ASCO Gastrointestinal Cancers Symposium 2025

GONO studies presented at ASCO Gastrointestinal Cancers Symposium 2025:

• UNICORN – By Dr. Filippo Ghelardi
• IPD pooled analysis dMMR/MSI GEA – By Dr. Alessandra Raimondi

UNICORN study

At ASCO GI 2025 in San Francisco (USA), Dr Filippo Ghelardi presented on behalf of GONO investigators the results of the multicenter, Italian UNICORN trial by Fondazione GONO Onlus. UNICORN is a window-of-opportunity, multicohort, umbrella platform phase II trial enrolling patients with locally advanced colorectal cancer (CRC) who are candidates for upfront surgery. Patients are treated with a short-course preoperative treatment according to his/her tumor’s specific molecular profile. Specifically, Dr Ghelardi presented the results of cohorts 4 and 5 (patients with pMMR/MSS tumors) and cohorts 6 and 7 (patients with dMMR/MSI-H tumors). Fourteen patients were enrolled in each cohort and received a short course (one cycle) preoperative treatment for 1 month with the multifunctional, Fc-enhanced, anti-CTLA4 antibody botensilimab alone (BOT 1 mg/Kg on day 1 for cohorts 4 and 6) or in combination with the antibody botensilimab-PD-1 agent balstilimab (BAL 3 mg/Kg intravenously on days 1 and 15 for cohorts 5 and 7). In each cohort, treatment was followed by surgery (on day 35 +/- 5 from treatment start) and standard of care, multidisciplinarily assessed, post-operative management. Primary endpoint of the trial was major pathological response (residual viable tumor ≤ 10% of tumor bed).

All patients enrolled (n=56) received treatment and underwent radical surgery. Treatment was well tolerated, and no severe immune-mediate adverse events (IMAEs) occurred. Expectedly, a numerically higher proportion of patients enrolled in the combination cohorts experienced any IMAE (56%, as opposed to 25% in the monotherapy arms). Surgery was shortly delayed, by less than 4 weeks, in only one patient enrolled in cohort 7 due to treatment-related grade 3 thyroiditis.

The primary endpoint was met in all cohorts except for the BOT monotherapy pMMR/MSS cohort. Specifically, in pMMR/MSS pts pMR rates were 0% and 36% in BOT and BOT/BAL cohorts respectively. In patients with dMMR/MSI-H disease, pMR rates were 36% and 100% in the monotherapy and combination cohorts, respectively. Following surgery, among pts with pMMR/MSS disease a numerically lower proportion of subjects who received adjuvant chemotherapy was reported in the combination vs monotherapy arm (57% in cohort 5 and 71% in cohort 4), possibly as a consequence of tumor downstaging.
Dr Ghelardi also reported preliminary efficacy data. After a median follow-up of at least 5 months in each cohort (up to 13.2 months in cohort 4), 4 progression events had occurred. One event was reported in cohort 4 and 3 events in cohort 6. All events occurred in patients who had not achieved a major response to preoperative treatment. No event had occurred in any of the combination arm.

UNICORN represents a step further in the definition of a new paradigm in the management of patients with locally advanced CRC, revolving around chemo-free, immunotherapy-based, pre-operative/definitive strategies. While these approaches are more consolidated in patients with dMMR/MSI-H colon and rectal cancers, UNICORN is one of the first trials highlighting their activity and preliminary efficacy in patients with pMMR/MSS tumors. Further studies with the combination, possibly with a longer treatment duration, are warranted.

IPD pooled analysis dMMR/MSI GEA

At ASCO GI 2025 in San Francisco (USA), Dr. Alessandra Raimondi presented on behalf of GONO investigators the results of an individual patient data (IPD) pooled analysis of seven clinical studies (INFINITY, NEONIPIGA, PROSECCO, MAGIC, CLASSIC, ARTIST, ITACA-S) sponsored by Fondazione GONO Onlus.

This was a multinational IPD pooled analysis including patients affected by resectable gastroesophageal adenocarcinoma (GEA) selected for mismatch repair deficient/microsatellite instability high (dMMR/MSI) status. Patients received dual immunotherapy with anti-CTLA-4 and anti-PD-(L)1 immune-checkpoint inhibitors (ICI) followed or not by surgery plus or minus adjuvant ICI in the INFINITY and NEONIPIGA phase II trials, respectively; perioperative FLOT chemotherapy and surgery in the frame of the PROSECCO retrospective study, and surgery alone or plus older perioperative or adjuvant chemo(radio)therapy regimens in the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials.

The primary endpoints of the IPD analysis were the evaluation of rates of pathologic complete response (pCR) defined as TRG1a according to Becker et al. scale and major to complete pathologic response (MPR) defined as TRG1a/b Becker according to the preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed.

Overall, the IPD included 197 patients. Of these, 49 received immunotherapy +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery, respectively. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care chemotherapy, immunotherapy demonstrated a higher rate of pathologic response as compared to FLOT chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; MPR 78.6% vs 10%, OR 39.3 p<0.001). In the overall IPD population, no significant differences in terms of OS and EFS were shown in patients treated with immunotherapy, FLOT plus surgery, old chemo(radio)therapy plus surgery as compared to patients treated with surgery alone.

In resectable dMMR/MSI GEA, upfront ICI showed higher pathologic response versus FLOT chemotherapy although comparable survival outcomes compared to surgery alone, with the limitations of study design and of the sample size. The impact on survival of immunotherapy versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. Additionally, the high rate of major-complete pathologic response may provide the rationale to perform organ-sparing surgical procedures or non-operative management in order to reduce the surgical morbidity and mortality and to improve the quality of life.