ESMO Congress 2025

GONO studies presented during 2025 ESMO Congress:

• Translational analyses of AtezoTRIBE and AVETRIC trials – By Dr. Martina Carullo
• TriComB Study – By Dr. Paolo Ciracì
• An individual patient data-based pooled analysis of nine randomized trials – By Dr. Ada Taravella

Translational analyses of AtezoTRIBE and AVETRIC trials

Immune checkpoint inhibitors (ICIs) have shown limited efficacy in proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC), highlighting the need for predictive biomarkers.

At the last ESMO congress in Berlin, Dr. Martina Carullo presented results of a newly developed, tumor-derived, artificial intelligence (AI)-powered prediction score (AI-PS) able to identify patients with pMMR mCRC who may benefit from ICIs from two first-line academic phase II clinical trials, AtezoTRIBE and AVETRIC. To this end, we leveraged the Lunit SCOPE IO platform, able to perform a comprehensive evaluation of both cancer and stromal cell populations in the tumour microenvironment.

The AI-PS was trained in pMMR mCRC patients enrolled in the experimental arm of the phase II randomized AtezoTRIBE trial (FOLFOXIRI/bevacizumab + atezolizumab; training cohort), with the final output incorporating densities of lymphocytes, tumor and mitotic cells on cancer area and fibroblasts, macrophages and endothelial cells on cancer stroma. To dichotomize cases as AI-PShigh or AI-PSlow, a PFS-based cut-off of 0.8831 was set.

The AI-PS was then tested as a predictive marker in the overall AtezoTRIBE population (FOLFOXIRI/bevacizumab ± atezolizumab; application cohort) and validated in the single-arm AVETRIC trial (mFOLFOXIRI/cetuximab + avelumab; validation cohort). TGCA and CPTAC-COAD open datasets served as exploratory cohorts.

In the application cohort, the AI-PS was able to predict clinical benefit from the addition of atezolizumab to FOLFOXIRI/bevacizumab, with improved outcomes in AI-PShigh but not AI-PSlow patients (high, HR PFS: 0.69, 95%CI 0.45-1.04; OS: 0.54, 95% CI 0.33-0.88; low, HR PFS: 1.34, 95%CI 0.66-2.72; OS: 1.70, 95% CI 0.69-4.20; PFS: pint: 0.114, OS: pint: 0.025).

In the validation cohort, patients with AI-PShigh tumors exhibited significantly improved outcomes compared to those with AI-PSlow tumors. In contrast, no differences were observed between AI-PS groups in open datasets of patients not treated with ICIs, supporting its role as a predictive rather than prognostic biomarker. These data support further validation of the developed AI-PS.

In conclusion, our AI-based analysis lays the foundation for a novel approach to refine patient selection for ICI-based investigational treatments in pMMR mCRC.

TriComB Study

At the ESMO Congress 2025 in Berlin, Dr. Paolo Ciracì presented, on behalf of the GONO investigators, the first results of the phase II TriComB study.

TriComB was designed to evaluate the safety and activity of the sequential administration of capecitabine and trifluridine-tipiracil, in combination with bevacizumab, as first-line treatment for patients with metastatic colorectal cancer who were deemed unfit for upfront irinotecan- or oxaliplatin-based chemotherapy.

The study was supported by preclinical evidence suggesting a synergistic antitumor effect between capecitabine and trifluridine-tipiracil, based on their complementary mechanisms of resistance.
In the first part of the trial (phase I), the recommended dose of the combination was identified. At ESMO 2025, preliminary efficacy and safety data from patients enrolled in the expansion phase (phase II) were presented.

Between January 2022 and August 2024, 38 patients from 16 Italian oncology units were enrolled, including 6 patients treated at the recommended dose in the phase I of the study.

The TriComB trial met its primary endpoint, resulting in an objective response rate of 55%. Furthermore, the administration of capecitabine followed by trifluridine-tipiracil, in combination with bevacizumab, in a 28-day cycle, resulted in an encouraging disease control rate of 84% and a median progression-free survival of 10.3 months.

The regimen was feasible; however, it was associated with a non-negligible incidence of grade 3-4 hematological toxicities and thromboembolic events, which should be interpreted in the light of the relative frailty of the enrolled patients.

Overall, these findings support further investigation of the TriComB regimen as a novel therapeutic option for patients with proficient mismatch repair and BRAF wild-type metastatic colorectal cancer.

An individual patient data-based pooled analysis of nine randomized trials

At ESMO Congress 2025, Dr. Ada Taravella, on behalf of GONO Foundation, presented an international individual patient data pooled analysis evaluating the clinical relevance of disease-free survival (DFS) and secondary surgery in liver-limited metastatic colorectal cancer (LL-mCRC) patients subjected to secondary curative after achieving disease control to first-line chemotherapy plus a biologic agent (anti-EGFRs or bevacizumab). This topic is of marked relevance because early relapse after surgery and uncertainties on the relationship between DFS and post-surgical overall survival (psOS) have raised concerns about the use of DFS as a surrogate endpoint of long-term outcomes.

855 patients from nine phase II/III trials (FIRE-3, FIRE-4, TRIBE, TRIBE2, TRIPLETE, MOMA, MACBETH, VALENTINO, ATEZOTRIBE) were included, and 357 (42%) underwent R0/1 liver metastasectomy. In the resected cohort, DFS and psOS were strongly correlated (ρ=0.73), with a patient-level R² of 0.69, which was borderline to the 0.70 ideal cut-off for surrogacy. Instead, trial-level surrogacy was modest (R²=0.32). To compare outcomes of resected patients experiencing early relapse (≤6 months from surgery) and unresected patients, overall survival since surgery and minimum disease load (post-minOS) in unresected patients were compared. No post-minOS differences were detected (24.8 vs 21.7 months; HR 0.88, 95% CI 0.70–1.11; p=0.29). However, patients with high baseline tumor burden score (TBS) were more likely to benefit from surgery (24.1 vs 17.8 months; HR 0.69, 95% CI 0.45–1.05; p=0.083), unlike those with medium/low TBS (27.4 vs 26.6 months; HR 1.12, 95% CI 0.74–1.69; p=0.588) (p of interaction = 0.10). Anyhow, secondary liver resection was still associated with a meaningful reduction of exposure to systemic therapy, even in case of early relapse (47% vs 57%, p<0.001)

This analysis supports DFS as a clinically meaningful endpoint after secondary liver surgery in LL-mCRC treated with contemporary therapy and suggests it may serve as a surrogate biomarker in non-comparative trials. Importantly, surgery should not be dismissed solely due to early relapse, particularly in patients with high initial disease burden, who may still derive survival and quality-of-life benefits.