TPS3684 Background: Patients with metastatic colorectal cancer (mCRC) who progress after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic agents, and anti-EGFR therapies have limited therapeutic options and a poor prognosis. Median overall survival (mOS) is approximately 6 months with single-agent regorafenib or trifluridine/tipiracil. The addition of bevacizumab to trifluridine/tipiracil has improved mOS to 10.8 months, while fruquintinib, a selective VEGFR-1–3 inhibitor, demonstrated a mOS of 7.4 months compared with 4.8 months for placebo in refractory mCRC. However, combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors have shown clinical benefit, primarily in patients with microsatellite-stable mCRC without liver metastases, likely due to liver-associated immunosuppression. The QUINTIS trial evaluates whether fruquintinib plus the PD-1 antibody tislelizumab can improve outcomes in this clinically defined subgroup compared with the current standard of care of trifluridine/tipiracil plus bevacizumab. Methods: QUINTIS is a prospective, randomized, open-label, multicenter phase II trial enrolling 140 patients with metastatic colorectal adenocarcinoma without active liver metastases who have previously received fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and, when indicated, an EGFR inhibitor. Participants are randomized 1:1 to Arm A (experimental): fruquintinib 5 mg orally once daily (days 1–21 of a 28-day cycle) plus tislelizumab 400 mg intravenously on day 1 every 6 weeks; or Arm B (control): trifluridine/tipiracil 35 mg/m² orally twice daily (days 1–5 and 8–12 of a 28-day cycle) plus bevacizumab 5 mg/kg intravenously every 2 weeks. No prior treatment with the study drugs is permitted. Randomization is stratified by time since prior anti-angiogenic therapy ( < 12 vs. ≥12 months), BRAF/RAS mutation status, and history of liver metastases (never vs. treated). The primary endpoint is progression-free survival; secondary endpoints include overall response, overall survival, and quality of life. Translational research includes tumor, blood, and stool sampling to explore biomarkers of response and resistance, including systemic inflammation and the diet–microbiota–immune axis. Patient enrolment started in October 2025, and enrolment will take place at 30 sites. Clinical trial information: EU CTIS No. 2024-519111-34-00.

Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [18F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.

Many real-world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ-1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first-line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ-1-in (meeting all inclusion criteria) or TOPAZ-1-out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ-1-out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ-1-in, and 446 (32.9%) as TOPAZ-1-out. After a median follow-up of 14.5 months (95% CI: 13.7-36.5), OS was 16.1 months in TOPAZ-1-in and 12.5 months in TOPAZ-1-out (HR 0.69, 95% CI: 14.6-16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1-8.1, p < 0.0001). Median OS in the TOPAZ-1-out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93-1.42; p = 0.09). Among TOPAZ-1-out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ-1-out patients experienced no significant increase in adverse events compared with the TOPAZ-1-in group. Real-world data suggest CGD may be effective in TOPAZ-1-out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

Colorectal cancer predominantly affects older adults (ie, those aged 70 years or older). Along with shifting demographic trends, the number of patients with colorectal cancer in this age group is estimated to sharply increase globally over the next few decades. During the past decade, new treatment modalities and systemic therapeutic options have been introduced through well conducted clinical trials that shaped and fundamentally redefined the treatment landscape. However, older adults with reduced physiological reserves, functional impairment, comorbidities, and geriatric syndromes are under-represented in such studies. Yet, for this population, growing evidence for geriatric assessment and management shows patient-centred benefits with the potential to further improve outcomes, parallel to the broadening armamentarium of medical innovations. The purpose of this Review is to summarise the evidence base of the current therapeutic landscape of colorectal cancer and guide management of older adults in daily clinical practice through pragmatic decision making.

3575 Background: The randomized FIRE-4 study evaluated the effect of cetuximab rechallenge versus investigator’s choice in the 3 rd -line treatment of patients (pts) with RAS-wildtype (RAS-wt) metastatic colorectal cancer (mCRC). The present analysis focuses on the time between the end of initial anti-EGFR-based treatment and start of 3 rd -line therapy (TIS-3) as a potential predictor of response. Methods: In FIRE-4, all pts received induction therapy with FOLFIRI plus cetuximab. After 1 st PD, an anti-EGFR-free “window therapy” was recommended. At diagnosis of 2 nd PD, pts who had responded to induction therapy were re-evaluated for RAS status and, after exclusion of RAS mutations, were offered randomization to either rechallenge with cetuximab plus chemotherapy or investigator’s choice. Overall survival in 3 rd -line (OS-3) was evaluated as a primary endpoint. Results: Of the 87 pts entering 3 rd -line treatment in FIRE-4, 45 received (FOLF)IRI plus cetuximab (rechallenge arm), and 42 received investigator’s choice (standard arm). Numerically superior outcome parameters regarding ORR-3 (OR 2.70), PFS-3 (HR 0.87) and OS-3 (HR 0.86) were observed in the rechallenge arm, without, however, reaching the level of statistical significance. To evaluate the relevance of TIS-3, we focused on the median (13.8 months) and the first quartile (9.0 months). Based on these cut-off values, treatment effects were evaluated in pts with longer and shorter TIS-3 intervals (see Table). Conclusions: Longer TIS-3 intervals were associated with longer survival times in 3 rd -line treatment. This observation was particularly true for pts receiving cetuximab rechallenge, but also for those receiving investigator’s choice. Clinical trial information: NCT02934529 . Treatment arm N Interval PFS (mo) HR OS (mo) HR FOLF(IRI) + Cetuximab 21 > 13.8 mo 7.4 0.475P=0.019 20.0 0.639P=0.187 24 < 13.8 mo 4.1 12.6 34 > 9.0 mo 5.9 0.680P=0.274 19.6 0.601P=0.173 11 < 9.0 mo 4.0 10.8 Investigator’s choice 23 > 13.8 mo 5.6 0.772P=0.415 16.2 0.516P=0.055 19 < 13.8 mo 4.4 12.2 32 > 9.0 mo 5.5 0.690P=0.313 16.9 0.458P=0.042 10 < 9.0 mo 4.5 7.8

Background:Despite therapeutic advances, gastroesophageal cancers remain associated with high mortality. While most deaths are cancer-related, improvements in therapy and supportive care may alter mortality patterns over time. This study aimed to characterize causes of death and associated clinical factors in a large real-world European cohort. Methods:We retrospectively included 2518 patients with histologically confirmed esophageal, gastric, or gastroesophageal junction carcinomas treated at the Medical University of Vienna between 1994 and 2024. Causes of death were obtained from Austria's national death registry and categorized using International Classification of Diseases (ICD) codes. Fine-Gray competing risk models were applied to identify factors associated with cancer- and non-cancer-related deaths. Results:At data cutoff, 1863 patients (74%) had died. Of these, 85% of deaths were cancer-related, 12% non-cancer-related, 2% unknown, and <1% suicide. Tumor stage was the strongest predictor of cancer-related mortality, with subdistribution hazard ratios (sHR) increasing from 2.34 (95% CI 1.91-2.86) in stage 2 to 7.42 (95% CI 6.15-8.96) in stage 4 disease compared with stage 1 (all p < 0.001). A higher comorbidity burden also independently increased cancer-related mortality. Non-cancer-related death was primarily associated with older age (≥65 years; sHR 2.21, 95% CI 1.12-4.35, p = 0.021) and stomach tumor location (sHR 1.56, 95% CI 1.08-2.23, p = 0.017), while more recent diagnosis (2020-2024) was linked to a lower risk of both cancer- and non-cancer-related mortality (cancer-related: sHR 0.60, 95% CI 0.47-0.76, p < 0.001; non-cancer-related: sHR 0.43, 95% CI 0.25-0.74, p = 0.002), likely reflecting a combination of evolving treatment strategies, improvements in supportive care, and shorter follow-up in the most recent cohort. Conclusion:Cancer progression remains the predominant cause of death in patients with gastroesophageal cancer, with tumor stage as the key prognostic factor. These high mortality rates emphasize the need for improved antitumoral treatment and timely palliative care approaches.

Mismatch-repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastroesophageal adenocarcinoma (GEA) is associated with favorable prognosis but limited benefit from perioperative chemotherapy. Although immune checkpoint inhibition (ICI)-based approaches have shown promising activity in early-phase studies, the optimal therapeutic combinations and the feasibility of non-operative management (NOM) in resectable disease remain unclear. This exploratory, retrospective, multicenter, real-world study included 55 patients with resectable dMMR/MSI-H GEA, who were divided into subgroups, characterized and compared according to treatment strategy (chemotherapy, chemoimmunotherapy, immunotherapy and initial resection). Pathological and clinical complete response (pCR, cCR), progression-free (PFS) and overall survival (OS) were evaluated. Patients received chemotherapy (n=10), chemoimmunotherapy (n=16), immunotherapy (n=13), or initial resection without subsequent systemic treatment (n=16). Forty five (82

Surgery after response to first-line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real-world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first-line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow-up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty-four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic-net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism-corrected AUC of 0.65. First-line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

TPS255 Background: c-Met protein is often expressed in several solid tumors, including metastatic colorectal cancer (mCRC). Temab-A is an antibody-drug conjugate that targets c-Met protein and is conjugated to a topoisomerase 1 inhibitor payload. A phase 1 study in patients (pts) with advanced solid tumors, including mCRC, reported a manageable safety profile and promising antitumor activity with Temab-A monotherapy (NCT05029882). Herein, we describe a phase 2 study of Temab-A in combination with SOC regimens in pts with mCRC. Methods: This open-label, randomized, global, multicenter, phase 2 study (NCT06820463; AndroMETa-CRC-533) includes 2 substudies. Eligible pts (≥18 years) must have histologically confirmed mismatch repair-proficient mCRC, measurable disease (per RECIST v1.1), and no prior systemic therapy for mCRC. In substudy 1, eligible pts must have KRAS/NRAS -mutant primary tumor or right-sided KRAS/NRAS -wildtype primary tumor. For substudy 2, eligible pts must have KRAS/NRAS/BRAF -wildtype and left-sided primary tumor. Substudies 1 and 2 comprise a dose-escalation (D-ESC; guided by a BOIN design) followed by a dose-expansion (D-EXP) phase. During D-ESC, pts receive escalating doses of Temab-A (Q4W) with either FOLFOX + bevacizumab (BEV; substudy 1: N~18) or 5-fluorouracil (5-FU)–folinic acid + panitumumab (PAN; substudy 2: N~12) in 28-day cycles. During D-EXP, ~135 pts for each substudy are randomized 1:1:1 to high- or low-dose arms (substudy 1: Temab-A + FOLFOX + BEV; substudy 2: Temab-A + 5-FU–folinic acid + PAN) or SOC (substudy 1: FOLFOX + BEV; substudy 2: FOLFOX + PAN). In both substudies, pts receive treatment until disease progression, intolerable toxicity, or other discontinuation criteria are met. Objectives and endpoints are listed in the table. Clinical trial information: NCT06820463 . Objectives Primary Evaluate safety, tolerability, and efficacy (as measured by OR) of Temab-A in combination with SOC regimensOptimize Temab-A dose in combination with SOC regimens Secondary Assess additional efficacy outcomesEvaluate PK of Temab-A in combination with SOC regimens Endpoints Primary OR (CR, PR by Inv) Secondary PFS, DOR, disease control (by Inv), OS Exploratory PROs (in the randomized stages) CR, complete response; DOR, duration of response; Inv, investigator; OR, overall response; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; PROs, patient reported outcomes.

Background Since results of the ToGA trial were published in 2010, the addition of trastuzumab to chemotherapy is the standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic gastroesophageal adenocarcinoma. Yet, data from European real-world cohorts are scarce. Methods We evaluated baseline characteristics and treatment regimens of gastroesophageal adenocarcinoma patients with advanced and metastatic disease (stage IV) treated at XXX between 01/01/2010 and 31/12/2023. Log-rank tests were performed to analyze differences in survival. Results In our cohort of 369 advanced/metastatic gastroesophageal cancer patients, 78 (24%) of tumors with known HER2-status were HER2 positive. First-line chemotherapy with trastuzumab was administered to 60 HER2-positive patients (16% of the overall cohort) and showed statistically significantly improved overall survival compared to patients treated with chemotherapy only (17.3 vs. 11.9 months, HR=0.62, p=0.0011). Regarding tumor location, 15 (25%) patients had esophageal, 23 (38%) gastroesophageal junction and 22 (37%) gastric cancer. However, no statistically significant survival benefit was observed with the addition of trastuzumab in tumor location subgroups (p=0.058, p=0.088, p=0.07). Conclusion Our data support the results from the ToGA trial in a real-world cohort and underline the importance of HER2 testing and administration of trastuzumab in clinical routine. Although not included in the initial ToGA trial, esophageal adenocarcinoma patients express HER2 to a significant extent and further analyses are needed to investigate the benefit of trastuzumab and other anti-HER2 treatment options in this subgroup.

Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options. The addition of durvalumab or pembrolizumab to cisplatin–gemcitabine improves overall survival (OS), but validated biomarkers of benefit remain limited. Immune-mediated adverse events (imAEs) have been proposed as treatment-emergent clinical correlates of immune activation. Methods: We retrospectively analyzed an international cohort of patients with locally advanced or metastatic BTC treated with first-line cisplatin–gemcitabine plus durvalumab. Primary endpoints were OS and progression-free survival (PFS). The principal exposure was the occurrence of any imAE. A post hoc complete-case Cox model was adjusted for age, sex, primary tumor site, prior surgery, ECOG performance status, disease stage, albumin, bilirubin, and neutrophil-to-lymphocyte ratio (NLR); analyses of individual AEs were exploratory. Exact AE onset dates were not consistently available, precluding a reliable formal time-dependent exposure analysis. Results: A total of 1358 patients were included; all received durvalumab, and 276 (20.3%) developed at least one imAE. In the fully baseline-adjusted model, any imAE remained associated with a lower risk of death (adjusted HR 0.72, 95% CI 0.57–0.92; p = 0.008) and progression or death (adjusted HR 0.63, 95% CI 0.52–0.77; p < 0.001). In exploratory baseline-adjusted analyses of individual imAEs, other imAEs remained associated with OS (HR 0.39, 95% CI 0.24–0.62; p < 0.001) and PFS (HR 0.56, 95% CI 0.40–0.77; p < 0.001), while hypothyroidism remained associated with PFS only (HR 0.65, 95% CI 0.43–0.97; p = 0.034); rash and hyperthyroidism were not independently associated after full baseline adjustment. In AE-focused exploratory models, decreased appetite and hyponatremia were associated with worse outcomes, neutropenia with better outcomes, and ALT elevation with worse PFS. Baseline corticosteroid use was uncommon (n = 21), and all steroid analyses are vulnerable to confounding by indication and exposure-timing bias. Conclusions: Treatment-emergent imAEs may represent potential prognostic markers or clinical correlates of benefit, but they are not validated surrogate endpoints. Prospective studies with precise AE-onset capture are required.

Background This study aimed to determine the optimal second-line treatment strategy in patients with metastatic pancreatic cancer, hypothesizing that liposomal irinotecan (nal-IRI) combined with S-1 would be superior to nal-IRI with 5-fluorouracil (5-FU)/leucovorin (LV). Methods This was an international, multi-center, open-label, randomized phase I/II superiority trial. Patients with pancreatic adenocarcinoma, previously treated with gemcitabine-based treatment, were enrolled. Patients were randomly allocated to receive either nal-IRI plus S-1 (S-1 arm) or nal-IRI plus 5-FU/LV (5-FU arm). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), (serious) adverse events (SAEs), response rate, and health-related quality of life. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a Cox model. This trial is registered with ClinicalTrials.gov (NCT03986294) and is completed. Results Between November 10, 2021 and May 23, 2023, 120 patients were randomized to the S-1 arm (n=61) or the 5-FU arm (n=59). Three patients were excluded due to ineligibility. Median PFS was 2.2 months in the S-1 arm vs. 3.3 months in the 5-FU arm (HR 1.27; 95% CI 0.84-1.91, p=0.26). Median OS was 6.0 months in the S-1 arm vs. 9.1 months in the 5-FU arm (HR 1.47; 95% CI 0.99-2.17, p=0.054). The most common grade 3-4 AEs were diarrhea (13.8%) and nausea (10.3%) in the S-1 arm, and diarrhea (14.0%), asthenia and mucositis (both 7.0%) in the 5-FU arm. Conclusion Second-line treatment with nal-IRI plus S-1 did not improve PFS and OS compared to nal-IRI plus 5-FU/LV in patients with metastatic pancreatic cancer following first-line gemcitabine-based chemotherapy.

BACKGROUND:Currently, data concerning the prognostic impact of metastatic sites in biliary tract cancers (BTC) are limited. OBJECTIVE:The aim of the present study is to evaluate the prognostic impact of metastatic sites in patients with BTC treated with cisplatin-gemcitabine-durvalumab (CGD). PATIENTS AND METHODS:The study population comprised a large worldwide cohort of patients treated with CGD. The primary objectives were overall survival (OS) and progression-free survival (PFS) based on the location and number of metastatic sites. RESULTS:A total of 666 patients with locally advanced (111) or metastatic (555) BTC treated with CGD were included in the study. None of the metastatic sites were shown to have a prognostic impact on OS at multivariate analysis. Patients with one to two metastatic sites had longer OS (hazard ratio [HR] 0.59; p = 0.005) and PFS (HR 0.73; p = 0.03) compared with those with three to five metastatic sites in the univariate analysis but not in the multivariate analysis. No statistically significant differences were observed in OS or PFS across different metastatic sites limited to a single organ. Patients with progressive disease (PD) on first-line CGD with a change in metastatic sites from baseline showed no statistically significant differences in OS2 (defined as the time from PD on first-line therapy to death for any cause) compared with those without a change in metastatic sites (HR 0.88; p = 0.60). CONCLUSIONS:Our study did not show statistically significant differences in outcomes associated with location and number of metastatic sites in a large population of patients with BTC treated with CGD.

3543 Background: BRAF V600E mutation in metastatic colorectal cancer (mCRC) is associated with poor prognosis. Registrational approval of anti-EGFR antibodies does not exclude their use in BRAF V600E mutated (mut) mCRC, while current guidelines explicitly advise against the use of anti-EGFR-directed therapy and recommend the use of chemotherapy plus anti-VEGF antibodies. The present analysis of single-patient data evaluates the therapeutic benefit from anti-EGFR- vs. anti-VEGF-directed therapy in BRAF V600E mut mCRC. Methods: We conducted a pooled analysis of eight first-line AIO-studies (FIRE-1, FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including 251 evaluable pts with BRAF V600E mut and RAS wild-type mCRC. Right-sided primary tumors (RSPT) included tumors from the caecum to the colon transversum, while left-sided tumors (LSPT) included the splenic flexure to the rectum. Results: Of 251 BRAF V600E mut pts, exact primary tumor location was available in 230 pts. In this cohort, 117 were male (50.9%) and 113 female (49.1%). LSPT was observed in 106 (46.1%) pts compared to 124 (53.9%) with RSPT. In the entire cohort, median OS (mOS) of LSPT vs. RSPT did not differ significantly (15.2 months vs. 13.4 months; HR 0.96; 95% CI, 0.70–1.29; P=0.77). Pts with LSPT showed a numerical survival benefit with anti-EGFR therapy compared to anti-VEGF therapy (17.8 months vs. 11.8 months; HR 0.71; 95% CI, 0.45–1.14; P=0.16). This effect was observed independent of sex. In contrast, pts with RSPT showed a trend towards inferior outcome with anti-EGFR vs. anti-VEGF therapy (11.6 months vs. 17.1 months; HR 1.31; 95% CI, 0.84–2.05; P=0.23). This effect was primarily driven by females, who experienced a significant survival disadvantage with anti-EGFR therapy (10.2 months vs. 17.1 months; HR 1.85; 95% CI, 1.05–3.25; P=0.031). For males, however, both anti-VEGF and anti-EGFR antibodies were associated with comparable outcome. Conclusions: The present analysis performed in the first-line treatment of BRAF V600E mut mCRC suggests a survival benefit from anti-EGFR antibodies in pts with LSPT, independent of gender. Male pts with RSPT appear to derive comparable benefit from anti-EGFR and anti-VEGF antibodies, while female pts exhibit a survival disadvantage from anti-EGFR antibodies. Clinical trial information: NCT00433927 (FIRE-3), NCT02934529 (FIRE-4), NCT04034459 (FIRE-4.5), NCT01249638 (ML22011), NCT00254137 (CIOX), NCT01991873 (PANAMA), NCT01328171 (VOLFI). [clinicaltrials.gov].

Cholangiocarcinoma (CCA) represents a diverse group of malignancies. It is often identified at a late stage after the opportunity for curable resection has passed. An international educational meeting on CCA was held in Barcelona in September 2024. The meeting described the challenges with obtaining accurate epidemiological estimates for CCA because of misdiagnosis and marked regional differences, reflecting the prevalence of socioeconomic risk factors. Early-stage CCA is usually asymptomatic, and when symptoms appear, they are nonspecific. Diagnosis and treatment planning should involve a multidisciplinary team (MDT) from the outset. The European Society for Medical Oncology (ESMO) guidelines recommend molecular testing using next-generation sequencing when advanced disease is diagnosed. Biopsy sampling is technically challenging; if insufficient quality tissue is collected for molecular testing, liquid biopsy can be used. If the tumour is unresectable, the recommended first-line treatment is cisplatin + gemcitabine + durvalumab a programmed cell death ligand 1 [PD-L1] inhibitor or pembrolizumab a programmed cell death protein 1 [PD-1] inhibitor. The development of targeted therapies has led to these treatments being recommended as second- or third-line therapy for patients with actionable gene alterations, while 5-fluorouracil-based chemotherapy is recommended for those without. Robust data support the use of ivosidenib in patients with IDH1 mutations (phase 3), and phase 2 trials showed efficacy of pemigatinib and futibatinib for patients with FGFR2 gene fusions, trastuzumab deruxtecan and zanidatamab for patients with HER2 overexpression/amplification, and dabrafenib + trametinib for patients with BRAFV600E mutations. It is hoped that wider dissemination of the content from this meeting will improve outcomes of patients with CCA by encouraging earlier referral, increasing the use of early molecular testing, an MDT approach, and maximising the use of targeted therapies. Continued efforts to raise awareness, implement education outreach opportunities, and involve patient advocacy groups are encouraged to improve CCA outcomes. Cholangiocarcinoma (CCA) is the second most common type of liver cancer. While CCA can be cured if it is diagnosed early enough, it is often identified too late for surgical removal to be feasible. Therefore, there are unmet needs in the management of CCA. An educational initiative called the Expert eXchange meeting in acute myeloid leukaemia and CCA on Targeted therapy (EXACT) program was set up to address the unmet needs in this patient group. The aim of the expert meeting was to discuss how to improve the diagnosis and management of CCA. Expert doctors who treat patients with CCA (oncologists) from 16 countries met in Barcelona, Spain on September 12, 2024, to discuss evidence related to CCA, including using examples of real patients with difficult-to-manage disease. The experts also reviewed recent advances and ongoing research of new therapies, such as molecular biomarkers and targeted therapies, which could improve patient outcomes after CCA is treated. It emerged that there are many interventions that have the potential to positively influence CCA outcomes, including (1) referral to a specialist at the earliest stage of symptom development when CCA is suspected; (2) obtaining a tissue sample for biopsy and molecular testing; (3) testing for genetic mutations, and if present, using therapies targeted to these mutations; (4) raising awareness of CCA through education and outreach initiatives; and (5) involvement of a multidisciplinary team to care for patients throughout their cancer journey.

History of malignant disease is a common exclusion criterion in clinical cancer trials, yet data on the impact of cancer survivorship on outcome in gastroesophageal cancer patients are scarce. Retrospective association analyses of self-reported prior or concurrent malignancies with patient characteristics, tumor characteristics, symptoms and overall survival (OS) were performed in 1491 gastroesophageal cancers patients treated between 01/01/2000 and 31/12/2021 at the Medical University of Vienna. Of 1491 patients 255 (18

OBJECTIVES:This post hoc analysis of the SUNLIGHT trial sought to assess the response to treatment with trifluridine/tipiracil (FTD/TPI) + bevacizumab and FTD/TPI in patients with refractory metastatic colorectal cancer using tumor shrinkage (TS), early TS (ETS), duration of TS (DTS) and depth of response (DpR) as response-related parameters. METHODS:TS was defined as any decrease from baseline of the sum of the longest diameter of target lesions. TS at first assessment was specified as ETS. DpR was defined as the maximum percentage change from baseline of the sum of the longest diameters of target lesions. DTS was defined as the time from first TS to first increase in tumor size, progressive disease, or death. RESULTS:In the FTD/TPI + bevacizumab group, 48 % had TS and 39 % had ETS. In the FTD/TPI group, 21 % had TS and 17 % had ETS. In patients achieving ETS, median DTS was prolonged with FTD/TPI + bevacizumab compared to FTD/TPI (3.8 versus 2.1 months; HR: 0.34 [95 % CI: 0.22, 0.53]; P < 0.0001). Magnitude of DpR was greater with FTD/TPI + bevacizumab than with FTD/TPI. CONCLUSION:The survival benefit of treatment with FTD/TPI + bevacizumab versus FTD/TPI is likely associated with the improvement of ETS and DpR.

Standard of care first-line systemic treatment for advanced biliary tract cancer includes chemo-immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo-immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo-immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty-eight patients were included in this study. Two hundred twenty-seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first-line chemo-immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil-to-lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

BACKGROUND:Cisplatin, gemcitabine, and durvalumab combination is a standard first-line treatment for advanced biliary tract cancer. This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced biliary tract cancer treated with cisplatin, gemcitabine, and durvalumab in real-world clinical practice. METHODS:Patients with unresectable, locally advanced, or metastatic biliary tract cancer treated with cisplatin and gemcitabine plus durvalumab across 39 centers in 11 countries in Europe, the United States, and Asia were included in this analysis. RESULTS:The cohort included 513 patients with advanced biliary tract cancer. The 5 most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (hazard ratio [HR] = 0.49, P = .018) and overall survival (HR = 0.11, P = .023), while TP53 mutations were linked to worse PFS (HR = 1.62, P = .0047) and TERT mutations to worse overall survival (HR = 8.92, P = .0012). No other genomic alterations were statistically associated with outcomes. Subgroup analysis showed that TP53 mutations negatively affected PFS and overall survival in intrahepatic cholangiocarcinoma, while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma. No gene alterations were linked to outcomes in gallbladder cancer. CONCLUSIONS:This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and overall survival and highlights the negative prognostic roles of TP53 (PFS) and TERT (overall survival) mutations, providing valuable insights for personalized treatment strategies in biliary tract cancer.