The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC) yet benefits only about half of patients. Using patient-derived xenografts, we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, whereas HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, nongenetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients. SIGNIFICANCE:FOLFIRI response biomarkers in mCRC are lacking. Evidence in patient-derived xenografts, tumoroids, and patients shows that chemosensitivity arises from functional relaxation, rather than (epi)genetic inactivation, of the HR DNA repair pathway. Integrative analyses yield a chemopredictive algorithm centered on the expression of the RAD51 recombinase, with potential to refine patient stratification.

Objectives To evaluate sex differences in baseline clinical characteristics, analgesic response, safety profiles and treatment variations among cancer patients initiating WHO step III opioid therapy.Methods and analysis This post hoc analysis used data from a four-arm, multicentre, randomised, comparative, superiority phase IV trial in cancer patients with moderate-to-severe pain requiring WHO step III opioids. The study was conducted across 44 specialist palliative care centres in Italy. Overall, 498 patients were evaluated, including 277 men (55.6%) and 221 women (44.4%). Eligible participants had locally advanced or metastatic tumours and persistent moderate-to-severe pain. Patients were centrally randomised (1:1:1:1) to morphine, oxycodone, buprenorphine or fentanyl around the clock. Follow-up lasted 28 days, with assessments on days 1 day, 3 days, 7 days, 14 days, 21 days and 28 days. Physicians could adjust opioid doses, add adjuvants or switch opioids as clinically indicated. Adverse drug reactions (ADRs) were recorded. Baseline assessments included oncological history, comorbidities, Karnofsky performance status and self-reported psychological status. Pain intensity (PI) was measured on a 0–10 Numerical Rating Scale for average PI (API) and worst pain over the previous 24 hours at each visit. Analgesic response was classified per Farrar’s criteria as non-responders (no improvement or worsening), poor responders (<30% PI reduction) or responders (≥30% reduction). Responders with final API ≤4 were also classified as responders per Corli’s criteria; others were non-responders. Statistical analyses included χ2 and Fisher’s exact tests, t-tests, Mann-Whitney tests, linear mixed models and logistic regression.Results PI did not differ significantly between sexes. However, in the fentanyl group, dose increased over time differently between sexes (sex-by-time interaction: p=0.0026). Opioid switching from buprenorphine was more often due to inadequate pain control in men, and due to uncontrollable ADRs in women. Among patients with colorectal cancer, women showed greater pain reduction of the worst pain according to Farrar’s criteria (91.3% vs 61.8%, p=0.022). ADRs incidence was higher in women than in men for transdermal buprenorphine (93.2% vs 77.9%, p=0.016). Higher baseline emotional tension was negatively associated with analgesic response (OR 0.64, 95% CI 0.41 to 1.00). Other efficacy and safety outcomes were not statistically significant.Conclusions Overall pain reduction did not differ by sex; however, men and women exhibited distinct patterns in dose escalation, opioid switching and ADR profiles. Accounting for sex differences may support more tailored and effective opioid selection in cancer pain management.Trial registration number NCT01809106.

Background The first randomisation results from the PACT-21/CASSANDRA trial demonstrated that cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) is a standard neoadjuvant treatment option for resectable/borderline resectable (R/BR) pancreatic adenocarcinoma (PDAC). Here, we report the results of the second randomisation comparing long versus short pre-operative chemotherapy. Methods PACT-21/CASSANDRA was a 2 × 2 factorial phase 3 trial involving 17 academic hospitals across 10 regions in Italy. Eligible patients were aged 18–75 years with pathologically confirmed R/BR PDAC and were first randomly assigned to either PAXG or fluorouracil, leucovorin, irinotecan, oxaliplatin (mFOLFIRINOX). Patients without progression or limiting toxicity after 4 months were randomised to receive 2 further months of the same chemotherapy either before (long) or after (short) surgery. The trial was designed under a two-sided superiority hypothesis (H0: HR long versus short = 1.0; H1: HR ≠ 1.0). Randomisation lists were stratified according to previous chemotherapy. The primary endpoint was event-free survival (EFS) in the intention-to-treat (ITT) population. Secondary endpoints were radiological, CA19.9 and complete pathological response, R0 and N0 resections, chemotherapy dose-density, and overall survival (OS). Analyses were performed using SAS version 9.4. This trial is registered with ClinicalTrials.gov (NCT04793932) and EudraCT (2020-003080-26 and 2024-519031-42-00). Findings Between Feb 23, 2021, and Sept 03, 2024, 86 patients were assigned to long and 79 to short preoperative chemotherapy. No difference in EFS was observed between the two groups in the intention-to-treat population (unadjusted HR 0.98; 95% CI; 0.68–1.41; P = 0.90). CA19-9 response (58 [97%] of 60 versus 41 [84%] of 49 patients; P = 0.02), pathological complete response (4 [5%] of 86 versus 0 of 79 patients; P = 0.05), N0 resection rate (39 [45%] of 86 versus 21 [27%] of 79 patients; P = 0.01), and chemotherapy dose-density were improved by longer chemotherapy. OS data are not yet mature. Interpretation Long and short preoperative chemotherapy obtains similar EFS in R/BR PDAC. Future research should focus on more effective treatment regimens and explore the optimal post-operative therapy. Funding MyEverest and Codice Viola (patients’ associations).

BACKGROUND:Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS:HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION:to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

OBJECTIVE:To evaluate regional compliance with European Society of Gynaecological Oncology quality indicators for the surgical treatment of endometrial and cervical cancer and to assess the degree of centralization within a large regional Italian health care system. METHODS:A cross-sectional population-based assessment was conducted across all 111 hospitals in Lombardy, Italy. Disease-specific questionnaires derived from European Society of Gynaecological Oncology quality indicators for endometrial and cervical cancer were distributed between January and March 2024. Surgical volumes for 2022-2023 were independently validated through administrative datasets using International Classification of Diseases diagnostic and procedural codes. Endometrial and cervical cancer were analyzed as separate disease-specific domains within a single regional quality-assessment framework. RESULTS:A total of 2948 endometrial and 628 cervical cancer surgeries were performed during the study period. For endometrial cancer, 21 centers fulfilled all essential qualitative criteria, whereas 6 simultaneously met the volume, minimally invasive surgery, and nodal staging benchmarks. Nineteen centers performed more than one procedure per month and satisfied essential standards, accounting for 60% of regional cases; this monthly activity threshold was used only as an exploratory descriptor and not as an accreditation benchmark. Sentinel lymph node staging ≥70% and minimally invasive surgery ≥60% were achieved primarily in high-volume institutions. Molecular classification, including POLE testing, was available in 42.3% of centers in-house and through network collaboration in 42%. For cervical cancer, multi-disciplinary team availability exceeded 85%, but fertility-sparing protocols and structured ultra-staging were inconsistently implemented. Across both diseases, delays beyond 6 to 8 weeks for initiation of adjuvant therapy were frequent. CONCLUSIONS:Endometrial and cervical cancer care in Lombardy is partially aligned with European Society of Gynaecological Oncology-derived quality standards, with relevant disease-specific and institutional variability. These cross-sectional data provide a baseline for strengthening referral pathways, molecular diagnostic workflows, surgical staging quality, and time-to-treatment monitoring.

Medical decision analysis is a method to make rational clinical decisions under uncertainty, enabling a mathematical combination of probabilities and utilities (i.e. values assigned to outcomes under risk). Decision analysis is commonly used in health economics, but it is underexploited in the clinic. With a view to fostering the use of medical decision analysis at the cancer patient bedside, this paper provides basic templates for some typical clinical decisions in cancer treatment, namely affecting: the quantity/quality of life trade-offs in curable cancer; adjuvant/neoadjuvant treatments; cytoreductive treatments; active surveillance / watchful waiting choices; treatment of advanced cancer; cancer follow-up. The clinical use of medical decision analysis is challenged by several difficulties, which are briefly recalled. Contrary to clinical research, medical decision analysis does not build new evidence: it simply provides physicians with a method to personalize clinical decisions on the basis of available evidence. Its added value in clinical practice correlates with the complexity of a decision. However, it also has a great potential in medical education, in order to empower clinicians with skills improving their ability to rationally shape medical decisions and share them properly with their patients.

TPS4124 Background: Moving stage III Colon Cancer (CC) into the precision medicine space is a priority in view of the lack of molecular markers driving adjuvant treatment. Retrospective studies have demonstrated the tremendous prognostic impact of circulating tumor DNA (ctDNA) analysis after curative intent surgery, and suggested that lack of conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy reflects treatment failure. With these premises, we have designed the PEGASUS trial (NCT04259944). Methods: PEGASUS is a prospective multicentric study designed to prove the feasibility of using liquid biopsy (LB) to guide the post-surgical and post-adjuvant clinical management in 140 microsatellite stable Stage-III and T4N0 Stage-II CC patients. The LUNAR1 test (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a 3:1 matched cohort of 420 patients from the TOSCA trial (NCT00646607). A LB executed 2-4 weeks post-surgery will guide a “Molecular Adjuvant” treatment: i) ctDNA+ patients will receive CAPOX for 3 months and ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment. At the end of the “Molecular Adjuvant” treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled “Molecular Metastatic” systemic treatment for 6 months or until radiological progression or toxicity: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months and at the end of treatment: in case of positivity will be switched to FOLFIRI. ctDNA+/- patientswill receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio-images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer. Clinical trial information: NCT04259944 .

BACKGROUND:Rectal surgery after total neoadjuvant therapy is a standard of care for proficient mismatch repair or microsatellite stable (pMMR/MSS) stage II-III rectal cancer. In patients who have clinical complete response, non-operative management (avoidance or delay of surgery and intensive surveillance) offers a patient-centred opportunity. However, its effect on metastatic recurrence remains uncertain. This study aimed to determine whether non-operative management compromises distant relapse-free survival in patients with clinical complete response after total neoadjuvant therapy. METHODS:NO-CUT was an investigator-driven, multicentre, single-arm, phase 2 trial across four participating cancer centres in Italy in patients aged 18 years and older with Eastern Cooperative Oncology Group performance status of 0-1, with stage II-III adenocarcinoma of the lower-to-middle rectum, and with treatment-naive disease. Patients received four cycles of capecitabine (1000 mg/m2 orally twice a day on days 1-14 every 3 weeks) and oxaliplatin (130 mg/m2 intravenously on day 1 every 3 weeks), followed by capecitabine (825 mg/m2 orally twice a day) concurrently with radiotherapy (50-54 Gy in 25 fractions during 5 weeks). Patients who had a clinical complete response according to modified Memorial Sloan Kettering Cancer Center criteria underwent non-operative management and patients without clinical complete response received surgery. The primary endpoint was 30-month distant relapse-free survival after non-operative management in the intention-to-treat population. This trial was registered on EudraCT (2017-003671-60) and is now complete. FINDINGS:Between June 6, 2018, and Aug 22, 2023, 180 patients with stage II-III adenocarcinoma of the lower-to-middle rectum were enrolled and started treatment. 179 patients with pMMR/MSS rectal cancer were included in the intention-to-treat population, 165 (92%) of which completed total neoadjuvant therapy and 47 (26%) had a clinical complete response and entered non-operative management. After a median follow-up of 35 months (IQR 21-50), 30-month distant relapse-free survival was 95% (95% CI 88-100) in the non-operative management group and 74% (95% CI 68-82) in the overall population. Diarrhoea (eight [4%] of 180) and neutropenia (seven [4%] of 180) were the most common grade 3-4 adverse events, consistent with expected toxicity of this regimen. No treatment-related deaths occurred. In exploratory analyses, circulating tumor DNA positivity after TNT showed both predictive and prognostic value. INTERPRETATION:In pMMR/MSS stage II-III rectal cancer, total neoadjuvant therapy followed by non-operative management allows organ preservation in some patients without compromising distant relapse-free survival, supporting non-operative management as a treatment option in clinical practice. FUNDINGS:Fondazione AIRC ETS, Fondazione Oncologia Niguarda ETS, Grande Ospedale Metropolitano Niguarda, Ministero Salute, and AIRC 5xMille 2018.

Background & purpose: Radiotherapy plays a key role in breast cancer treatment however, radiation-induced dermatitis can impact on treatment delivery and patient quality of life. The primary outcome was to compare Mepitel (R) Film versus standard treatment in preventing radiotherapy skin toxicity onset. Methods: A multicentre randomised controlled phase III study compared standard treatment (aqueous-urea cream - Excipial U hydrolotion applied at the beginning of radiotherapy and antiseptic cream - Flammazine or Ialugen Plus applied at the onset of moist desquamation) versus Mepitel (R) Film in patients with breast cancer undergoing post-operative radiotherapy. The primary outcome was the proportion of moist desquamation (RTOG score >= 2) in the experimental and control groups. Results: During the study (2016-2020), 161 patients were randomized, 154 (95.7 %) were evaluable. Skin toxicity Radiation Therapy Oncology Group (RTOG) score >= 2 was observed in 9.5 % and 13.9 % of experimental and control groups respectively (Relative Risk = 0.68, 95 %CI 0.28-1.66; p = 0.393). RTOG scores > 0 were 90.5 % and 94.9 % in experimental and control groups respectively (Relative Risk = 0.95, 95 %CI 0.87-1.04; p = 0.294). Multivariable analysis, controlled for age, diabetes, BMI and smoking exposure, showed a risk reduction of RTOG > 0 of 38 % (HR = 0.62 95 %CI 0.49-0.96, p = 0.028), and a risk reduction of RTOG > 1 of 33 % (HR = 0.67 95 %CI 0.26-1.76, p = 0.420) in the experimental group. The median time to recovery from RTOG grade > 0 toxicity was 17 and 32 days for experimental and control groups, respectively (p = 0.027). At multivariable analysis, time to recovery was 38 % faster in the experimental group (HR = 1.38 95 %CI (0.99-1.93) p = 0.059). Conclusions: Although the study did not demonstrate a statistically significant reduction in RTOG > 2 skin toxicity, there was evidence of a reduction in the rate of skin toxicity and an improvement in time to recovery. The device was well tolerated by patients.

OBJECTIVE:This study aimed to evaluate the adherence of ovarian cancer care in Lombardy, Italy to European Society of Gynaecological Oncology (ESGO) quality indicators and identify organizational strengths and gaps within the regional service delivery. METHODS:A cross-sectional assessment was conducted and distributed to all 111 hospitals in Lombardy between January 15 and March 15, 2024. The survey, based on ESGO quality indicators, examined surgical volume, access to multi-disciplinary tumor boards, peri-operative resources, and molecular diagnostics. Surgical volumes from 2022 to 2023 were cross-validated using administrative data (International Classification of Diseases and Current Procedural Terminology codes). Institutions were categorized by annual procedure volume: <10, 10 to 24, 25 to 49, and ≥50 surgeries per year. Adherence to ESGO standards was analyzed across these strata. RESULTS:A total of 52 hospitals reported performing ovarian cancer surgeries during the study period, totaling 1866 procedures. Only 8 centers (15.4%) met the ESGO quality criteria, yet they managed 64.4% of patients, indicating partial centralization. Although 71.2% of hospitals used dedicated gynecologic oncologists and 78.8% had functional multi-disciplinary tumor boards, BRCA and homologous recombination deficiency testing were available in only 44.2% and 38.5% of centers, respectively. A substantial number of patients were still treated in low-volume centers (<10 surgeries per year), raising concerns about surgical expertise and outcome quality. In addition, prospective documentation of surgical outcomes and complications was inconsistently implemented. CONCLUSIONS:Ovarian cancer care in Lombardy is partially centralized, with high-volume centers managing most cases and generally adhering to ESGO indicators. However, disparities persist in molecular testing, peri-operative outcome documentation, and equitable access to high-standard care. Strategic investments in diagnostics, referral networks, and data infrastructure are essential to optimize regional outcomes.

Supplementary Tables S1-S6_S17-S18

Tumor burden, stage and metastatic extent are associated with the presence of circulating tumor DNA (ctDNA). However, the association between genomic alterations and the presence of ctDNA remains unclear. We retrospectively analyzed patients with non-small cell lung cancer (NSCLC) with available Next-Generation Sequencing (NGS) analysis on both tissue and blood treated at the University of Chicago. NGS on tissue biopsies was conducted using the internal Oncoplus assay (168 genes). NGS on blood samples was conducted using the Guardant360 assay. Plasma ctDNA concentration was measured by the Variant Allele Frequency (VAF). Spearman rank correlation coefficient was used to assess the relationship between increasing number of mutations and VAF. Wilcoxon rank-sum test was used to compare the distribution of VAF between subgroups. A total of 221 patients were identified. Adenocarcinoma was the predominant histological subtype, accounting for 89.6% (n=199) of cases. The cohort was predominantly Caucasian (55.4%) and female (66.2%). The median age at diagnosis was 65 years. At the time of index liquid biopsy, 85.1% of patients had metastatic disease. Among the 221 patients, 129 (58.6%) harbored actionable mutations, with EGFR exon 19 or 21 mutations being the most prevalent (n=80, 36.2%). This study found a weak but significant association between VAF and mutation count in the tissue biopsy: for total mutations including both significant alterations and variants of unknown significance (r = 0.146, p=0.032) and for significant mutations only (r = 0.160, p=0.018). These associations were stronger in the KRAS G12C mutated sub-cohort for both total (r=0.471, p=0.036) and significant mutations (r=0.573, p=0.008). Significantly higher ctDNA VAF was observed in TP53 (p=0.006) and STK11 (p=0.05) mutant tumors. Our results showed a correlation between increasing number of alterations and ctDNA shedding. The association was stronger for KRAS G12C mutated tumors. The relationship between genetic changes and ctDNA release is supported by the increased ctDNA VAF seen in TP53 and STK11 mutant tumors. Robert Cameron, Anna Di Lello, Faith Abodunrin, Sulin Wu, Alessandra Esposito, Apameh Pezeshk, Valter Torri, Christine Bestvina, Marina Garassino. The association between tissue genomic alterations and ctDNA shedding in non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4548.

Neoadjuvant chemo-immunotherapy transformed early stage non-small cell lung cancer (NSCLC) treatment. However, the prognostic value of different pathological responses and the impact of adjuvant immunotherapy within a chemotherapy-immunotherapy perioperative strategy remains unclear. We estimated time-to-event outcomes by graphical reconstruction of event-free survival curves by pathological response (major pathological response, no major pathological response) reported in early stage NSCLC neoadjuvant or perioperative chemotherapy-immunotherapy trials. The major pathological response 1%-10% subgroup, previously unreported, was retrieved by removing patients achieving pathological response from the major pathological response group. Survival analysis by pathological response and comparison between neoadjuvant or perioperative strategies within subgroups were assessed. A statistically significant event-free survival difference according to pathological response was found, showing a prognostic gradient shifting from pathological response (good), major pathological response 1%-10% (intermediate), and no major pathological response (poor). There was no difference between neoadjuvant or perioperative strategies within subgroups; however, a trend for event-free survival benefit with perioperative and neoadjuvant chemotherapy-immunotherapy was observed in major pathological response 1%-10% and no major pathological response patients, respectively. In conclusion, a pathological response-based algorithm could better tailor early stage NSCLC treatment.

LBA4004 Background: Preoperative mFOLFIRINOX is a treatment option for patients (pts) with resectable/borderline resectable (R/BR) pancreatic ductal adenocarcinoma (PDAC). Methods: CASSANDRA (NCT04793932) is a multicenter phase 3 superiority trial randomizing pts ≤75y with R/BR PDAC, stratified by site and CA19.9, in a 2 by 2 factorial design to receive either PAXG (oral daily capecitabine 1250 mg/m 2 with biweekly cisplatin 30 mg/m 2 , nab-paclitaxel 150 mg/m 2 , gemcitabine 800 mg/m 2 ; arm A) or mFOLFIRINOX (biweekly 5-fluorouracil 2400 mg/m 2 , irinotecan 150 mg/m 2 , oxaliplatin 85 mg/m 2 ; arm B; 1 st random) for either 6 months before or 4 months before and 2 months after surgery (2 nd random). The results of 1 st random are presented. The primary endpoint is event-free survival (EFS = absence of progression, recurrence, 2 consecutive CA19.9 increases ≥20% separated by ≥ 4 weeks, unresectability, intra-operative metastasis, death) in the intention-to-treat population (ITT). Secondary endpoints are overall survival (OS), radiological, CA19.9, and pathological response rate, resection rate, toxicity, QoL in the ITT. With 173 events (260 pts) the study has a power of 80% to demonstrate a statistically significant difference at 5% two sided stratified logrank test under the alternative hypothesis of HR=0.65. EFS and OS were analyzed by Kaplan-Meier and log-rank test, HR estimated by Cox proportional hazard model. Results: Between Nov 2020 and Apr 2024, 260 eligible pts (tab 1) were randomly assigned to either arm A (N=132) or B (N=128). At data cutoff on March 1, 2025, with a median follow-up of 23.9 mos, 3y EFS was 30% (CI 20% – 40%) in arm A and 14% (CI 5% – 23%) in arm B with HR 0.66 (CI 0.49-0.89, p=0.005). In A/B, disease control rate was 98%/91% (p=0.009); CA19.9 reduction>50% 88/64% (p=<0.001); resection rate 75/67% (p=0.165); pathologic stage < II 35/23% (p=0.03); main G3-4 toxicity was: neutropenia 44/30%; fatigue 8/8%; diarrhea 2/5%; nausea/vomiting 7/10%; neuropathy 7/4%; AST/ALT 3/8%; infections 6/9%. Conclusions: Neoadjuvant PAXG significantly improved EFS compared to mFOLFIRINOX in pts with R/BR PDAC. Clinical trial information: NCT04793932 . A B Age 65 (42-76) 63 (41-76) Females 68 (52%) 62 (48%) KPS 90-100 123 (93%) 117 (91%) cStage I-II III 119 (90%)13 (10%) 115 (90%)13 (10%) RBR 63 (48%)69 (52%) 63 (49%)65 (51%) CA19.9 Normal Increased Median 32 (24%)261 43 (34%)226

BACKGROUND:Perioperative chemotherapy is a standard option for treatment of patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). This study aimed to assess the superiority of PAXG (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) over mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) in this population. METHODS:CASSANDRA is a randomised, open-label, 2 × 2 factorial phase 3 trial, involving 17 Italian academic hospitals. Eligible patients were aged 18-75 years with pathologically confirmed resectable or borderline resectable PDAC. Randomisation was performed by a central web-based system using R-code lists with a computerised algorithm. The design adopted a 1:1 randomisation, with a block stratification by centre and carbohydrate antigen 19-9. Participants were first randomly assigned PAXG (total daily capecitabine dose of 1250 mg/m2 in a 625 mg/m2 twice a day dosage and intravenous cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 every 14 days) or mFOLFIRINOX (intravenous fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and oxaliplatin 85 mg/m2 every 14 days) for 4 months, followed by a second randomisation to 2 months of additional chemotherapy either before or after surgery. The primary endpoint was event-free survival (EFS) in the intention-to-treat population and the safety population included all patients who received at least one cycle of the assigned therapy. The results of the first randomisation are reported here. The trial, registered on ClinicalTrials.gov (NCT04793932) and EudraCT (2020-003080-26 and 2024-519031-42-00), completed accrual and reached the necessary events for first randomisation primary analysis but follow-up of overall survival is ongoing. FINDINGS:Between Nov 3, 2020, and April 24, 2024, 132 eligible patients were assigned to PAXG and 128 to mFOLFIRINOX. In the PAXG group, the median age was 65 years (IQR 60-70), 68 (52%) of 132 patients were female, and 64 (48%) were male. In the mFOLFIRNOX group, the median age was 63 years (IQR 57-69), 62 (48%) of 128 patients were female, and 66 (52%) were male. All 260 patients received at least one assigned chemotherapy administration. PAXG prolonged the median EFS compared with mFOLFIRINOX (16·0 months [95% CI 12·4-19·8] vs 10·2 months [8·6-13·5]; hazard ratio 0·63 [0·47-0·84]; p=0·0018). At least one grade 3 or worse adverse event was observed in 87 (66%) of 132 patients in the PAXG group and in 78 (61%) of 128 patients in the mFOLFIRINOX group, including one fatal event. INTERPRETATION:PAXG significantly improved EFS compared with mFOLFIRINOX in resectable or borderline resectable PDAC. Preopertive PAXG could be considered a standard option for resectable or borderline resectable PDAC. Accordingly, preoperative PAXG should be considered as the standard comparator group for future trials in this setting. FUNDING:MyEverest and Codice Viola.

Non-small-cell lung cancer (NSCLC) is a leading cause of death for cancer worldwide. Standard treatment for patients for whom surgical resection is not feasible is concurrent (PACIFIC regimen) or sequential (PACIFIC-like regimen) chemoradiotherapy with platinum-based doublet chemotherapy followed by durvalumab maintenance. The progression-free survival (PFS) rate after the PACIFIC regimen was 55.3% at 12 months, with the primary site of recurrence being intrathoracic. In retrospective studies, a relevant proportion of patients presented a combination of intrathoracic failure and limited extra-thoracic metastatic disease. For patients with local progression only, or with loco-regional progression and limited metastatic burden, the use of chemotherapy or other agents without the addition of a local therapy may represent a missed opportunity for a second curative intent treatment approach. The AUSTRAL trial, a phase II, interventional, multicenter, single-arm, study (ClinicalTrials.gov identifier, NCT06680050) aims to investigate the combination of thoracic irradiation ± Stereotactic Body Radiation Therapy (SBRT) to oligometastatic sites followed, after 2 to 4 weeks, by durvalumab and ceralasertib, administered until progression or severe toxicity. The study population will include 21 stage III NSCLC patients with loco-regional relapse after >12 months from the end of CRT ± ≤3 metastatic lesions following PACIFIC/PACIFIC-like regimens. The study will last approximately 40 months and involve 7 Italian and 2 Swiss sites. Primary hierarchical endpoints are safety, assessed by the continuous toxicity monitoring approach, and efficacy, assessed by PFS. Secondary endpoints are objective response rate (ORR), 6- and 12-month PFS and OS rate.