728 Background: Oligometastatic disease (OMD) in pancreatic ductal adenocarcinoma (PDAC) is an emerging clinical entity. The limited extension of the disease prompt to explore the role of metastases-directed therapies (MDT); however, their actual survival and clinical benefits remain uncertain. Additional studies with larger effectives are needed to clarify the role of MDT in clinical practice. Methods: We conducted a retrospective multicenter, observational French-Belgian study to evaluate the impact of MDT on event-free survival (EFS) and overall survival (OS) in patients with OMD-PDAC. OMD was defined as metastases (mets) involving no more than 2 organ and ≤5 mets (Leonhardt CS. ESMO Open 2023). Eligible patients were adults with histologically confirmed PDAC who underwent a resection of the primary tumor, with concurrent or subsequent MDT of MDT. OS was defined as the delay from MDT to death from any cause; EFS was calculated from the date of MDT until radiologically confirmed disease progression, recurrence or death. The ALTOPANC score—based on known prognostic factors (CA 19-9 >90 U/mL, > 1 met, and non-pulmonary mets)—was correlated with OS and EFS. Results: Between 01/2011 and 12/2024, 155 patients with OMD-PDAC were included; 138 had metachronous metastases. Sites of mets included liver (n=71, 45%), lung (n=61, 39%), periaortic lymph nodes (n=13, 8%) and peritoneum (n=5, 3%). At time of the met's diagnosis, 107 patients (71%) had a single met, and 25 (17%) patients had presented two mets. After a median follow-up of 4.42 years, median EFS and median OS in the entire population were of 0.8 and 3,4 years respectively. MDT modalities consisted in surgery (n=69, 45%), radiotherapy (n=50, 32%), and thermoablation (n=36, 23%). In the multivariate Cox model, higher CA 19-9 level (HR = 1.29, 95% CI: 1.13–1.48, p = 0.0002) and the presence of 2 (HR = 2.54, 95% CI: 1.32–4.88, p <0.0001) or ≥3 treated mets (HR = 4.39, 95% CI: 2.18–8.84, p <0.0001) were independent adverse prognostic factors for OS. Thermoablation was independently associated with an improved OS compared to other technics (HR=0.51, 95%CI: 0.27–0.96, p =0.0127). The ALTOPANC score was significantly associated with EFS :2-year EFS rates were 53.1%, 23.8%, 8.3%, and 0% in patients with scores of 0, 1, 2, and 3, respectively (p < 0.001). A similar trend was observed for OS. Conclusions: 1) This real-world, study shows promising results of MDT in patients with OMD-PDAC, particularly thermoablation ; 2) among patients with favorable prognostic profile (low ALTOPANC score) may have the higher benefit. A prospective randomized study is warranted to confirm these results.

PURPOSE The choice of adjuvant chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is mainly guided by patients' general condition. We hypothesized that tumor morphology may predict differential treatment benefit and tested whether deep learning applied to histology images could derive a biomarker of relative benefit from gemcitabine (GEM) versus modified FOLFIRINOX (mFOLFIRINOX) in resected PDAC. PATIENTS AND METHODS Standard whole-slide images from a retrospective multicentric series of 231 patients who underwent curative-intent pancreatectomy and received adjuvant mFOLFIRINOX (n = 54) or GEM (n = 177) were used to train regimen-specific histology models on disease-free survival (DFS), which were then combined into PANCprAId, a biomarker estimating personalized relative benefit from adjuvant GEM versus mFOLFIRINOX. External validation was performed in the randomized PRODIGE-24/CCTG PA6 trial (n = 313). RESULTS In PRODIGE-24/CCTG PA6, the treatment-specific histology scores used to construct PANCprAId stratified outcomes among patients treated with GEM (hazard ratio [HR], 1.69 [95% CI, 1.04 to 2.73]; P = .03) and mFOLFIRINOX (HR, 2.02 [95% CI, 1.4 to 3.0]; P < .001). When combined into PANCprAId, the biomarker identified subgroups with differential relative benefit from adjuvant GEM versus mFOLFIRINOX, with significant treatment interactions for DFS (interaction P = .003) and cancer-specific survival (interaction P = .001). Predicted sensitivity to each regimen was associated with distinct epithelial and stromal features. CONCLUSION Histology-based deep learning can derive a predictive biomarker of relative benefit from adjuvant GEM versus mFOLFIRINOX in resected PDAC.

e16441 Background: Pancreatic ductal adenocarcinoma is one of the most lethal malignancies with a 5-year survival rate under 5%. Locally advanced pancreatic ductal adenocarcinoma (LAP) represents 30-40% of cases at the diagnosis, with an overall survival around 15 months. Optimizing chemotherapy in LAP is still a huge challenge. A concomitant inhibition of epithelial mesenchymal transition (EMT) process may potentiate chemotherapy efficacy and decrease the development of resistances. Netrin-1 is upregulated in many metastatic cancers including 60% of pancreatic cancer and promotes tumor invasiveness and metastases development through EMT induction. NP137, a first-in-class anti-Netrin-1 monoclonal antibody, has shown in phase I study the ability to inhibit EMT, potentially overcoming resistance (Cassier et al., Nature, 2023). The goal of LAP-NET1 (NCT05546853) is to evaluate the safety and efficacy of the combination of modified FOLFIRINOX with anti-Netrin-1 targeting (NP137). Methods: LAP-NET1 is a phase 1b multicentric trial studying the combination of modified FOLFIRINOX with NP-137 every 2 weeks for 12 cycles in patients naive of systemic treatment with LAP according to National Comprehensive Cancer Network criteria. A safety lead-in phase will initially enroll 3-12 patients to confirm the recommended dose of NP137 (14 or 9 mg/kg) according to a 3+3 de-escalation protocol, followed by an expansion phase of 40 patients. The primary endpoint is the proportion of patients experiencing adverse events (AEs) of any grade and grade 3/4 AEs (CTCAE v 5.0) related to the experimental treatment at 6 months. Secondary endpoints are best overall objective response according to RECIST 1.1, 12-month progression-free survival (PFS-12m), 12-month overall survival (OS-12m), surgical resection rate, quality of life (EORTC QLQ-C30), time to deterioration and ancillary outcomes based on spatial transcriptomic and classic bulk RNA sequencing. Clinical trial information: NCT05546853 .

4197 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by aggressive tumor dissemination and resistance to therapy; processes significantly driven by the epithelial-to-mesenchymal transition (EMT). Netrin-1 is a key regulator for EMT. NP137, an anti-netrin-1 antibody, has shown to inhibit EMT in preclinical models and in a phase 1 monotherapy trial. Methods: LAPNET-01 (NCT06203821) is a single arm phase Ib clinical study to assess the combination of NP137 with mFOLFIRINOX in naive locally advanced unresectable PDAC. A safety lead-in (3–12 pts, 3+3 design, NP137 14 vs 9 mg/kg) was followed by a 40-patient expansion. Treatment consisted of NP137 + mFOLFIRINOX every 2 weeks, up to 12 cycles. The primary endpoint was safety at 6 months (all-grade and grade 3/4 adverse events [AEs], CTCAE v5.0). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), surgical conversion rate and exploratory transcriptomic analyses. Laser capture microdissection was performed on 22 pre-treatment and 6 surgery samples to allow microbulk RNA sequencing. Immunohistochemistry was also performed on pre-treatment samples. Results: A total of 43 patients were enrolled in this trial. NP137 was well tolerated. AE occurred in 100% of patients (58% grade ≥ 3). ORR and disease control rate were 29% and 95%. Median PFS was 10.9 months (95% CI, 10.0 – 15.6) and median OS was 16.4 months (95% CI, 12.8 – NR) with 21 patients still alive at time of the data cut-off. Surgery was made possible in 23% of patients. Microbulk RNA sequencing revealed that the main pathway downregulated with the combination mFOLFIRINOX+NP137 is EMT, bringing a clinical validation of the main mechanism of action of NP137. Moreover, patients with tumors expressing high levels of the netrin-1 receptor neogenin (high-NEO1) at baseline (both at the RNA and proteic level (IHC)) demonstrated an improved outcomes compared to the low-NEO1 subgroup including longer median PFS (15.7 vs 10.2 months, p = 0.01) and longer median OS (not reached vs 16.5, p = 0.024). These results are consistent with experimental data demonstrating the implication of NEO1 in PDAC EMT and its progression. Conclusions: NP137 in combination with mFOLFIRINOX demonstrates a favorable safety profile, promising clinical activity and a mechanistically distinct mode of action supported by translational analyses. These results warrant further investigation of netrin-1 blockade in randomized trials and provide a rationale for biomarker-driven development of NP137 in PDAC. Further work is ongoing to better characterize the distribution of NEO1 in first-line unresectable PDAC. Clinical trial information: NCT06203821 .

BACKGROUND & AIMS:Anti-FGFR therapies changed the treatment landscape for patients with previously treated, advanced, or metastatic cholangiocarcinoma (CCA) harbouring FGFR2 fusions/rearrangements. However, primary resistance to FGFR inhibitors remains a key challenge. In the present real-world study, we aimed to evaluate the prognostic impact of concomitant GAs in patients with FGFR2-positive CCA treated with pemigatinib. METHODS:This study included PEMIREAL-PEMIBIL patients treated with pemigatinib in second or later lines. Only patients who underwent extensive DNA- and/or RNA-based next-generation sequencing (NGS) analysis were considered. Primary endpoint was progression-free survival (PFS), with overall response rate, disease control rate and overall survival (OS) as secondary endpoint. OS and PFS were calculated by Kaplan-Meier and log-rank test. Multivariate analysis used cox-regression model. Level of statistical significance p was 0.05. RESULTS:Of 72 patients of PEMIREAL-PEMIBIL, 63 patients had evaluable NGS data, with concomitant GAs identified in 28 patients (44.4%). The most frequently observed concomitant GAs involved BAP1 (7/63, 11.1%), CDKN2A (7/63, 11.1%), TP53 (6/63, 9.5%), CDKN2B (5/63, 7.9%), PTEN (3/63, 4.7%) and IDH1 (1/63, 1.5%). A significantly shorter PFS was observed in patients with CDKN2A mutations compared to CDKN2A wild-type tumours (4.79 vs. 8.66 months, p = 0.0011, HR: 3.48 95% CI: 0.91-13.24), and similarly in patients with BAP1 mutations compared to BAP1 wild-type tumours (5.97 vs. 8.52 months, p = 0.025, HR:2.55 95% CI: 0.72-9.00). No significant differences in OS were observed. CONCLUSIONS:Our results support the negative prognostic role of BAP1 and CDKN2A GAs on PFS in patients with locally advanced or metastatic CCA with FGFR2 gene fusion/rearrangement treated with pemigatinib in a real-world setting.

Netrin1, a developmental cue, is a master regulator of tumour epithelial-to-mesenchymal transition (EMT)1, a mechanism that is known to drive resistance to chemotherapy2. A netrin1 antibody (NP137)3 has been shown to inhibit tumour EMT in preclinical1 and clinical4 settings. In animal models of pancreatic cancer, netrin1 and its receptor neogenin have been shown to promote tumour progression5, EMT5 and metastasis6. Here we report the results of a phase 1b study that assesses the combination of NP137 with modified FOLFIRINOX (mFOLFIRINOX) in first line patients with locally advanced pancreatic cancer (ClinicalTrials.gov: NCT05546853 ). Forty-three patients were enrolled and received mFOLFIRINOX plus NP137 every other week for up to 12 cycles. NP137 was well tolerated. Median progression-free survival (PFS) was 10.85 months (95% confidence interval, 10.03-15.61) and median overall survival was 16.43 months (95% confidence interval, 12.75-non-reached), with 21 patients remaining alive at the time of data cut-off. Post-therapy conversion surgery occurred in 23% of patients. Laser capture microdissection was performed on pre-therapeutic biopsies and surgical specimens. Microbulk RNA sequencing confirmed that the main pathway that was down-regulated with the combination of mFOLFIRINOX plus NP137 was EMT. Moreover, survival outcomes were extended for patients with tumour cells that expressed high levels of the netrin1 receptor neogenin-median PFS 15.65 months in neogenin-high versus 10.22 months in neogenin low. Our results support the idea that netrin1 blockade alleviates resistance to chemotherapy by inhibiting EMT, particularly in neogenin-high pancreatic cancer.

Bevacizumab shows inter-individual pharmacokinetic variability, with an exposure-response relationship in metastatic colorectal cancer (mCRC) patients. This study explores whether a double dose of bevacizumab, compared to a standard dose, increases efficacy in mCRC patients treated with bevacizumab-based chemotherapy as first-line therapy and who have a low initial trough concentration of bevacizumab. PHARBEVACOL is a multicenter, randomized, double-blind, two-parallel group trial. All patients will receive first-line bi-weekly 5 mg/kg bevacizumab-based chemotherapy and those with low initial bevacizumab concentrations (≤15.5 mg/L) will be randomized to either continue the standard dose (5 mg/kg every 14 days) or receive a double dose (10 mg/kg every 14 days). The primary objective is to evaluate the effect of doubling dose on progression-free survival (PFS). During a screening phase, the first serum trough concentration will be measured on day 14, before the second infusion of bevacizumab. We hypothesize a 40 % PFS in the control group at 9 months versus 60 % in the study group, corresponding to a hazard ratio of 0.56. With 80 % power, a 5 % two-sided type I error, and a minimum 12-month follow-up, 116 patients need to be included. Since only 50 % of screened patients will be eligible for randomization, approximately 244 patients will be screened. Recruitment is scheduled to begin in February 2025.

PURPOSE Immunoscore (IS) and circulating tumor DNA (ctDNA) are two emerging technologies in improving prognostication and tailoring adjuvant treatments in patients resected from a stage III colon cancer (CC). Here, we analyzed the prognostic value of the two biomarkers in patients who participated in the randomized phase III IDEA-France and HORG trials. METHODS Plasma samples were collected after surgery and before adjuvant chemotherapy. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed 16-plex protein chain reaction assay. Multivariable analyses for time to recurrence (TTR; patients without recurrence or death due to CC) and overall survival (OS) were performed using ctDNA and IS results, along with other parameters including treatment duration and disease risk group. RESULTS Of the 554 patients with available ctDNA results, 445 were ctDNA-negative (80.3%) and 109 were ctDNA-positive (19.7%); baseline characteristics showed more T4/N2 and venous embolism/lymphatic invasion/perineural invasion+ in ctDNA-positive patients. With a median follow-up of 6.7 years, the 2-year TTR rate was 43.5% (95% CI, 34.1 to 52.6) for ctDNA-positive patients and 88.1% (95% CI, 84.7 to 90.8) for ctDNA-negative patients ( P < .0001). ctDNA was confirmed as an independent prognostic marker for both TTR (adjusted hazard ratio [adjHR], 5.21 [95% CI, 3.59 to 7.58]; P < .001) and OS (adjHR, 4.84 [95% CI, 3.40 to 6.89]; P < .001). ctDNA remained the most significant prognostic factor irrespective of disease stage, treatment duration, and IS results. IS was not prognostic in ctDNA-positive patients but remained a significant prognostic tool for ctDNA-negative patients. CONCLUSION In this combined analysis of two adjuvant trials dedicated to patients with stage III CC after surgery, ctDNA was detectable in 19.7% of the patients and was confirmed as a major independent prognostic biomarker. IS seems to bring additional prognostic information in the 80.3% of patients who are ctDNA-negative.

BACKGROUND:In RAS wild-type (WT) metastatic colorectal cancer (mCRC), preliminary data have suggested that circulating tumor DNA (ctDNA) may select patients for anti-EGFR rechallenge therapy. METHODS:RASINTRO is a prospective nonrandomized study evaluating anti-EGFR rechallenge strategy in third and later line treatment in RAS/BRAF WT mCRC. Liquid biopsies for ctDNA analysis were collected before the first (C1) and second (C2) cycles of anti-EGFR rechallenge therapy. The primary endpoint was the progression-free survival (PFS) according to RAS/BRAF mutational status on ctDNA at C1. RESULTS:Among 74 patients screened between November 2017 and March 2020, 62 were enrolled: median age, 66.1 years; median number of previous lines of therapy, 3; panitumumab or cetuximab rechallenge alone (66.2%) or with chemotherapy (33.8%); ctDNA RAS/BRAF status at C1, 42 WT (67.7%) and 20 mutated (32.3%). Median PFS (3.3 vs 1.9 months: hazard ratio (HR) = 0.43; P <.01) and overall survival (OS) (7.9 vs 4.9 months; HR = 0.46; P =.01) were significantly longer for patients with ctDNA RAS/BRAF WT vs mutated at C1. Among the 32 patients with ctDNA RAS/BRAF WT at C1 and available blood samples at C2, those who have experienced an early decrease of >50% in ctDNA concentration (n = 15) had a significantly longer median PFS (4.2 vs 2.8 months; HR = 0.39; P =.01) and OS (10.2 vs 4.2 months; HR = 0.39; P =.02). CONCLUSION:This study showed that anti-EGFR rechallenge therapy in refractory disease is more effective in patients with RAS/BRAF WT on ctDNA, and in those who experienced an early decrease of >50% in ctDNA concentration. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03259009.

BACKGROUND:Advanced pancreatic ductal adenocarcinoma (aPDAC) has a poor prognosis with median overall survival (OS) of about 12 months. It is therefore important to explore factors that predict the efficacy of third-line chemotherapy (L3) to identify patients who may benefit from this controversial treatment. METHODS:We conducted a multicenter retrospective cohort-based study of 202 French patients treated for aPDAC who received at least three treatment lines from January 2011 to March 2022. We used penalized Cox regressions to predict progression-free survival (PFS) and OS in patients on L3. RESULTS:Median age at the start of L3 was 64.3 years old and 63.5% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1. The most frequent regimens for L3 were FOLFIRI (25.2% of patients). Median PFS was 2.2 months, while median OS was 4.2 months. In multivariate models, we identified the following predictors of both PFS and OS: age, sex, surgery for the primary tumor, FOLFIRINOX as the first-line therapy, duration of first and second-line treatments, and for L3: ECOG-PS level, peritoneum, liver and/or lung metastasis and depletion of therapeutic resources. The model incorporating these factors provided acceptable discrimination between event and event-free patients at 6 months post-L3 (area under the ROC curve of 0.83 for PFS and 0.73 for OS). CONCLUSION:The characteristics of patients and their aPDAC are readily available in clinical practice and were able to predict survival with L3. The online calculator we propose here could help physicians determine whether L3 chemotherapy would be beneficial.

BACKGROUND:Perioperative FLOT (fluorouracil, oxaliplatin, and docetaxel) triplet chemotherapy is the standard of care for localised and resectable gastric and gastro-oesophageal junction adenocarcinoma. We aimed to compare a modified FLOT regimen (also known as TFOX) with FOLFOX as first-line treatment for patients with HER2-negative advanced gastric and gastro-oesophageal junction adenocarcinoma. METHODS:PRODIGE 51-FFCD-GASTFOX is an open-label, multicentre, randomised, phase 3 trial conducted at 96 medical centres in France. Eligible individuals were aged 18 years or older, had histologically confirmed, HER2-negative adenocarcinoma of the stomach or gastro-oesophageal junction that was locally advanced unresectable or metastatic and previously untreated, measurable disease per Response Evaluation Criteria in Solid Tumours, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were randomly assigned (1:1), using the minimisation method, to receive FOLFOX (folinic acid 400 mg/m2, oxaliplatin 85 mg/m2, and 5-fluorouracil bolus 400 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks) or TFOX (docetaxel 50 mg/m2, folinic acid 400 mg/m2, and oxaliplatin 85 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks). Randomisation was stratified by centre, ECOG performance status, (neo)adjuvant chemotherapy or chemoradiotherapy, tumour stage, tumour location, and pathological histological subtype. The primary endpoint was progression-free survival (assessed in the intention-to-treat population), defined as time from randomisation to the first radiological or clinical progression (or both), or death due to any cause, whichever occurred first. Secondary endpoints included overall survival (defined as time from randomisation to death due to any cause) and objective response rate (defined as the proportion of patients with a best overall complete or partial response). Hazard ratio and 95% CIs were estimated using an unstratified Cox proportional hazards model. When the proportional hazards assumption was violated, the restricted mean survival time was used to estimate the treatment effect size. This study is registered with ClinicalTrials.gov, NCT03006432, and EudraCT, 2016-002331-16. FINDINGS:Between Dec 19, 2016, and Dec 26, 2022, 507 patients were randomly assigned (254 to the TFOX group and 253 to the FOLFOX group [intention-to-treat population]). The median age was 64·2 years (IQR 56·7-70·8), and 399 (79%) participants were male and 108 (21%) were female. At median follow-up of 42·8 months (25·8-49·9), the median progression-free survival was 7·59 months (95% CI 7·06-7·95) in the TFOX group versus 5·98 months (5·65-6·97) in the FOLFOX group. The assumption of proportional hazards was violated (p=0·013); therefore, the 12-month restricted mean progression-free survival was calculated: 7·52 months (7·06-7·97) in the TFOX group versus 6·62 months (6·16-7·09) in the FOLFOX group (p=0·0072). The median overall survival was 15·08 months (13·70-16·72) in the TFOX group versus 12·65 months (10·94-14·00) in the FOLFOX group (proportional hazards assumption was confirmed; HR 0·82 [0·68-0·99]; p=0·048) and the objective response rate was 62·3% (56·0-68·3) versus 53·4% (47·0-59·8; p=0·045). The most common grade 3 and 4 treatment-emergent adverse events were diarrhoea (37 [15%] in the TFOX group vs 18 [7%] in the FOLFOX group), peripheral neuropathy (80 [32%] vs 49 [20%]), neutropenia (67 [27%] vs 44 [18%]), and fatigue (40 [16%] vs 20 [8%]). Serious treatment-related adverse events occurred in 66 (27%) participants in the TFOX group and 33 (13%) in the FOLFOX group. There were two (<1%) treatment-related deaths in the TFOX group (one due to septic shock and one due to gastrointestinal perforation) and one (<1%) in the FOLFOX group (due to septic shock). INTERPRETATION:The modified FLOT/TFOX regimen significantly improved progression-free survival, overall survival, and objective response rate compared with FOLFOX in previously untreated patients with advanced HER2-negative gastric and gastro-oesophageal junction adenocarcinoma. The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy. FUNDING:Fédération Francophone de Cancérologie Digestive.

Background This article summarizes the French intergroup guidelines regarding rectal adenocarcinoma (RA) management published in September 2023, available on the French Society of Gastroenterology website. Methods This work was supervised by French medical and surgical societies involved in RA management. Recommendations were rated from A to C according to the literature until September 2023. Results Based on the pretreatment work-up, RA treatment was divided into four groups. T1N0 can be treated by endoscopic or surgical excision alone if there is no risk factor for lymph node involvement. For T2N0, radical surgery with total mesorectal excision is recommended, but rectal conservation is possible for small tumors (<4cm) after complete/subcomplete response following chemoradiotherapy. For T12N+ or T3+any N, total neoadjuvant treatment (TNT) followed by radical surgery is the gold standard, but rectal conservation is possible for small tumors after complete/subcomplete response following TNT. T3N2 or T+any N are an indication for TNT followed by radical surgery. Immunotherapy shows promise for dMMR/MSI RA. For metastatic tumors, recommendations are based on less robust evidence and chemotherapy plays a major role. Conclusion These guidelines aim at providing a personalized therapeutic strategy and are constantly being optimized. Each case should be discussed by a multidisciplinary team.

BACKGROUND:Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS:VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS:The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION:Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

Background: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. Patients and methods: In all, 101 patients >= 75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks +/- 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. Results: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. Conclusion: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged >= 75 treated for locally advanced rectal cancer.

BACKGROUND:Evidence suggests that ctDNA may be a reliable biomarker to monitor metastatic colorectal cancer (CRC) evolution. Nevertheless, evidence on the potential of liquid biopsy in this setting is still low quality, mostly consisting of retrospective studies. METHODS:COPERNIC is an international, multicenter clinical trial. The pilot study aims to confirm the predictive potential of early on-treatment ctDNA dynamics, and inform the design of a larger ctDNA-driven trial. Advanced CRC patients who are candidates for ≥3rd lines of systemic therapy undergo longitudinal blood sample collection during treatment (day 1, 15 and 29 for 2- or 4-weekly treatment regimens; day 1, 22 and 43 for 3-weekly treatment regimens) and at each imaging assessment. ctDNA analyses are carried out with the FoundationOne Liquid CDx and FoundationOneMonitor assays, and ctDNA changes during treatment are correlated with radiologic response (as assessed every 8-12 weeks by RECIST v1.1). The primary objective is to select the optimal timepoint and cut-off value for early ctDNA changes (at day 15/22) to predict progressive disease as best radiological response with a high positive predictive value. The cut-off value for ctDNA will be defined based on nonparametric ROC-curves with bootstrapping. Based on the expected rate of progressive disease and statistical assumptions, 109 patients are needed to be screened to have 87 assessable patients. COPERNIC is sponsored by the Institut Jules Bordet, and supported by Roche and Foundation Medicine. Recruitment is open in 13 centres across Belgium and France. The study is registered with clinicaltrials.gov (NCT05487248).