In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival ...relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.
Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) ...currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.
Background
An older age at the diagnosis of prostate cancer has been linked to worse prostate cancer–specific survival (PCSS). However, these studies were conducted before the approval of many ...life‐prolonging drugs. This study was aimed at describing outcomes in a contemporary cohort of men diagnosed with de novo metastatic prostate cancer (mPCa) and assessing associations with the age at diagnosis while controlling for known prognostic factors.
Methods
The Surveillance, Epidemiology, and End Results registry was used to identify men diagnosed with mPCa from 2004 to 2014. Men were classified by 4 age groups: ≤54, 55 to 64, 65 to 74, and ≥75 years. The median overall survival, PCSS, and restricted mean survival times for any‐cause mortality and prostate cancer–specific mortality (PCSM) were calculated. Multivariable and subdistribution hazard ratios for PCSM according to age group and with controlling for race, marital status, and income were estimated.
Results
Compared with men aged ≤54 years, men aged ≥75 years experienced a mean PCSS at 5 years that was 6.7 months shorter (95% confidence interval CI, 5.5‐7.8 months). In multivariable analyses, men aged ≥75 years had a 49% increase in the rate of PCSM in comparison with those aged ≤54 years (95% CI, 1.39‐1.60). The subdistribution hazard ratio for PCSM between these groups was 1.41 (95% CI, 1.32‐1.50).
Conclusions
Age was found to be an independent predictor of shorter PCSS in men diagnosed with de novo mPCa even in an era with more effective therapies. Further work is needed to determine the reason for poor outcomes in older men with mPCa.
Men 75 years old or older who are diagnosed with de novo metastatic prostate cancer have worse prostate cancer–specific survival than younger men. When it is appropriate, older men should be considered for all potentially effective therapies.
Neoadjuvant chemotherapy (NAC), which aims to eliminate micrometastatic disease, has been established as the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing ...radical cystectomy (RC). This is based on randomized controlled trials showing a survival benefit of NAC prior to RC compared to RC alone. It was anticipated that a similar survival benefit would also be seen when NAC was given prior to bladder preserving approaches, but the e phase III RTOG 8903 study which explored this concept was reported to be a negative study. However, there are a number of important caveats to be considered. First, the profile of patients opting for bladder preservation has changed from the older, frailer non-surgical candidates, to now also include younger, fitter patients opting for bladder preservation and who are also more likely to tolerate NAC. In recent years, there have also been important advances in systemic chemotherapy, immunotherapy, radiation techniques, and supportive care. As such revisitng the role of NAC prior to bladder preserving approaches in MIBC appears warranted.
Patients with advanced or metastatic urothelial cancer who had had a response to platinum-based chemotherapy were randomly assigned to best supportive care alone or best supportive care plus avelumab ...(an anti–PD-L1 antibody) every 2 weeks until progression. Patients receiving avelumab had significantly longer overall survival (21 months) than those receiving only best supportive care (14 months).
JCO
Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) ...significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 95% CI, 0.63 to 0.91; 2-sided
= .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.
•Urothelial carcinoma (UC) can be chemotherapy sensitive and immunogenic.•Immunogenic effects of chemotherapy support an immunotherapy maintenance strategy.•Avelumab maintenance significantly ...prolonged overall survival in a phase 3 trial.•Guidelines recommend avelumab as 1L maintenance for nonprogressed advanced UC.•Avelumab prolongs overall survival across patient subsets and is well tolerated.
Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 95% CI, 0.56–0.86; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin- or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1− tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.
To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl ...auristatin E, to cells that express Nectin-4.
EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma mUC) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 PD-(L)1 inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective.
Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease.
Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.
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