ASCO Annual Meeting 2024_Logo
May 31 - June 4, 2024 / Chicago

2024 ASCO Annual Meeting

GONO studies presented during 2024 ASCO Annual Meeting:

ERASE CRC Study

Exploiting ctDNA as marker of post-surgical and post-adjuvant minimal residual disease: the ERASE platform

ERASE CRC Veronica Conca
Dr. Veronica Conca at the ASCO Annual Meeting 2024

At the last ASCO Congress 2024 in Chicago, the GONO Foundation research group presented the trial ongoing  ERASE-CRC.

ERASE-CRC is part of an international effort to evaluate the use of liquid biopsy as a tool to guide colorectal cancer adjuvant treatment.

Indeed circulating tumor DNA (ctDNA) positivity, a biomarker of minimal residual disease (MRD), after primary tumor resection or at the end of adjuvant therapy is associated with higher risk of recurrence. Intensifying the adjuvant and/or the post-adjuvant treatment could be a valuable strategy in these cases.

ERASE-CRC is a prospective, open-label, multicentre study, including three phase 2 trials enrolling ctDNA-positive patients with radically resected stage III or high-risk stage II (one major prognostic factor or at least two minor prognostic factors) adenocarcinoma of the colon or intraperitoneal rectum. CtDNA is centrally assessed through a tissue-informed method, F1Tracker. 

In the phase II ERASE-CRC Part 1 study, patients that are ctDNA-positive after surgery (2-6 weeks) are randomized 1:1 to  6 months of either FOLFOX or CAPOX at investigators’ choice (standard arm) versus FOLFOXIRI (experimental arm). In the phase II single arm ERASE-HER2 study, ctDNA-positive patients with HER2 amplified and RAS wild-type tumors received FOLFOX plus trastuzumab and tucatinib for 12 cycles.

In the phase II ERASE-CRC Part 2 study, ctDNA-positive patients after the end of an oxaliplatin-based adjuvant therapy (either in the context or outside ERASE-CRC Part 1 or ERASE-HER2) are randomized 1:2 to observation (standard arm) or trifluridine/tipiracil for 6 cycles (experimental arm). 

The primary endpoint is the clearance rate of ctDNA after the adjuvant (ERASE-CRC Part 1 and ERASE-HER2) or the post- adjuvant treatment (ERASE-CRC Part 2) with target accrual of 300, 18 and 159, respectively. 

At the moment, 42 Italian Oncology Units are participating in the study. Currently, 35 and 13 patients have been randomized in ERASE-CRC Part 1 and 2. NCT05062889

Presentation posterLearn more about the study

TRIPLETE Study

Negative hyperselection and mechanisms of acquired resistance to anti-EGFR-based regimens: tissue and liquid biopsy analysis of TRIPLETE

Strudio TRIPLETE - Veronica Conca
Dr. Veronica Conca at the ASCO Annual Meeting 2024

Preliminary findings from the IN BILICO project were presented by the GONO Foundation research group at the last ASCO Congress 2024 in Chicago.

We performed a translational analysis of the TRIPLETE trial, in which patients with RAS/BRAF wt metastatic colorectal cancer (mCRC) were treated in first line with FOLFOX/panitumumab or mFOLFOXIRI/panitumumab. From previous findings, anti-EGFR sensitivity seems restricted to negatively hyperselected RAS/BRAF wt cases, according to PRESSING1/2 panels. In this work, we analysed tissue and plasma at baseline (BP) using Next-Generation Sequenzing (NGS) in order to confirm the utility of hyperselection and evaluate the acquisition of resistance mutations in plasma at the time of disease progression (PDP).
134 (31%) patients from TRIPLETE had available NGS data from tissue, BP and PDP.

Tissue and plasma analyses at baseline failed to provide fully concordant results: tissue analysis revealed locally unknown RAS mutations in 6 (4%) cases.

Patients with pMMR tumors (102) were grouped as PRESSING-positive or negative based on the detection of alterations included in the PRESSING panel. PRESSING-1 or PRESSING-1/2 alterations were found in 22% of tissue samples, 15% BP and 20% PDP.

Inconsistently with previous data, negative hyperselection both through tissue and plasma analysis failed to demonstrate a prognostic role among pMMR RAS/BRAF wt mCRC pts treated with first-line chemotherapy plus panitumumab. Indeed, no differences between PRESSING-positive and negative patients were reported in terms of ORR, PFS or OS, regardless of primary tumor location. The confounding effect of the associated chemotherapy backbone is a potential explanation for this finding.

The occurrence of RAS mutations in ctDNA at the time of PD (9%) was significantly correlated with worse post-progression survival. As additional mechanism of acquired resistance, MAP2K1 mutation were found at PD in 2 cases, while no other PRESSING alteration was found.

Presentation poster

TRIBE & TRIBE2 Studies

p16 expression as a marker of irinotecan sensitivity in metastatic colorectal cancer: a translational analysis of TRIBE and TRIBE2 studies

Studio TRIBE - Marco Germani

At the last 2024 ASCO Annual Meeting in Chicago, the GONO Foundation research group presented a translational analysis investigating the role of the p16, the protein product of CDKN2A gene, as a prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). In preclinical models of mCRC, demethylation of CDKN2A induces the upregulation of topoisomerase I, finally resulting in hypersensitivity to irinotecan. Therefore, it sounded appealing to investigate the relevance of this biomarker in the randomized phase III GONO studies TRIBE and TRIBE, where an intensified regimen consisting of three drugs -including 5-FU, oxaliplatin and irinotecan- (FOLFOXIRI/bevacizumab) was compared to oxaliplatin-based (FOLFOX/bevacizumab) and irinotecan-based (FOLFIRI/bevacizumab) doublet regimens. Overall, 152 out of 231 (66%) patients of the TRIBE2 trial showed immunohistochemical (IHC) overexpression of p16 (p16+) and were the sole driving benefit from the addition of irinotecan to FOLFOX in terms of progression-free survival (PFS) (median: 12.8 vs 9.4 months, p=0.0008) and overall survival (OS) (median: 30 vs 21.4 months, p=0.026). No PFS and OS benefit from the triplet was observed in p16- patients (p=0.69 and p=0.85, respectively). When the sole patients treated with FOLFIRI in the TRIBE study were considered, p16+ outperformed p16- patients in terms of median PFS (median: 11.3 vs 8.7 months, p=0.041) and OS (median: 33 vs 17.9 months, p=0.024). These findings suggest that IHC p16+ mCRC patients may drive greater benefit from irinotecan-based strategies, as compared to p16- ones. Our findings should be addressed in prospective randomized trials.

Presentation poster

TriComB Study

Phase I trial of FTD/TPI in addition to capecitabine plus bevacizumab as first-line therapy of metastatic colorectal cancer patients: the TRICOMB study

Studio TriComB - Beatrice Borelli

At ASCO Annual Meeting 2024 in Chicago, Dr. Borelli Beatrice on behalf of GONO investigators presented results of phase I TRICOMB study, which investigated the safety of Trifluridine/Tipiracil plus Capecitabine and Bevacizumab as first-line treatment in metastatic colorectal cancer (mCRC) patients.

A synergistic effect of the sequential administration of Capecitabine and Trifluridine/tipiracil has been shown both in vitro and in vivo models, and Capecitabine plus bevacizumab is a standard option for previously untreated unresectable mCRC patients deemed not fit for upfront chemotherapy doublets.

A dose escalation design was used to identify the recommended dose of Trifluridine/tipiracil in association with Capecitabine plus bevacizumab. Globally 11 patients were enrolled: 6 and 5 patients were treated with 25 mg/sqm BID and 30 mg/sqm BID of Trifluridine/tipiracil, respectively.

Since 3 out of 5 patients treated with 30 mg/sqm BID experienced dose limiting toxicity, 25 mg/sqm BID was identified as the recommended dose of Trifluridine/tipiracil.
The Overall Response Rate was 73% in the overall population and 67% in the group treated at the recommended dose. Main serious adverse events (G3-G4) were neutropenia (36%) and diarrhea (18%).

The phase 2 of TRICOMB study is ongoing in 14 Italian Oncology Units to evaluate antitumor activity of Trifluridine/Tipiracil plus Capecitabine and Bevacizumab in the same patients’ population.

Presentation posterLearn more about the study