In a perspective in The New England Journal of Medicine, Julia A. Beaver, MD, and Richard Pazdur, MD, of the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence (OCE), discussed issues surrounding “dangling” accelerated approvals of anti–PD-1/PD-L1 antibodies—ie, approvals for which the agent has continued marketing authorization in the indication despite an absence of confirmed benefit in required confirmatory trials. Several dangling approvals were the focus of discussion at an FDA Oncologic Drugs Advisory Committee (ODAC) meeting in April, with some votes in favor of continuing accelerated approvals (in triple-negative breast and urothelial cancers) and others against (in certain liver and gastric cancers).
Julia A. Beaver, MD
Richard Pazdur, MD
‘Dangling’ Accelerated Approvals
The development of anti–PD-1 and anti–PD-L1 antibodies has resulted in a large number of approvals in the setting of large volumes of constantly emerging information over a short period. The FDA has approved six PD-1 or PD-L1 inhibitors for more than 75 indications over the past 6 years.
Of the first 76 approvals, 35 were accelerated, prompting a recent OCE evaluation of all accelerated approvals. A total of 10 indications were dangling accelerated approvals. Of them, nine involved single-arm trials with endpoints of response rate and response duration. Seven showed response rates of 10% to 20%, with the approvals being granted on the basis of prolonged durations of response and the absence of other available therapies in the particular treatment setting.
Discussions between the OCE and commercial sponsors resulted in voluntary withdrawal of the following four approvals:
- Atezolizumab for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after any platinum-containing chemotherapy or within 12 months after receiving neoadjuvant or adjuvant chemotherapy
- Durvalumab for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy or within 12 months after receiving neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
- Nivolumab for patients with metastatic small cell lung cancer with disease progression after platinum-based chemotherapy and at least one other line of therapy
- Pembrolizumab for patients with metastatic small cell lung cancer with disease progression during or after platinum-based chemotherapy and at least one other previous line of therapy.
Results From Recent ODAC Meeting
The six dangling approvals discussed at the ODAC meeting follow:
- Atezolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status
- Atezolizumab combined with protein-bound paclitaxel (nab-paclitaxel) for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1
- Nivolumab for patients with hepatocellular carcinoma who were previously treated with sorafenib
- Pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or in patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status
- Pembrolizumab for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, with disease progression during or after two or more previous lines of therapy
- Pembrolizumab for patients with hepatocellular carcinoma who were previously treated with sorafenib.
On April 28, Roche announced that the FDA ODAC voted 7 to 2 in favor of maintaining accelerated approval of atezolizumab in combination with nab-paclitaxel for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1, as determined by an FDA-approved test. In addition, the panel voted 5 to 3 in favor of maintaining the accelerated approval of pembrolizumab as first-line treatment for patients with cisplatin- and carboplatin-ineligible locally advanced or metastatic urothelial carcinoma.
On April 29, Roche announced that the FDA ODAC voted 10 to 1 in favor of maintaining 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, as determined by an FDA-approved test or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
On April 30, the FDA ODAC voted 8 to 0 in favor of continuing the accelerated approval for pembrolizumab in sorafenib-pretreated patients with hepatocellular carcinoma; 6 to 2 against maintaining accelerated approval of pembrolizumab for the treatment of pretreated patients with PD-L1–positive recurrent or advanced gastric or gastroesophageal junction adenocarcinoma; and 5 to 4 against continuing the indication of nivolumab as a single agent for patients with hepatocellular carcinoma who have been previously treated with sorafenib.
Success of Accelerated Approval Process
The authors observed that the mechanism of accelerated approval has been highly successful in answering unmet needs, by making active therapies rapidly available to patients with limited treatment options. They noted that of the more than 155 accelerated approvals granted for oncology indications, only 10 (including the 4 anti–PD-1/PD-L1 antibody indications) have been withdrawn.
As related by the authors, the FDA sees discussion of the remaining dangling approvals in the context of evolving available therapies as a necessary process. They stated: “[T]he fact that a clinical trial did not meet its endpoints does not necessarily mean that the drug is ineffective. A failure to demonstrate efficacy might be attributable to the selection of the primary endpoint, the power calculation, hierarchical statistical testing procedures, biomarker selection, trial design, or an inability to select the patients most likely to have a response. If there are clear reasons why a trial may not have achieved its primary endpoint and an unmet medical need still exists, the FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirement.”
DISCLOSURE: Dr. Beaver and Dr. Pazdur reported no conflicts of interest.
REFERENCE
1. Beaver JA, Pazdur R: ‘Dangling’ accelerated approvals in oncology. N Engl J Med. April 21, 2021 (early release online).
