Giovanni Farinea

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.

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.

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.

While microsatellite instability-high (MSI-H) colorectal cancer (CRC) exhibits high sensitivity to immunotherapy, microsatellite stable (MSS) CRC is a particularly immune-resistant disease. Whether microsatellite status remains unvaried in solid tumours or changes over time under treatment pressure is largely unknown, as, to our knowledge, no previous cases have been reported in the literature. Here, we report the case of a patient with MSI-H CRC who experienced a long-lasting complete response to first-line pembrolizumab, but subsequently relapsed after more than 4 years with an MSS phenotype, which acts as an immune escape mechanism. This case may present new challenges in this field that have not been previously described.

Introduction: Patients with biliary tract cancers (BTCs) often require antibiotic therapy before starting systemic treatment that includes an immune checkpoint inhibitor. This study aimed to evaluate the prognostic impact of antibiotic therapy administered in the 15 days prior to the start of chemoimmunotherapy in patients with BTC. Methods: The study population included patients with metastatic or locally advanced BTC from Western and Eastern populations treated with first-line chemoimmunotherapy. The aim of the study was to evaluate the impact of antibiotic therapy in the 15 days prior to starting oncological treatment (AT population) compared to patients who did not receive antibiotic therapy (NAT). Univariate and multivariate analyses were used to evaluate predictive factors for overall survival (OS) and progression-free survival (PFS), while prognostic factors were analyzed by univariate and multivariate analysis using Cox regression model. Results: A total of 666 patients were enrolled in the study: 93 (14%) in AT cohort and 573 (86%) in NAT cohort. In the AT population, the incidence of cholangitis (p = 0.0017), alanine aminotransferase elevation (p = 0.0009), fever (p = 0.0021), decreased appetite (p = 0.0007), itching (p = 0.0081), and rash (p = 0.012) was significantly higher compared to the NAT. The median OS was 15.9 months (95% confidence interval [CI]: 13.8–18.3) in NAT cohort versus 10.1 months (95% CI: 7.9–12.4) in AT cohort (NAT vs. AT, hazard ratio [HR]: 0.43, 95% CI: 0.27–0.70, p = 0.0006), while median PFS was 8.5 months in NAT cohort versus 5.4 months in AT cohort (NAT vs. AT, HR: 0.49, 95% CI: 0.34–0.71, p = 0.0001). Multivariate analysis confirmed the prognostic role of antibiotic for OS and PFS. Finally, NAT cohort showed better overall response rate compared with AT cohort (31.4% vs. 20.4%, p = 0.03). Conclusions: The use of antibiotic therapy in the 15 days prior to starting chemoimmunotherapy is an independent unfavorable prognostic factor for survival in our cohort of patients with advanced BTC treated with cisplatin, gemcitabine and durvalumab.