Luca Campedel

Background: Small-cell lung cancer (SCLC) is a highly aggressive disease with limited treatment options beyond first-line platinum-based chemotherapy. Although various second-line regimens such as topotecan and cyclophosphamide-adriamycin-vincristine have been evaluated, clinical outcomes remain poor, particularly in patients with platinum-resistant or refractory disease. The combination of paclitaxel and doxorubicin showed encouraging results in early-phase trials, but data on its use in real-world settings are lacking. This study aimed to assess the efficacy and safety of this chemotherapy regimen in patients with previously treated SCLC in a real-world clinical setting. Methods: Data were retrospectively collected from all consecutive patients with previously treated SCLC at a single institution in France between 2000 and 2024. Results: A total of 149 patients were included, of whom 79.9% had platinum-resistant or refractory disease at the time of paclitaxel-doxorubicin initiation. The median progression-free survival (PFS) was 2.4 months [95% confidence interval (CI): 2.1–3.8], and the median overall survival (OS) was 5.1 months (95% CI: 4.7–6.0). The objective response rate was 22.2% in the overall population and 27.7% when excluding patients not evaluable for response. The disease control rate was 41.6% including all patients and 52.1% when excluding non-evaluable cases. In multivariable analysis, an Eastern Cooperative Oncology Group performance status of 2–4 compared to 0–1 was associated with shorter PFS [hazard ratio (HR) =1.9, 95% CI: 1.22–2.8, P=0.004] and OS (HR =2.73, 95% CI: 1.76–4.2, PConclusions: This real-world study suggests that the paclitaxel-doxorubicin combination provides some clinical activity in previously treated SCLC, including in platinum-resistant/refractory disease. Although toxicities were common, they were generally manageable. These findings support further investigation of this regimen with careful patient selection.

Introduction: Primary urethral cancer (PUC) is rare, and limited data exist on optimal treatment and survival, particularly in metastatic cases. The objective of this study was to describe treatment patterns, responses and survival in a contemporary cohort.Patients and Methods: Data from patients diagnosed with PUC between January 1, 2000 and December 31, 2018, were retrospectively collected from nine French tertiary centres. To enhance the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled.Results: We identified 71 patients (62% males, 38% females). The most common histological types were urothelial (40.0%), squamous cell (34.3%) and adenocarcinomas (14.3%). At diagnosis, 35.2% had localized disease, 49.3% had locally advanced disease and 15.5% had distant metastases. Twenty‐seven patients had a metachronous metastatic cancer. Multimodal therapy was used in 24% of localized and 57.1% of locally advanced disease. Among the 60 patients with non‐metastatic disease, median disease‐free survival (DFS) was 21.2 months. Nodal involvement was associated with worse DFS (HR: 2.03, p = 0.039), while multimodal treatment did not improve DFS (HR: 1.22, p = 0.5419). For metastatic patients, median overall survival was 15.2 months, and progression‐free survival was 6.4 months. Main study limitations were an overrepresentation of locally advanced disease and the small cohort size.Conclusions: This retrospective study highlights the significant heterogeneity in terms of histology, stage at diagnosis and treatment of PUC. This study is one of the few to describe treatments and survival in metastatic PUC patients. Efforts must be made to improve survival in these patients.

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221

Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221

There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

The objective of this study was to determine the proportion of phase 3 clinical trials investigating a systemic therapy for patients with prostate, breast, lung, or colorectal cancer that excluded patients with Chronic Kidney Disease (CKD) and the exclusion criteria chosen, if any. A search was conducted using the ClinicalTrials.gov database to identify eligible studies. Of the 268 included trials, 185 (69%) had at least one renal exclusion criteria. Of these 185 trials, 116 (63%) had an undefined exclusion criterion. Only disease site was associated with exclusion of patients with CKD in the univariate analysis, but no factors in the multivariate analysis. There are several potential barriers to including patients with CKD in clinical trials. Nevertheless, solutions can be proposed to allow the inclusion of these patients. This would allow them to access to innovative therapeutic strategies, but also allow a better applicability of trial results to this patient population.

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). Results: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients’ IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. Conclusion: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.