ESMO GI Congress 2024

GONO studies presented during 2024 ASCO Annual Meeting:

• INFINITY Study – By Dr. Alessandra Raimondi
• TRINITY Study – By Dr. Vincenzo Nasca
• ANITA Study – By Dr. Virginia Genovesi
• AtezoTRIBE Study – By Dr. Martina Carullo
• FOLFOXIRI/bev – By Dr. Federica Marmorino

INFINITY Study

At ESMO GI Annual Meeting 2024 in Munich (DE), Dr. Alessandra Raimondi on behalf of GONO investigators, presented the updated results of the multicentre, multicohort, phase II INFINITY study, which investigated the safety and activity of the immunotherapy combination with tremelimumab plus durvalumab as pre-operative (Cohort 1) or potentially definitive (Cohort 2) treatment for gastric/gastroesophageal junction cancer with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-high) status.

All patients enrolled in the two Cohorts of the study received single-dose tremelimumab 300 mg plus durvalumab 1500 mg q4 weeks for 3 cycles. In Cohort 1 all patients underwent surgery; in Cohort 2, in case of evidence of clinical complete response (cCR), namely no evidence of tumor at radiologic-endoscopic restaging and liquid biopsy for minimal residual disease, patients undergo non-operative management (NOM), that is omission of surgery and an intensive follow up with radiology, endoscopy and liquid biopsy, for disease persistence/relapse they receive surgery. For Cohort 2 the primary endpoint is 2-year cCR rate.

The first results of the Cohort 1 of the INFINITY study were previously presented at ASCO Gastrointestinal Cancers 2023, showing that a chemotherapy-free combination immunotherapy treatment with tremelimumab plus durvalumab achieved a 60% rate of pathological complete response and 80% major-to-complete pathological complete response rate in a cohort of 15 evaluable patients.

The updated results of Cohort 1 with an extended follow up of 28 months confirmed the promising survival outcomes, with 24-month gastric cancer specific-progression-free survival (PFS) and overall survival (OS) rates of 76% and 80%, respectively. Moreover, the preliminary results of Cohort 2 were first presented. Overall, 18 patients were enrolled, 1 had grade 2 toxicity and decided to undergo surgery. Among 17 evaluable patients, 13 (76%) had cCR and started NOM and 4 (24%) did not have cCR and underwent surgery. At median follow up of 8 months, only 1 patient had an early tumor re-growth during NOM and underwent salvage surgery, with a 12-month gastrectomy-free survival of 78%. Any grade and grade ≥3 immune-related adverse events occurred in 13 and 3 patients, all resolved with treatment as per protocol.

The follow up of Cohort 2 is ongoing, in order to evaluate the primary endpoint of the study and possibly provide the first evidence on a surgery-free management of highly selected patients with dMMR/MSI-high gastric/gastroesophageal junction cancer.

TRINITY Study

At ESMO GI Annual Meeting 2024 in Munich (Germany), Dr. Vincenzo Nascaf, on behalf of GONO investigators, presented a new trial-in-progress conceptualized and promoted by GONO Foundation, the TRINITY trial (clinical trial identifier: NCT06253650), focused on improving the outcomes of patients with localized/locally advanced HER2 positive gastric/gastroesophageal adenocarcinoma (GEA).

Despite standard treatment involves a combination of peri-operative chemotherapy (with FLOT regimen), and radical surgery, around half patients will experience disease relapse. Currently, no biomarkers can accurately predict which patients will recur, but growing evidence in gastrointestinal cancers suggest that a novel tool, liquid biopsy, can identify patients at highest risk of relapse, by detecting the presence of minimal residual disease (MRD) after a curative treatment. MRD is defined as the persistence of circulating tumor DNA (ctDNA) after surgery or adjuvant treatment, which is strongly associated with relapse. Further, the choice of peri-operative treatment in GEA is independent of molecular characteristics, but recent trials in the advanced setting (DESTINY-Gastric01,02,03) showed that Trastuzumab-deruxtecan (T-DXd) possesses high activity in patients with HER2 positive GEA.

Based on this rationale, Filippo Pietrantonio and colleagues designed the TRINITY trial, a multicenter, randomized, open-label phase II study which will enroll 46 patients with HER2 positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of MRD detected by the SignateraTM assay in a liquid biopsy collected between 2 and 6 weeks after surgery.

The trial is designed with an observational phase enrolling patients with HER2 positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd plus either capecitabine or 5-fluorouracil for 6 cycles, or to the control arm with standard post-operative FLOT for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies.
The primary objective is ctDNA clearance (that is, ctDNA negativization), without disease recurrence at 1 year after randomization. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety.

The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints, and the observational phase of the trial will also help us elucidate potential mechanisms of resistance to standard treatment.
Enrollment is ongoing.

ANITA study

Insights into the clinical impact of molecular characterization in biliary tract cancer: preliminary results of the ANITA study

Preliminary findings from the ANITA study were presented by the GONO Foundation at the last ESMO Gastrointestinal Cancers Congress 2024, held in Munich from 26 to 29 June 2024.

ANITA is an observational multicenter study, enrolling 621 advanced biliary tract cancer patients treated at 10 referral Italian cancer centers between 2017 and 2023. Primary aim of the study was to evaluate how the molecular profiling of these tumors has been implemented across the years and if this translated into significant changes into the management of biliary tract cancer patients. Indeed, molecular cholangiocarcinoma is emerging as a paradigm for precision oncology: however, approved and reimbursed targeted agents are nowadays limited to inhibitors of FGFR2 gene rearrangements and/or fusions or immune checkpoint inhibitors for pretreated mismatch repair deficient/microsatellite instability high disease, and the clinical impact of extended molecular characterization is therefore unclear.

Two abstracts presented by Dr. Virginia Genovesi provided interesting and new insights into the debate. GONO investigators first reported that extended molecular profiling (EMP) was performed in 62.5% of the enrolled cases: as expected, in the majority of the cases EMP was conducted among intrahepatic cholangiocarcinoma patients, which are known to be enriched for currently targetable molecular alterations. Of interest, the authors reported a significantly progressive increase in the EMP rate over the years, indicating that the relevance of EMP in biliary tract cancer has gaining momentum in referral centers. Among EMP-assessed patients, 42.3% carried an ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I-IV alteration. Notably, the patients with an ESCAT I-IV-associated disease reported a significantly longer median overall survival (OS) compared to those without alterations. More in details, OS was significantly longer for patients with an ESCAT I-IV- associated disease who also received a matched targeted treatment (TT), whereas there was no difference between patients with an ESCAT I-IV- associated disease who were untreated with TT and those who did not receive EMP at all. Among patients treated with EMP-guided TT, median OS since the diagnosis of advanced disease achieved 67.9 months, clearly indicating that EMP and TT could have dramatic impact on patient outcome.

In a parallel abstract, Dr. Genovesi and colleagues assessed the prognostic role of FGFR2 gene rearrangements and/or fusions and IDH1 mutations among patients treated with systemic chemotherapy for advanced disease. These alterations currently represent the most frequent targetable molecular changes in biliary tract cancer, and some previous retrospective data on small series suggested a potential prognostic impact among patients treated with chemotherapy. In the ANITA dataset, neither FGFR2 nor IDH1 alterations represented independent prognostic factors for OS. Moreover, they did not seem to confer differential sensitivity to platinum-based standard first-line chemotherapy. These findings reinforce the evidence that the longer OS observed in molecularly-defined subgroups is largely explained by the patient exposure to matched TT, rather than by a more indolent disease course.

Additional analyses are ongoing to further characterize the ANITA population.

AtezoTRIBE Study

The presence of liver metastases does not predict resistance to immunotherapy in proficient MMR metastatic colorectal cancer (mCRC): a secondary analysis of the AtezoTRIBE study

At the last ESMO GI congress, the GONO Foundation research group presented a secondary analysis of the Atezotribe study, that previously showed a modest benefit from the addition of atezolizumab (atezo) to 1st-line FOLFOXIRI/bevacizumab (bev) and identified Immunoscore IC as a potential predictor of ICI efficacy in the proficient mismatch repair (pMMR) population.
The presence of liver metastases is associated with an immune-suppressive tumor microenvironment and, consequently, with poor efficacy of immune checkpoint inhibitor (ICI)-based therapies. However, limited data are available from randomized clinical trials investigating ICI-based treatments in mCRC.

Based on these considerations, a comprehensive evaluation of liver metastases among mCRC patients enrolled in the AtezoTRIBE trial was performed, investigating the association of hepatic involvement with a panel of tumor immune-related biomarkers – including MMR, TMB, Immunoscore IC, Immunoscore, Tumor-Infiltrating lymphocytes (TILs) assessed by optical microscope, PD-L1 expression by Tumor Proportion Score (TPS), and the immune 27-gene signature DetermaIO – and treatment outcome, in the cohort of patients with pMMR tumor.

Out of 202 pMMR patients, 151 (75%) had liver metastases. No differences in terms of immune-related features were observed between tumors with and without liver metastases, with the exception of a lower prevalence of high TILs-tumors in the presence of liver metastases (33% vs 52%, p = 0.03). Immunoscore IC was more frequently high in the absence of liver metastases but without reaching statistical significance (42% vs 29%, p= 0.089).

Liver involvement had a negative prognostic impact both in the FOLFOXIRI/bev (HR for PFS 1.81 [95% CI: 1.02-3.21]; HR for OS 2.00 [95% CI: 1.01-3.99]) and in the FOLFOXIRI/bev/atezo arm (HR for PFS 1.75 [95% CI: 1.18-2.61]; HR for OS 1.69 [95% CI: 1.04-2.75]). The presence or not of liver metastases did not affect the efficacy of adding atezo to first-line FOLFOXIRI/bev in terms of both PFS (P for interaction :0.99) and OS (P for interaction:0.80).

Among patients with pMMR tumours with liver metastases, a trend for a higher benefit from FOLFOXIRI/bev/atezo as compared to FOLFOXIRI/bev was reported among patients with IS IC-high tumors than IS IC-low tumors in terms of both PFS (HR: 0.52 [95% CI 0.25-1.07] vs HR 1.07 [95% CI 0.67-1.72]) and OS (HR 0.65 [95% CI 0.28-1.49] vs HR 0.94 (95% CI 0.55-1.62)).
In conclusion, the presence or not of liver metastases does not affect the efficacy of adding atezo to first-line FOLFOXIRI/bev, differently than the Immunoscore IC. Although based on unplanned post-hoc exploratory subgroup analyses, a potential predictive impact of the Immunoscore IC was observed also among patients with pMMR tumors with liver metastases.

FOLFOXIRI/bev

FOLFOXIRI/bevacizumab versus doublets/bevacizumab as initial therapy of unresectable liver-only, right-sided and/or RAS or BRAF mutated metastatic colorectal cancer (mCRC): an individual patient data-based pooled analysis of randomized trials.

At the last ESMO GI Congress 2024 in Munich, the GONO Foundation research group presented results from an analysis investigating the efficacy and activity of FOLFOXIRI/bevacizumab (bev) over doublets/bev in metastatic colorectal cancer (mCRC) patients with unresectable liver-only, right-sided and/or RAS/BRAFV600E mutated (mut).
Recently, in the setting of mCRC patients with liver only disease with right-sided and/or RAS/BRAFV600E mut tumours, the CAIRO5 study demonstrated a statistically significant advantage in terms of PFS and ORR without an OS difference in favour of the FOLFOXIRI/bev compared to doublet/bev.

Therefore, it sounded appealing to investigate the efficacy and activity of FOLFOXIRI/bev in liver-only, right-sided and/or RAS/BRAFV600E tumours mut patients enrolled in the randomized phase III/II trials (TRIBE, TRIBE2, CHARTA and STEAM) where FOLFOXIRI/bev was compared to doublet regimens/bev as upfront treatment in mCRC patients.

Among 1617 mCRC treated in the 4 phase II/III trials, we selected 300 eligible patients with liver-only right-sided and/or RAS/BRAFV600E mut tumours, demonstrating that patients receiving FOLFOXIRI/bev showed longer PFS (median: 12.3 vs 10.3 months, HR:0.75, p = 0.02) and higher ORR (64% vs 53%, OR:1.54, p = 0.076) compared with doublets/bev.
In terms of OS, patients treated with FOLFOXIRI/bev achieved better OS with a statistically not significant trend (median: 29.1 vs 23.2 months, HR:0.85, [95%CI 0.64-1.26], p = 0.25) than those treated with doublets/bev.

Regarding to R0 resection rate, our analysis reported no differences between two treatment arms (27% vs 24%, OR:1.15, p = 0.696 and no significant interaction was found between treatment effect and the achievement of R0 resection in terms of both PFS (p interaction=0.81) and OS (p interaction=0.53).

These findings suggest that FOLFOXIRI/bev provides a meaningful advantage to mCRC patients with initially unresectable liver-only, right-sided and/or RAS/BRAFV600E mut, thus corroborating the choice of triplet as upfront therapy for these patients, regardless of the opportunity to achieve the R0 secondary resection of their liver metastatic lesions.