Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes

Abstract

Background First-line therapy for treatment of advanced urothelial carcinoma includes combination platinum-based chemotherapies, though resistance and long-term toxicity concerns to these regimens cause limitations in progression-free survival and overall survival. Maintenance treatment with an alternative agent such as the PD-L1 inhibitor, avelumab (Bavencio ® ), after initial chemotherapy has been shown to prolong overall survival. The aim of this review is to provide a landscape clinical use of avelumab in the treatment of advanced urothelial carcinoma with a focus on patient selection and outcomes. Methods This review includes the most up to date phases and results from clinical trials published in peer-reviewed journals. Results Three studies were included, one phase 1B trial, one phase 1B trial with 2 year follow-up, and one phase 3 trial. Patients receiving avelumab maintenance therapy at 10 mg/kg IV every two weeks had an overall better performance status, though those with an increased ECOG-PS, increased Bellmunt risk score, or failure of ≥3 chemotherapies had poorer responses. Patients over the age of 65 had a higher ORR (18–25%) compared to younger patients (13–14%). Patients with PD-L1 positive tumors had a significantly increased CR median ORR (13.8%), median PFS (5.7 months), and median 12-month OS rate (79.1%) compared to control subjects receiving best supportive care (1.2%, 2.1 months, 60.4%, respectively). TRAEs were seen in 86.7% of patients, with 32.4% of patients experiencing a ≥grade 3 AE. The most common AE was IRR (32.4%, ≥grade 3 1.01%) and irAE 25.6% of any grade, including various rashes and pruritus AEs, immune-related thyroid disorders, and immune related hepatitis. There were 3 reported treatment-related deaths (0.05%). Ongoing phases of one of the trials is investigating the use of docetaxel and avelumab together after failure of one chemotherapy. Conclusion Avelumab as a maintenance therapy after platinum-based chemotherapy failure or in platinum-ineligible patients with advanced or metastatic urothelial carcinoma is an effective option with increased ORR, PFS, and OS with a similar safety profile to other chemotherapies. Ongoing studies currently in recruitment and active clinical trials will yield valuable insights into optimizing avelumab therapy in conjunction with chemotherapies and/or immunotherapies, better characterization of response for PD-L1 positive tumors, and a clearer insight into clinically validated prognostic factors to improve patient outcomes.

Occult urothelial carcinoma with mediastinal metastasis: A case report

“…For metastatic UC, gemcitabine combined with cisplatin is one of the standard regimens of systemic chemotherapy (49,50). In recent years, the use of immunotherapy in UC treatment has gradually become a remedial measure for first-line chemotherapy failure or as second-line treatment (51)(52)(53). In addition, antibody-drug conjugates have been approved for UC treatment (53,54).…”

Concomitant Immunotherapy and Metastasis-Directed Radiotherapy in Upper Tract Urothelial Carcinoma: A Biomarker-Driven, Original, Case-Based Proof-of-Concept Study

“…PD-L1 status has limited utility, but it has been proven that patients with PD-L1 positive mUC receiving avelumab had a significantly increased median objective response rate (13.8%), median progression-free survival (5.7 months), and a median 12-month overall survival rate (79.1%) compared to patients receiving the best supportive care (1.2%, 2.1 months, 60.4%, respectively). [54] Another proposed biomarker for immunotherapy is microsatellite instability. In 2017, MSI-H was recognized as the first tissue/site-agnostic indication for the use of the ICI pembrolizumab (an anti-PD1 antibody) based on the result of five single-arm, multicohort, multicenter trials (KEYNOTE-016, -164, -012, -028, and -158).…”

Opportunistic Infections and Immune-Related Adverse Events Associated with Administering Immune Checkpoint Inhibitors: A Narrative Review

“… Drug Target Type Refs. Nivolumab PD-1 Human IgG4, anti-PD-1 [ 39 , 40 , 41 ] Pembrolizumab PD-1 Humanized IgG4, anti-PD-1 [ 37 , 42 , 43 , 44 ] Atezolizumab PD-L1 Humanized IgG1, anti-PD-L1 [ 45 , 46 , 47 ] Cemiplimab PD-1 Human IgG4, anti-PD-1 [ 48 , 49 ] Ipilimumab CTLA-4 Human IgG1, anti-CTLA-4 [ 8 , 50 , 51 ] Avelumab PD-L1 Human IgG1 anti-PD-L1 [ 52 , 53 , 54 , 55 ] ...…”