Expert Discusses Urothelial Carcinoma's Newest Agent

Imfinzi (durvalumab) — a PD-L1 inhibitor – gained Food and Drug Administration (FDA) approval last month to treat patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy, or for patients who have disease progression within a year of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The approval was based on the single-arm phase 1/2 Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.

In the study, the objective response rate per blinded independent central review was 17 percent. At the data cutoff, the median duration of response was not reached.

Please provide some background on Imfinzi leading up to its approval.

In an interview with CURE, Christophe Massard, M.D., Ph.D., medical oncologist, senior consultant of the Drug Development Department and Department of Medical Oncology, and chairman of the Early Drug Development Multidisciplinary Tumor Board, Gustave Roussy Institute, discussed the latest developments with Imfinzi in urothelial carcinoma.Imfinzi is a selective, high-affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. An ongoing, multicenter, phase 1/2 open-label study (NCT1693562) is evaluating the safety and antitumor activity of Imfinzi monotherapy in patients with advanced solid tumors, including locally advanced/metastatic urothelial carcinoma. An interim analysis of 61 patients with urothelial carcinoma in this study indicated that Imfinzi was well tolerated and associated with antitumor activity, particularly in patients with PD-L1—high disease (at least 25 percent of tumor cells or tumor-infiltrating immune cells express PD-L1), resulting in its breakthrough therapy designation by the FDA.

What adverse events were seen with Imfinzi on the trial?

What should patients and doctors look out for regarding serious or immune-related AEs?

In [the] phase 1/2 open label study of locally advanced/metastatic urothelial carcinoma patients [that led to the approval of Imfinzi, the treatment] was administered at 10 mg/kg every two weeks. Imfinzi showed favorable efficacy and an excellent safety profile in locally advanced/metastatic urothelial carcinoma patients.Grade 3/4 treatment-related adverse events [AEs] occurred in less than 10 percent of patients. Grade 3/4 immune-mediated adverse events occurred in a minority of patients. Among patients with any-grade treatment-related AEs of special interest, patients received systemic steroids. Imfinzi, like other immune checkpoint blockers, generates atypical types of tumor responses—pseudoprogression, but also hyperprogression. Moreover, they have a specific toxicity profile that is challenging the historical oncologists’ practices, with the need to learn how to deal with the clinical management of immune-related AEs.

What is the impact of Imfinzi's FDA approval?

Is there potential for the agent to replace chemotherapy?

Most immune-related AEs remain mild in intensity but between 5 percent and 10 percent of patients treated with anti—PD-1 immune checkpoint blockers will develop severe, sometimes life-threatening grade 3/4 dysimmune toxicities. For example, it was decided at Gustave Roussy to set up a network of oncologists and organ specialists to manage patients with immune-related AEs. This program is led by Aurélien Marabelle, MD, PhD; Stéphane Champiat, M.D.; and Olivier Lambotte, M.D., Ph.D.[The research] supports the manageable safety and tolerability of Imfinzi administered at 10 mg/kg every two weeks as monotherapy in patients with solid tumors and confirms its favorable clinical activity in previously treated patients with locally advanced/metastatic urothelial carcinoma for whom prognosis is poor. Imfinzi is clearly a new option for these patients.Based on these findings, Imfinzi appears to be an attractive alternative to chemotherapy. Further studies, including DANUBE (NCT02516241), BISCAY (NCT02546661) and Study 10 (NCT02261220), are evaluating Imfinzi as a monotherapy and in combination with other agents (tremelimumab, AZD4547, Lynparza [olaparib], AZD1775, and vistusertib) in urothelial carcinoma.