Abstract CT264: Mutant KRAS peptide vaccine combined with ipilimumab/nivolumab in advanced mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer: Preliminary analysis from a phase I study

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Immune checkpoint inhibitors (ICIs) have minimal activity in the ∼95% of metastatic CRC that are MMRp/MSS, largely due to significantly lower expression of neoantigens. Combining neoantigen vaccines targeting mutant KRAS (mKRAS), an oncogenic driver found in ∼40% of CRC, with ICIs, may sensitize metastatic mKRAS MMRp/MSS CRC to immunotherapy. Methods: This is a first-in-human Phase 1 trial (NCT 04117087) of mKRAS-VAX - a pooled synthetic long peptide (SLP) vaccine targeting the six most common KRAS mutations (G12D, G13D, G12V, G12C, G12A, G12R) - in combination with ipilimumab/nivolumab (ipi/nivo) in patients with heavily pretreated MMRp/MSS CRC (progression on 2 or more lines of chemotherapy). Key inclusion criteria included tumor expression of a KRAS mutation included in mKRAS-VAX and prior 5-fluorouracil, oxaliplatin, and irinotecan exposure. In the priming phase, patients received 4 weekly doses of mKRAS-VAX as well as ipilimumab (1mg/kg every 6 weeks for 2 doses) and nivolumab (3mg/kg every 3 weeks for 4 doses). In the boost phase, patients received mKRAS-VAX every 8 weeks and nivolumab (480mg every 4 weeks) up to 1 year total. Primary endpoints are safety and mKRAS-specific T cell response. Secondary endpoints are overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: At the time of data cutoff (December 13, 2024), 12 patients have been treated. Most adverse events were grade 1 (61.2%) or grade 2 (29.6%). 31.6% of AEs were immune-related including three that were grade 3 (2 adrenal insufficiency, 1 arthralgia). There was one grade 4 adverse event (sepsis), which was not treatment related. 8/12 (75%) patients achieved a mKRAS-specific T cell response to their tumor specific KRAS mutation as assessed by serial IFNγ ELISpot, with a median 9-fold increase from baseline. There was one RECIST partial response (8.3%) and 2/7 (29%) patients with active liver metastases had tumor shrinkage, a phenotype which is increasingly recognized as refractory to immunotherapy in MMRp/MSS CRC. The disease control rate (DCR) was 41.7% (5/12) with a median PFS was 3.7 months and median OS of 24.9 months. Conclusions: mKRAS-VAX and ipi/nivo is well-tolerated and induced mKRAS-specific T-cell responses. Moreover, this strategy resulted in meaningful clinical responses in chemorefractory metastatic mKRAS MMRp/MSS CRC with OS that was provocative. Ongoing studies of the T cell repertoire in blood and tumor tissue will be used to identify biomarkers that predict response to mKRAS-targeted immunotherapy. A Phase 1b clinical trial (NCT06411691) investigating mKRAS-VAX with ICIs balstilimab and botensilimab in advanced MMRp/MSS CRC and pancreatic ductal adenocarcinoma is underway. Citation Format: Hejia Henry Wang, Amanda Huff, Saurav Haldar, Maureen Berg, Christopher Thoburn, Katherine Bever, Michael Pishvaian, Valerie Lee, Dung Le, Eric Christenson, Marina Baretti, Jennifer Durham, Amy Thomas, Mark Yarchoan, Daniel Laheru, Julie Nauroth, Jiayun Lu, Hao Wang, Elizabeth M. Jaffee, Nilofer Azad, Neeha Zaidi. Mutant KRAS peptide vaccine combined with ipilimumab/nivolumab in advanced mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT264.