PolyPEPI1018 Plus TAS-102 Shows Safety in Patients with MSS, Metastatic CRC

The combination of the multipeptide vaccine PolyPEPI1018 and standard chemotherapy trifluride/tipiracil (TAS-102) was shown to be safe and well-tolerated in patients with advanced, chemo-refractory, microsatellite-stable (MSS) metastatic colorectal cancer (CRC), according to phase 1b trial (NCT05130060) results published in the Journal of Clinical Oncology - Oncology Advances.¹

Adverse events (AEs) attributed to PolyPEPI1018 were limited to grade 1 (60%) and grade 2 (33%) local injection-site reactions, which were mild and transient. The intensive vaccination schedule (every 2 weeks at 4 sites) was well-tolerated. No grade 4 AEs were attributed to the treatment.

The most common any grade AEs were fatigue (53.3%), neutrophil count decrease (46.7%), white blood cell decrease (40%), anemia (33.3%), nausea (26.7%), diarrhea, and dysgeusia (both at 13.3%).

The vaccine combination led to the development of both T-cell and antibody immune responses against the vaccine-targeted antigens.

Vaccine-specific CD4+ and CD8+ T-cell responses were detected in all 5 patients with available samples.

There was also promising preliminary activity in the efficacy end points, with a median overall survival (OS) of 8.7 months (95% CI, 6.4–15.2) and a median progression-free survival (PFS) of 4 months (95% CI, 2.2–6.1). These figures compare favorably with the pivotal RECOURSE (NCT01607957)² trial of TAS-102 monotherapy (median OS of 7.1 months, median PFS of 2 months).

MSS metastatic CRC is historically unresponsive to immunotherapy, creating a significant unmet medical need. In the patient population (n = 15), no patients achieved an objective tumor response, however, tumor shrinkage of some degree was observed in 4 patients. The disease control rate (DCR) was 53.3%, with 8 patients achieving stable disease as their best overall response.

Post hoc analysis revealed a stark and clinically significant difference in outcomes based on the presence of active liver metastases (LM). In patients without LM (n = 3), median PFS was 9.7 months, median OS was 14.8 months, and DCR was 100%.¹

In patients with LM (n = 12), median PFS was 2.4 months, median OS was 7.2 months, and DCR was 42%.

These findings align with emerging data suggesting the liver's immunoprivileged environment is a major barrier to the success of immunotherapies in metastatic CRC.

The study also explored the use of a patient's HLA genotype to predict their potential to mount an effective immune response to the vaccine. A proprietary method was used to predict the number of vaccine antigens for which a patient could generate T-cell epitopes based on their specific HLA alleles.

Notably, patients predicted to have a broader immune response (AGP HIGH, ≥ 2 antigens) had a considerably longer median OS (10.3 months) than those predicted to have a narrower response (4.6 months) (AGP LOW, < 2 antigens).

This was a single-arm, open-label, investigator-initiated study. PolyPEPI1018 was administered subcutaneously at 4 sites on days 1 and 15 of each cycle. TAS-102 was administered orally twice daily on days 1–5 and 8–12 of each 28-day cycle. The median age of patients was 55 years (range, 31–71).

This study's relevance, as articulated by the Journal of Clinical Oncology - Oncology Advances’s associate editor Albiruni R. Abdul Razak, MB BCh, MRCPI, CCT, is that it "addresses the critical unmet need in [MSS] metastatic CRC, a setting where immunotherapy has historically shown minimal benefit. By combining the novel multi-peptide vaccine PolyPEPI1018 with TAS-102, the trial demonstrates that chemo-immunotherapeutic strategies can elicit tumor-specific immune responses and signal potential survival benefit, laying groundwork for future treatment development in this resistant disease type."

REFERENCES

1.Hubbard J, Zemla T, Zhu M, et al. PolyPEPI1018 cancer vaccine and TAS-102 for patients with advanced, chemo-refractory, microsatellite-stable metastatic colorectal cancer: A phase 1b nonrandomized study. JCO Oncol Adv 2, e2500108(2025). doi:10.1200/OA-25-00108.

2.Study of TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies (RECOURSE). ClinicalTrials.gov. Updated September 19, 2024. Accessed November 7, 2025. https://clinicaltrials.gov/study/NCT01607957