Travel/Accommodations/Expenses - 06/2022: Medison; Financial Interests, Personal, Other, Options: Pyxis; Financial Interests, Personal, Other, Medical lead: Pyxis. R. Ligresti: Financial Interests, Personal, Advisory Board: Immunovia, Steris; Financial Interests, Institutional, Member of Board of Directors: HMH Partners. M.S. Bhutani: Financial Interests, Personal, Other, Consultant: Oncosil, Starpax; Financial Interests, Institutional, Research Grant: Nanobiotix, Augmenix. O. Pollack-Shragai: Financial Interests, Institutional, Full or part-time Employment, VP Clinical Operations: Silexion; Non-Financial Interests, Leadership Role, VP Clinical Operations: Silexion; Non-Financial Interests, Institutional, Proprietary Information, As VP of Clin. Ops. I am exposed to proprietary information: Silexion. M. Shirvan: Financial Interests, Personal, Officer, Company CSO: Silenseed Ltd; Financial Interests, Personal, Stocks/Shares, I have stock options in Silenseed Ltd: Silenseed Ltd. M. Javle: Financial Interests, Personal, Advisory Board: QED, Taiho, Merck, Transthera, Incyte, Servier, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Oncosil, Incyte; Non-Financial Interests, Principal Investigator: QED, Basilea. E.M. O'Reilly: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BioNTech, Merck, AstraZeneca, Novartis, FibroGen, Astellas, Tempus, Merus, BMS, Berry Genomics, Exelixis, Incyte, Helio, Neogene, Newbridge, QED, Servier, Thetis, Vector, Yiviva; Financial Interests, Personal, Advisory Board, +Spouse: Ipsen; Financial Interests, Personal, Advisory Board, Spouse: Genentech/Roche, Eisai; Financial Interests, Personal, Advisory Board, + spouse: Autem; Financial Interests, Institutional, Local PI: Genentech/Roche, Arcus, Elicio; Financial Interests, Personal and Institutional, Coordinating PI: BioNTech; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Pertzye; Financial Interests, Institutional, Research Grant: Parker Institute for Cancer Immunotherapy; Non-Financial Interests, Other, Scientific and Medical Advisory Board: Pancreas Cancer Action Network; Non-Financial Interests, Member of Board of Directors: National Pancreas Foundation; Other, Editor: American Society of Clinical Oncology, American Association of Cancer Research (AACR); Other, Advisor/no compensation: Thetis, BioSapien. All other authors have declared no conflicts of interest.