2025 ASCO Annual Meeting

GONO studies presented during 2025 ASCO Annual Meeting:

• AtezoTRIBE Study – By Dr. Daniele Rossini
• ShorTRIP Study – By Dr. Martina Carullo
• HER2 – By Dr. Marco Maria Germani
• Triplete – By Dr. Veronica Conca

During the last ASCO Congress, the GONO Foundation research group presented an ancillary analysis of the AtezoTRIBE study, which previously demonstrated the potential benefit of adding immunotherapy to standard FOLFOXIRI/bevacizumab (bev) in mCRC patients with pMMR.

HLA subgroups (or HLA supertypes) are groups of HLA alleles that share similar structural and functional properties in antigen presentation to T cells. These supertypes cluster different genetic variants that, despite belonging to distinct loci, present similar peptides and may similarly influence the immune response against tumors.

Given emerging evidence that specific HLA supertypes may modulate immune responses and impact the efficacy of immune checkpoint inhibitors (ICIs), this analysis aimed to evaluate the prognostic and predictive role of HLA supertypes in pMMR mCRC patients enrolled in the AtezoTRIBE trial.

Among 153 patients assessed (102 treated with FOLFOXIRI/bev/atezolizumab and 51 with FOLFOXIRI/bev), the presence of B44 and DR9 supertypes was associated with worse prognosis in terms of both progression-free survival (PFS: median PFS 11.4 months for B44-positive vs 13.9 months for B44-negative, p = 0.004; 11.4 months for DR9-positive vs 13.2 months for DR9-negative, p = 0.04) and overall survival (OS: median OS 29.6 months for B44-positive vs 36.6 months for B44-negative, p = 0.038; 26.6 months for DR9-positive vs 33.9 months for DR9-negative, p = 0.017) in multivariable analysis.

Furthermore, both PFS and OS benefits from the addition of atezolizumab to FOLFOXIRI/bev were observed among A3-negative, but not A3-positive, patients (interaction p-values: PFS = 0.048, OS = 0.064), while B8-positive patients derived greater benefit compared to B8-negative patients (interaction p-values: PFS = 0.014, OS = 0.040).

These exploratory findings suggest that HLA supertypes may influence both prognosis and the efficacy of ICI-based treatments in pMMR mCRC patients. In particular, B8 and A3 supertypes could help identify patients more likely to benefit from the addition of ICIs to FOLFOXIRI/bev. These results highlight the potential of HLA profiling to optimize immunotherapy strategies in pMMR mCRC.

At the ASCO Annual Meeting 2025 in Chicago, the GONO Foundation research group presented results of the ShorTrip study, an Italian, prospective, multicentre, single-arm, phase II trial, investigating the triplet FOLFOXIRI as consolidation strategy after short-course radiotherapy (SCRT) as total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC).

Both FOLFIRINOX followed by long-course CTRT and SCRT followed by FOLFOX or CAPOX are well-established TNT options for LARC. Notably, no data exist concerning the feasibility and activity of SCRT followed by the triplet.

SCRT followed by 8 cycles of FOLFOXIRI was administered to patients with middle-high LARC and at least one high risk feature [cT4, cN2, involved mesorectal fascia (MRF+) or cT3N+]. The primary endpoint was the pCR rate and, according to the study design, the experimental regimen would have been considered promising if at least 21 pCRs were observed out of 63 enrolled patients.

However, after the first 11 patients starting consolidation treatment, a high incidence of severe neutropenia after the first cycle of FOLFOXIRI led to a protocol amendment. The revised strategy incorporated one cycle of FOLFOX after SCRT followed by 7 cycles of FOLFOXIRI.

From January 2022 to February 2024, 64 patients were enrolled. One patient withdrew consent after the 1° cycle of chemotherapy and was not evaluated for pathological response. 21 (33%) and 43 (67%) patients achieved pCR and major pathological response (MPR), respectively. All patients completed SCRT and almost 80% of patients received 8 cycles of consolidation treatment as planned with a significant improvement of the safety profile following the amendment (G3/4 pre vs post, neutropenia: 72% vs 47%, diarrhoea: 18% vs 8%, asthenia: 18% vs 4%).

SCRT followed by one cycle of FOLFOX and 7 cycles of FOLFOXIRI showed a promising activity with a feasible safety profile. This approach is worth of further studies, especially in the non-operative management scenario. Follow-up data are not mature to draw definitive conclusions about failure-free and overall survival data.

At ASCO Annual Meeting 2025, Dr. Marco Maria Germani, on behalf of GONO Foundation, presented the results of an international cooperation leaded by GONO investigators, and joining Italy with research groups from Germany (AIO), Japan (NCC) and US (CALGB/SWOG). This work focuses on the biological role of HER2 in proficient mismatch repair/microsatellite stable (pMMR/MSS) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

HER-2 amplification overexpression (HER2-pos) is reported in 3-5% of mCRCs. While anti-HER2 agents are under investigation in the first-line setting, HER2-pos has been associated with resistance to anti-EGFRs, the current preferred option in left-sided pMMR/MSS RAS/BRAF wt tumours. Activating HER2 mutations (mut) (1-2% of mCRCs) are believed to elicit the same biological effect. However, because this evidence was collected from retrospective, small, and heterogenous series, international guidelines do not clearly take a stand on the best therapeutic choice between chemotherapy plus anti-EGFRs or the anti-angiogenic bevacizumab (bev) if HER2-pos/mut is detected. GONO Foundation decided to address this issue, with a pooled analysis of individual clinical data of patients with previously untreated pMMR/MSS RAS/BRAF wt mCRC, from 8 phase II/III randomized clinical trials (RCT) (TRIBE2, ATEZOTRIBE, TRIPLETE, VALENTINO, PANDA, CALGB/SWOG 80405, PARADIGM, PANAMA).

1604 patients were included in the analysis. HER2-pos tumours were 81 (5%). First-line Progression-Free Survival (PFS) and Overall Survival (OS) were shorter in HER2-pos tumours, as compared to HER2-negative (neg) ones (median PFS: 9.8 versus 12.2 months, HR: 1.31 95% CI: 1.04 – 1.66, p=0.023; median OS: 28.0 versus 34.9 months, HR: 1.37 95% CI: 1.08 – 1.74, p=0.01), with convincing results also after adjustment for other covariates (padjPFS = 0.075; padjOS = 0.036). HER2 status did not predict benefit from biologics, with HER2-pos tumours treated with bev (N=20) achieving similar outcomes as compared to those treated with bev (N=61) in terms of both PFS (median: 9.8 versus 10.1 months, HR: 0.81, 95% CI: 0.48-1.39, p=0.44) and OS (median 32.9 versus 28.0 months, HR: 1.27, 95% CI: 0.73-2.22, p=0.40) with no interaction between HER2 status and the effect of biologic agents (pintPFS = 0.76; pintOS = 0.76).
These findings were confirmed in the key subgroup of left-sided tumors (pintPFS = 0.60; pintOS = 0.80). HER2-mut were found in 27 (2%) of 1408 HER2-neg tumours with HER2 mutational profile available. As compared to HER2 wt cases, HER2 mut resulted in numerically shorter PFS (9.4 versus 12.1 months, HR: 1.36, 95% CI: 0.90-2.06, p=0.14) and statistically significant shorter OS (23.7 versus 34.4 months, HR: 1.56, 95% CI: 1.02-2.38, p=0.04; padj = 0.15). No interaction between HER2 status and the effect of biologics was evident (pintPFS = 0.95; pintOS=0.95).

This is the largest analysis of HER2 status in RCT. Our data challenge the role of HER2-pos/mut as drivers of resistance to anti-EGFRs and of therapeutic decision in left-sided pMMR RAS/BRAF wt mCRC. Instead, HER2-pos/mut is a negative prognostic factor of outcome. HER2 profiling in first-line should be endorsed for enrolment in clinical trials with anti-HER2 agents.

At ASCO Annual Meeting 2025, Dr. Veronica Conca, on behalf of GONO Foundation, presented the updated results of TRIPLETE study, an Italian, prospective, multicentre, randomized phase III trial, investigating modified FOLFOXIRI plus panitumumab (experimental group) vs FOLFOX panitumumab (control group) as first line therapy for RAS/BRAF wt mCRC.

While FOLFOXIRI plus bevacizumab is a potential first-line treatment option, to date no evidence supports the use of the triplet in combination with an anti-EGFR antibody (cetuximab or panitumumab).
From September 2017 to September 2021, 435 patients were randomly assigned to control (n=217) and experimental (n=218) groups.

At the primary analysis, the primary endpoint, objective response rate (ORR) was not met, and no significant improvements were reported in Progression-Free Survival (PFS), early tumor shrinkage (ETS), depth of response (DoR), and R0 resection rate, with increased gastrointestinal adverse events.
At ASCO we present the overall survival (OS) data of the TRIPLETE study at 5-year follow-up and updated results of other endpoints.

Median follow-up was 60.2 months (IQR: 49.3-70.0). Median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR] 0.79 [95% CI: 0.63-0.99]; P=0.049). OS outcomes favoured the experimental group regardless of clinical features. No differences in ORR (75%/78%, odds ratio 0.84 [95% CI: 0.54-1.31], P=0.442), ETS rate (P=0.954), DoR (P=0.573), R0 resection rate (P=0.329), PFS (HR 0.95 [95% CI: 0.78-1.16]; P=0.606) were confirmed. Among patients alive at the time of disease progression, median Post-Progression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR 0.79 [95% CI: 0.62-1.01], P=0.062).
Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: 2nd-line 73%/71%, 3rd-line 51%/49%, 4th-line 31%/32%), as well as non-palliative locoregional treatments (control/experimental: 16%/16%).

These OS data support reconsidering mFOLFOXIRI/panitumumab as an effective option for fit patients with RAS/BRAF wild-type mCRC. Future efforts should aim at reducing toxicity and at better quantifying the overall benefit through pooled data analyses.