Roche has announced the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 10 to 1 in favor of maintaining the accelerated approval of atezolizumab for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express high levels of PD-L1 (PD-L1–stained tumor-infiltrating immune cells covering ≥ 5% of the tumor area) as determined by an FDA-approved test or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
In addition, according to a report in pharmaphorum, the panel voted 5 to 3 to maintain the accelerated approval of pembrolizumab as first-line treatment for patients with cisplatin- and carboplatin-ineligible locally advanced or metastatic urothelial carcinoma.
Yesterday’s ODAC meeting is part of an industry-wide review of accelerated approvals with confirmatory trials that have not met their primary endpoint(s) and have yet to gain regular approvals. The advisory committee provides the FDA with independent opinions and recommendations from outside medical experts though the recommendations are not binding.
The FDA's Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious condition, with specific postmarketing requirements to confirm the clinical benefit and convert to regular approval.
Accelerated Approvals
Atezolizumab was granted accelerated approval in 2017 for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy based on the positive overall response rate and duration of response results from the IMvigor210 study. Atezolizumab’s indication was subsequently focused on PD-L1–high patients, who would benefit the most based on findings from the IMvigor130 study in 2018. This phase III trial is the designated postmarketing requirement for the first-line metastatic urothelial carcinoma indication and met its co-primary endpoint of progression-free survival. IMvigor130 continues for overall survival results.
Based on the results of KEYNOTE-052, pembrolizumab received accelerated approval in May 2017 for the treatment of patients with previously untreated locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin. This single-arm trial demonstrated a confirmed overall response rate of 28.6% in 370 patients receiving pembrolizumab; the median duration of response was not reached at the time of initial approval. KEYNOTE-361, a randomized phase III trial evaluating pembrolizumab with or without platinum-based chemotherapy (gemcitabine in combination with either cisplatin or carboplatin) compared to platinum-based chemotherapy as first-line treatment of patients with advanced/metastatic urothelial carcinoma, including a subset of cisplatin-ineligible patients, was designated as the confirmatory trial to fulfill a postmarketing requirement to confirm benefit for the accelerated approval. The co-primary efficacy endpoints were progression-free and overall survival for the pembrolizumab/chemotherapy arm compared to the chemotherapy arm. Evaluation of overall survival in an additional arm of pembrolizumab monotherapy compared to chemotherapy arm was a secondary endpoint.
The external data monitoring committee for KEYNOTE-361 performed an early review and found that patients with PD-L1–low status in the pembrolizumab monotherapy arm had decreased survival compared with patients who received either cisplatin- or carboplatin-based chemotherapy. The trial was amended to halt enrollment of patients with PD-L1–low status to the pembrolizumab monotherapy arm, and the indication for the first-line treatment of cisplatin-ineligible patients was subsequently revised in 2018 and was restricted to patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (combined positive score [CPS] ≥ 10) as determined by an FDA-approved test, or patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. Subsequently, the final analysis of KEYNOTE-361 were released in June 2020 and demonstrated no benefit in either of the co-primary endpoints of progression-free or overall survival for pembrolizumab/chemotherapy compared to chemotherapy alone. Any further analyses should be considered exploratory and hypothesis-generating.
