Purpose: Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a “cold” tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. Patients and Methods: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients’ liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose–efficacy correlation. The host HLA genotype predicted multi-antigen–specific T-cell responses (P = 0.01) indicative of clinical outcome. Conclusions: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.

Re-treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies offers a promising approach to extend the continuum of care of patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) with no mutations of resistance in their circulating tumor DNA (ctDNA) at the time of treatment re-exposure. PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab and regorafenib in chemorefractory RAS and BRAF wt mCRC patients, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA. Eligible patients were randomly assigned 1 : 1 to receive anti-EGFR re-treatment with panitumumab followed by regorafenib after progression (arm A) versus the reverse sequence (arm B). The primary endpoint was overall survival (OS). Between December 2020 and December 2024, 428 patients underwent molecular screening, and 213 with RAS/BRAF ctDNA wt were randomized (arm A/B = 106/107). At a median follow-up of 31.9 months, no difference in terms of OS was observed between treatment arms, with a median OS of 11.7 and 11.6 months in arms B and A, respectively (hazard ratio 1.13, 85% confidence interval 0.90-1.41, P = 0.441). However, re-treatment with panitumumab was associated with higher objective response rate (ORR; first ORR: 16% versus 2%, P = 0.003; second ORR: 18% versus 0%, P = 0.013) and disease control rate (DCR; first DCR: 61% versus 36%, P < 0.001; second DCR: 62% versus 38%, P = 0.003), and longer progression-free survival (PFS; first PFS: 4.2 versus 2.4 months, P = 0.103; second PFS: 3.9 versus 2.7 months, P = 0.019) than regorafenib, regardless of the sequence of the study treatments. Anti-EGFR re-treatment should be regarded as an option in the continuum of care of chemorefractory mCRC patients with RAS and BRAF wt tumors, with no alterations of acquired resistance in their ctDNA.

In metastatic colorectal cancer (mCRC), remarkable advances have been achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, only in a small subset of tumours (4–5%), harbouring a deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) or mutations in the catalytic subunit of polymerase epsilon (POLE). Within this framework, several combination strategies have been investigated to sensitize proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC to ICIs, with disappointing results so far. However, at the last ESMO meeting, two phase II trials AtezoTRIBE and MAYA provided promising results in this field. In the comparative AtezoTRIBE trial, the addition of atezolizumab to FOLFOXIRI (5-fluoruracil, oxaliplatin and irinotecan) and bevacizumab led to a significant advantage in terms of progression free survival (PFS) in a population of untreated mCRC patients, not selected according to MMR/MSI status. In the single-arm MAYA trial, immune priming with temozolomide in pMMR/MSS chemo-resistant mCRC patients with silencing of O6-methylguanine-DNA methyltransferase (MGMT) allowed reporting signals of sensitivity to the subsequent therapy with nivolumab and a low dose of ipilimumab in some patients. Here, we discuss the rationale, results, criticisms and research perspectives opened by these two studies.