PURPOSE:We investigated whether circulating tumor DNA (ctDNA) changes may be useful to assess clinical outcomes in patients with metastatic colorectal cancer (mCRC) randomized in the TIME-PRODIGE-28 trial comparing biweekly maintenance with cetuximab alone with observation after 4-month fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab induction chemotherapy. EXPERIMENTAL DESIGN:ctDNA samples were collected at four time points from baseline until disease progression during the first chemotherapy-free interval and analyzed using next-generation sequencing and methylation marker approaches. Progression-free survival (PFS) and overall survival (OS) from randomization were analyzed according to ctDNA kinetics and EGFR-MAPK pathway alterations. RESULTS:Among 139 randomized patients, 104 (74.8%) had paired samples available. Patients with negative baseline ctDNA remaining negative after 4-month induction chemotherapy had significantly longer PFS from randomization (9.6 months) as compared with patients with a ctDNA decrease of ≥80% (3.4 months) or a ctDNA decrease of <80% (2.1 months; P = 0.013). Patients with EGFR-MAPK pathway alterations identified either in tissue or baseline ctDNA had worse PFS and OS from randomization. Acquired alterations found in 17 of 63 (26.9%) patients at disease progression during the first chemotherapy-free interval were associated with worse OS from reintroduction of the full induction chemotherapy (14.9 vs. 19.4 months; P = 0.025). CONCLUSIONS:Our findings show the prognostic impact of both ctDNA kinetics and EGFR-MAPK pathway alteration dynamics following induction chemotherapy with FOLFIRI-cetuximab in patients with mCRC. Prospective studies evaluating ctDNA-guided treatment strategies are needed to validate the clinical utility of ctDNA monitoring to improve patient selection for first-line treatment de-escalation and anti-EGFR-based maintenance regimens, including treatment adaptation over time.

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.

e16380 Background: With a 5-year overall survival (OS) rate <5%, PDAC is a major cause of cancer-related mortality. OPTIMIZE-1 is an open-label, single-arm, multicenter phase 1b/2 study to evaluate efficacy and safety of mitazalimab, a human CD40 agonistic IgG1 antibody, in combination with mFFX in untreated patients with mPDAC. The study met its primary endpoint with promising clinical efficacy vs. historical controls resulting in an overall response rate (ORR) of 54.4 % (unconfirmed; 42.1% confirmed) (Van Laethem 2024). We report the final efficacy analysis for patients treated with 450 and 900 µg/kg mitazalimab. Methods: Patients received mitazalimab on day 1 (priming dose), followed by a 2-week regimen starting with mFFX on day 8 and mitazalimab on day 10. The primary endpoint was ORR compared to 30% ORR for FFX alone. Secondary and exploratory endpoints include Duration of Response (DoR), Progression Free Survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Between 2021 and 2025 94 patients with mPDAC were treated with mFFX + mitazalimab (29 at 450 µg/kg and 65 at 900 µg/kg). 22 patients at 450 µg/kg and 57 at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. Efficacy outcomes for both dose levels are summarized in Table 1. The 900 µg/kg dose presented higher ORR, DoR, mPFS and mOS and has been selected for Phase 3 development. The primary efficacy analysis comprised 57 evaluable patients treated with 900 µg/kg mitazalimab + mFFX. Median follow up was 36 months and median exposure to treatment was 7 months. Eighteen patients remained treatment for more than 12 months, including seven who continued beyond 24 months. One patient remains on treatment. ORR was 54.4% (42.1% confirmed) and 22 patients achieved stable disease, for a disease control rate of 78.9%. Three patients achieved complete responses (CR) in target lesions, including one with CR in target and non-target lesions. Median DoR was 12.6 months, mPFS was 7.7 months and mOS was 14.9 months (12, 18, 24 and 30-mo OS rates of 58%, 37%, 26% and 21% respectively). Conclusions: Mitazalimab (900 µg/kg) in combination with mFFX continues to demonstrate clinically meaningful survival benefits compared with historical controls. The robust duration of response and encouraging long-term survival—six patients surviving >36 months—support continued development of mitazalimab in a confirmatory Phase 3 study. Clinical trial information: NCT04888312 . 450 µg/kg(N=22) 900 µg/kg(N=57) Median follow up (95% CI) 13.1 (12.1 - 13.9) 36.2 (30.9 - 36.7) ORR n % (90% CI) 5 (22.7) 24 (42.1) DoR (95% CI) NE (3.7 - NE) 12.6 (7.5 - 22.0) mPFS (95% CI) 5.3 (2.0 - 9.2) 7.8 (5.8 - 11.5) mOS (95% CI) 9.7 (5.9 - NE) 14.9 (10.0 - 17.3) 12-month OS, % (95% CI) 42.9 (21.9 - 62.3) 57.8 (43.9 - 69.4) 18-month OS, % (95% CI) 32.1 (11.1 – 55.7) 37.3 (24.8 - 49.9) 24-month OS, % (95% CI) - 26.1 (15.4 - 38.2) 30-month OS, % (95% CI) - 20.5 (11.0 - 32.1)

4218 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has poor prognosis and limited first-line treatment options. Ibrilatazar (ABTL0812) is a first-in-class oral agent that induces cytotoxic autophagy selectively in cancer cells. Favorable safety and tolerability of the combination with FOLFIRINOX were established in a Phase I study. D.S. and T.M. are equal contributors. Methods: PanC-ASAP is a Phase IIb double-blind, randomized, placebo-controlled (1:1) study evaluating the efficacy and safety of ibrilatazar (1300 mg TID) plus FOLFIRINOX versus placebo plus FOLFIRINOX as first-line therapy in mPDAC, conducted across 23 sites in the US, Spain, France, and Israel. Eligible patients had histologically confirmed mPDAC, ECOG PS 0–1, and no prior systemic treatment for metastatic disease. Treatment continued until disease progression or intolerable toxicity. Primary endpoint was progression-free survival (PFS), defined as time from randomization to radiographic disease progression or death, assessed by blinded independent central review in the intention-to-treat (ITT) population. Overall survival (OS) was a key secondary endpoint. Safety was assessed in all treated patients. Pre-specified stratification analysis revealed an imbalance in ECOG between arms (ECOG 0/1: 40%/60% ibrilatazar vs 54%/46% placebo), prompting an exploratory efficacy analysis by ECOG PS subgroup. Time-to-event endpoints were analyzed using Kaplan–Meier methods and log-rank tests. Results: In the ITT population (n = 140), median PFS for ibrilatazar vs placebo was 9.4 vs 7.9 mths (HR 0.95; 90% CI, 0.69-1.33; p = 0.814). An exploratory analysis by ECOG showed that, among patients with ECOG 0 (n = 66; ibrilatazar, n = 28; placebo, n = 38), median PFS of 11.1 vs 6.5 mths (HR 0.60; 95% CI, 0.34–1.08; p = 0.089), and median OS of 19.3 vs 12.0 mths (HR 0.57; 95% CI, 0.31–1.05; p = 0.072). Consistent trends favoring ibrilatazar were observed across efficacy endpoints, including objective response rate and duration of treatment. Safety profile of ibrilatazar plus FOLFIRINOX was consistent with the known FOLFIRINOX toxicities. The most common grade ≥3 treatment-emergent adverse events in the ibrilatazar vs placebo were neutropenia (21% vs 22%), diarrhea (21% vs 16%), and neurotoxicity (0% vs 14%). Conclusions: Although primary PFS endpoint was not met in the ITT population, exploratory analysis showed clinically meaningful and consistent efficacy improvements among ECOG 0 patients treated with ibrilatazar plus FOLFIRINOX, with 60% and 70% increases in median OS and median PFS respectively. These findings support further investigation in selected mPDAC populations and suggest ECOG may modify treatment benefit. Clinical trial information: NCT04431258 .

PURPOSE For elderly patients with pancreatic ductal adenocarcinoma (PDAC), FOLFIRINOX (FFX) is often contraindicated due to frequent grade III adverse events (AEs) limiting available data on this population. MATERIALS AND METHODS This retrospective single-center study identified patients older than70 years treated with FFX for PDAC (2011-2022). Tumor, G8 score calculation (score <14/17 indicates geriatric examination), geriatric, and nutritional parameters were collected. The primary end point was toxicity, defined as grade ≥3 GI AEs or unplanned hospitalization. Overall survival (OS) and toxicity associated factors were analyzed using Cox regression with stepwise selection. RESULTS We included 142 patients: 73 with metastatic PDAC (mPDAC) and 69 with non-mPDAC (nmPDAC). Median age was 74 years (71-84), with 43% age 75 years and older. 80% had Eastern Cooperative Oncology Group 0-1. G8 score ≤14 and severe malnutrition were more frequent in mPDAC (82% and 51%) than in nmPDAC (64% and 27%). Low muscle mass was present in >80% of cases. Median FFX exposure was four cycles in mPDAC and 4.5 in nmPDAC. Overall, 56% experienced toxicity, including two treatment-related deaths. Frequent grade ≥3 AEs included infections (26%), nausea/vomiting (22%), and diarrhea (18%). Early toxicity within 2 months was associated with worse OS. Factors linked to toxicity included metastatic status (hazard ratio [HR], 2.41) and psychiatric comorbidities (HR, 6.96), while cardiovascular disease (HR, 0.35) and history of cancer (HR, 0.22) were protective. In nmPDAC, multidimensional geriatric assessment (MGA) reduced toxicity in G8 ≤ 14 patients. CONCLUSION FFX is feasible in highly selected elderly patients with PDAC. Severe toxicity remains frequent and proactive supportive care—including MGA in cases of G8 ≤ 14—to avoid early severe toxicity that impact significantly survival.

Background:We evaluated the efficacy of endoscopic treatment (ET) for gastric neoplastic complications of autoimmune gastritis (AIG). We also assessed the safety of ET and the risk factors for the occurrence of neuroendocrine tumors (NETs) and gastric adenocarcinoma (GA). Methods:This was a retrospective, single-center, observational study. All patients diagnosed with AIG between 1987 and 2019 and had at least 1 upper endoscopy available were included. Results:The study population comprised 88 patients (68.2% female). The median follow up was 5 years (range 1-28). A total of 132 NETs were diagnosed in 39/88 patients (44.3%) (median age 50.0 years, range 27.0-85.0 years). The mean lesion size was 7.1 mm (range 1-30); there were 80 G1 NETs and 52 G2 NETs. Among the 132 lesions, 86.3% (114/132) were endoscopically resected, mostly by endoscopic mucosal resection (105/114, 92.1%), without complications. Only 1 patient underwent surgery. Twelve patients (13.6%) (7 females; median age, 76.0 years; range, 53.0-90.0 years) presented with GA. Of these, 66.7% (8/12) needed surgery, while 4 patients underwent exclusive endoscopic resection. Only 2 patients presented with NETs and GA (2.8%). Patients who presented with NETs were significantly younger at AIG diagnosis than patients with GA: 52.0 (18.0-85.0) vs. 67.0 (44.0-81.0) years (P=0.008). Patients who presented with GA were significantly older than those who presented with NETs: 76.0 (53.0-90.0) vs. 50.0 (27.0-85.0) years (P<0.001). Conclusion:ET of NETs for AIG is effective and safe. GA is rarer, occurs in significantly older patients, and usually requires surgery.

4009 Background: OSE2101 is an off the shelf vaccine made of 10 synthetic HLA-A2-restricted peptides targeting 5 tumor associated antigens. This multicenter, randomized, non-comparative, phase II study assessed FOLFIRI ± OSE2101 maintenance in aPDAC Pts without progression after 8 cycles of FFX. Methods: Eligible aPDAC Pts were randomized to FOLFIRI (Arm A) or FOLFIRI + OSE2101 (Arm B: subcutaneous injection on D1, D15, Q4W/6 doses then Q8W to M12 then Q12W up to M24). Stratification factors: tumor stage (locally advanced vs metastatic), best response to FFX (partial or complete response [CR, PR] vs stable disease [SD]), and center. Primary endpoint: overall survival (OS) rate at M12 in evaluable Pts (M12-OS; Fleming 2-stage design, H0: 25%; H1: 50%, 1-sided alpha: 2.5%, power: 90%); secondary endpoints: progression-free survival (PFS; RECIST v1.1), best response, duration of disease control (DDC), and safety. Results: 107 Pts (ITT) were randomized (53/Arm A, 54/Arm B) between 04/2021 and 05/2023. Median age 64 years (range:37-81), 53% men, 69% had metastases, 36%/64% had PR/SD to prior FFX. No evidence of imbalance in Pt characteristics was observed between arms. Median number of OSE2101 injections was 7.5 (1-14). Median treatment duration of FOLFIRI was 5.4 months in both arms. At data cut-off (Dec 9, 2024), median follow-up was 21.4 months with 101 evaluable Pts for M12-OS (49/Arm A, 52/Arm B; 4 consent withdrawals, 1 Pt’s decision, 1 treatment interruption >4 weeks). Number of death events (n/%) was 19/35.8% in Arm A and 18/33.3% in Arm B. M12-OS (95%CI) was 61% (46.2%-74.8%) in Arm A and 65% (50.9%-78.0%) in Arm B. Median (95%CI) OS and PFS (ITT) were 17.3 months (10.6–23.2) and 8.2 months (5.3–11.6) in Arm A, and 15.5 months (12.4–19.3) and 7.8 months (5.4–10.6) in Arm B. Other secondary endpoints are described in Table. Among 33 Pts with SD to prior FFX in Arm B, 6 (18%) had CR/PR (1/5) when adding OSE2101 to FOLFIRI vs 5 (no CR) among 35 Pts in Arm A. In the safety population, 7 SAEs/6 Pts (12%) in Arm A and 22 SAEs/14 Pts (26%) in Arm B were reported. No unexpected SAEs were observed with OSE2101 except 1 inappropriate administration, and no evidence of increased toxicity of FOLFIRI with OSE2101. Conclusions: TEDOPAM met its primary objective with minimal toxicity and positive outcomes of adding OSE2101 cancer vaccine to maintenance FOLFIRI, albeit mitigated by unexpectedly favorable OS in the control arm. Two complete responses were observed when adding OSE2101. Further follow-up is ongoing and translational analysis planned. Clinical trial information: NCT03806309 . ITT Arm AN=53 Arm BN=54 Best response, n (%) CR 0 (0.0) 2 (3.7) PR 12 (22.6) 10 (18.5) SD 28 (52.8) 34 (63.0) Progressive disease (PD) 8 (15.1) 8 (14.8) Missing 5 (9.5) 0 (0.0) DC rate, n (%) 40 (75.5) 46 (85.2) DDC (95% Cl) 8.8 (6.2-12.9) 9.8 (6.8-14.8)

Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).

BACKGROUND & AIMS:Patients with advanced hepatocellular carcinoma (HCC) generally experience poor outcomes despite current therapies, necessitating the development of alternative treatments. ADP-A2AFP is an investigational autologous T-cell therapy with an affinity-enhanced T-cell receptor (TCR) targeting alpha-fetoprotein (AFP). METHODS:We describe a phase I, open-label, first-in-human clinical trial of ADP-A2AFP (NCT03132792) in human leukocyte antigen-eligible participants with AFP-expressing HCC (or other tumor) not amenable to transplant/resection who progressed on, were intolerant to, or refused prior systemic therapy. Participants received lymphodepletion chemotherapy (cyclophosphamide 500 mg/m2/day for 3 days and fludarabine 20 mg/m2/day for 3 days, or cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days) followed by ADP-A2AFP intravenous infusion. Safety evaluation was the primary objective; response per RECIST v1.1 was the key secondary endpoint. RESULTS:Twenty-one participants, 20 with advanced HCC and one with gastric hepatoid carcinoma received ≥1 ADP-A2AFP infusion. All participants experienced ≥1 grade 3 or higher adverse event; 52.4% experienced ≥1 grade 3 or higher event considered related to ADP-A2AFP treatment. Six participants experienced cytokine release syndrome (grade 1-2: n = 5; grade 4: n = 1). Best overall responses were complete response (n = 1), partial response (n = 1), and stable disease (n = 12); overall response rate was 9.5%. Eight patients had a stable disease duration of ≥16 weeks. Infiltration of ADP-A2AFP TCR and CD8+ T cells was seen in AFP-positive areas of post-treatment tumor samples. A relationship was demonstrated between increased ADP-A2AFP dose and serum AFP reduction in responders. CONCLUSIONS:Lymphodepletion chemotherapy followed by ADP-A2AFP TCR T-cell therapy showed a manageable safety profile and preliminary indications of antitumor activity in these previously treated patients. IMPACT AND IMPLICATIONS:Adoptive T-cell therapy could be a much-needed additional treatment strategy for advanced hepatocellular carcinoma. Clinicians and researchers interested in the development of adoptive T-cell therapies for advanced solid tumors will be interested to learn that in this phase I trial, ADP-A2AFP T-cell receptor T-cell therapy was associated with an acceptable benefit-to-risk profile and encouraging antitumor activity, illustrating the treatment potential of adoptive T-cell therapy for advanced hepatocellular carcinoma. CLINICALTRIALS: GOV NUMBER:NCT03132792; first posted 2017-04-08.

4133 Background: With a 5 year overall survival (OS) rate <5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]

BackgroundBrain metastases (BM) are rare in pancreatic ductal adenocarcinoma (PDAC) and little data exists concerning these patients and their outcomes.AimWe aimed to analyze the management, practices, and outcomes of patients presenting BM from PDAC both in our institution and in all cases reported in the literature.MethodsWe conducted a retrospective, monocentric analysis using a data mining tool (ConSoRe) to identify all patients diagnosed with PDAC and BM in our comprehensive cancer center (Paoli-Calmettes Institute), from July 1997 to June 2022 (cohort 1). Simultaneously, we reviewed and pooled the case reports and case series of patients with PDAC and BM in the literature (cohort 2). The clinical characteristics of patients in each cohort were described and survival analyses were performed using the Kaplan-Meier method.ResultsIn cohort 1, 19 patients (0.3%) with PDAC and BM were identified with a median age of 69 years (range: 39-81). Most patients had metastatic disease (74%), including 21% with BM, at diagnosis. Lung metastases were present in 58% of patients. 68% of patients had neurological symptoms and 68% were treated by focal treatment (surgery: 21%, radiotherapy: 42%, Gamma Knife radiosurgery: 5%). In cohort 2, among the 61 PDAC patients with BM described in the literature, 59% had metastatic disease, including 13% with BM at diagnosis. Lung metastases were present in 36% of patient and BM treatments included: surgery (36%), radiotherapy (36%), radiosurgery (3%), or no local treatment (25%). After the pancreatic cancer diagnosis, the median time to develop BM was 7.8 months (range: 0.0-73.9) in cohort 1 and 17.0 months (range: 0.0-64.0) in cohort 2. Median overall survival (OS) in patients of cohort 1 and cohort 2 was 2.9 months (95% CI [1.7,4.0]) and 12.5 months (95% CI [7.5,17.5]), respectively.ConclusionBM are very uncommon in PDAC and seem to occur more often in younger patients with lung metastases and more indolent disease. BM are associated with poor prognosis and neurosurgery offers the best outcomes and should be considered when feasible.

Background After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine-based regimens or the modified FOLFIRINOX regimen (mFFX). While mFFX has been shown to be more effective than gemcitabine-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. Patients and Methods We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX-regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic AI-signatures were obtained by combining Independent Component Analysis, Least Absolute Shrinkage and the Selection Operator-Random Forest approach. We integrated a previously developed gemcitabine signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the Pancreas-View tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. Results Patients who were predicted to be sensitive to the administered drugs (n=164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX sensitive group treated with mFFX was 50.0 months (stratified HR: 0.31; 95% CI, 0.21-0.44; p<0.001) and 33.7 months (stratified HR: 0.40; 95% CI, 0.17-0.59; p<0.001) in the gemcitabine sensitive group when treated with gemcitabine. Comparatively patients with signature predictions unmatched with the treatments (n=86; 25.1%) or those resistant to all drugs (n=93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). Conclusions This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and gemcitabine.

Aim of the study The management of synchronous metastatic rectal cancer (SMRC) is complex and multimodal, involving chemotherapy, surgery and/or radiotherapy. The aim of this study was firstly to confirm the efficacy of the induction FOLFIRINOX, and secondly to evaluate the different therapeutic strategies and outcomes of patients. Patients and methods This French study combined data from a prospective FFCD trial and a multicenter cohort. Patients included had SMRC and had undergone induction triplet chemotherapy. Two groups of patients were defined according to the resectability of metastases at baseline: resectable (Res) and unresectable (URes). The primary endpoint was the objective response rate. Results 146 patients were included in 16 French centers and 65 patients in the FFCD1102 trial. In overall population the median age of patients was 59 years, 86% of tumors were of the lower or middle rectum, 33% were well-differentiated, 53% were RAS mutated and 7% BRAF mutated. Triplet induction was associated with 80% of objective response and 92% of disease control. After the induction phase, 69% and 48% of patients of Res and URes groups underwent rectal surgery, and secondary metastases resection was done in 79% and 39% of patients, respectively. Median overall survival (OS) for Res was 56.3 months (95% CI: 22.54-NA). Median OS for URes who had or not secondary metastases resection were 45.1 months (95% CI: 39.89-NA) and 21.1 months (95% CI 17.31-27.1), respectively. Patients with BRAF mutated tumors were more likely to have unresectable disease, and had worse survivals than the patients with RAS mutated or RAS/BRAF wild-type. Conclusion Triplet induction chemotherapy is a treatment of choice in selected patients with SMRC, allowing to adapt the therapeutic strategy to the response and invasiveness of the various sites. Structured abstract The management of metastatic rectal cancer is essentially based on three main therapeutic approaches: surgery, radiotherapy/chemoradiotherapy and chemotherapy. Induction triplet chemotherapy appears as a good choice for fit and young patients. It allows to adapt the therapeutic strategy to the response and invasiveness of the various sites. In this study dedicated to patients undergoing treatment for rectal cancer with synchronous metastases, FOLFIRINOX-based induction chemotherapy was associated with objective response rate of 77% and disease control rate of 92%. These results are similar with those of the FFCD 1102 trial and confirm the efficacy of induction chemotherapy with FOLFIRINOX with or without targeted therapy in these patients in daily routine practice. Surgery for metastases is a key factor in determining patient's outcome and triplet induction chemotherapy, associated with high response rates, enables a significant percentage of patients to undergo surgery and appears therefore to be a treatment of choice, particularly for patients whose disease is unresectable at baseline.