Alessandro Parisi

Messenger RNA vaccines have moved rapidly from the infectious-disease area into oncology. They now represent an attractive therapeutic option for gastrointestinal (GI) cancers. Personalised constructs, designed to elicit tumour-specific T-cell immunity, have shown acceptable safety and clear immunogenicity in early-phase trials of colorectal and pancreatic cancers. These early signals are encouraging, but several obstacles still exist for routine clinical use: tumour heterogeneity, immune evasion, the difficulty of selecting the right target antigens, and the stability of the delivery platform itself. The possibility of a combination with immune checkpoint inhibitors is currently being explored to deepen and prolong responses, although the durability of benefit remains to be established. In this review, we outline the current landscape of mRNA vaccine development for GI malignancies, with particular attention to delivery strategies and multimodal immunotherapy. Finally, we discuss the directions most likely to help move these agents from the laboratory into everyday clinical practice.

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

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.

As an extended analysis of the COVID-DELAY study, we aimed to assess the impact of the COVID-19 pandemic on diagnosis, staging, and survival outcomes among patients with colorectal cancer (CRC) diagnosis performed from 2019 to 2022. All consecutive newly diagnosed CRC patients referred to 11 Italian Oncology Departments between March and December 2019, 2020, 2021, and 2022 were enrolled. Access rate, demographics, diagnostic-therapeutic temporal intervals, and first-line progression-free survival (PFS) and OS among metastatic patients were assessed. Compared to 2019 (n = 690), an initial global reduction in new CRC cases in 2020 (n = 564, –18.3%) was observed, followed by a progressive increase in new CRC diagnoses in 2021 (n = 748, + 8.4%) and 2022 (n = 756, + 9.6%); a higher rate of TNM stage IV tumors was diagnosed in 2020 (35.4%) and 2021 (31.0%) compared to 2019 (29.6%), with normalization in 2022 (26.4%) (P < .001). Not clinically relevant differences between histological diagnosis and first oncological examination, cytohistological diagnosis and systemic treatment start, first oncological appointment and systemic treatment start, treatment start and first radiological assessment between 2020 and 2021-2022 years were found. After propensity score matching according to the year of diagnosis, median OS was significantly worse in 2020, 2021, and 2022 compared to 2019 (27.6 vs 24.8 vs not reached vs 38.9 months, respectively) (P < .001). Concordantly, the median PFS was significantly worse with each passing year: 13.0 vs 11.1 vs 9.2 vs 7.2 months in 2019, 2020, 2021, and 2022, respectively (P = .00027). A progressive normalization in the rate of new CRC diagnosis as well as TNM stages at diagnosis, in 2021 and 2022 compared to 2020 and 2019, was found. The increase in new CRC cases might have affected some diagnostic-therapeutic time intervals in 2021-2022 years compared to 2020. Significantly, compared to the pre-pandemic phase, pandemic years were independently associated with worse PFS and OS outcomes in patients affected by metastatic disease.