Julia A. Beaver, MD

Richard Pazdur, MD

In a Perspective article 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 (OCD), 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. Six such dangling approvals are slated for discussion at an FDA Oncologic Drugs Advisory Committee (ODAC) meeting to be held April 27–29, 2021.

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 of time. 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, several of which were duplicates of or similar to other indications, were dangling accelerated approvals. Of these, 9 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 (years in some cases) 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 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.

In all four cases, competitor antibodies in the same class had received regular approval for the same disease on the basis of survival benefit, resulting in a “change of the treatment landscape.”

Approvals to Be Discussed at ODAC Meeting

The six dangling approvals to be discussed at the ODAC meeting consist of:

• 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 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 including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy
• Pembrolizumab for patients with hepatocellular carcinoma who were previously treated with sorafenib.

[Editor’s note: The day after this Perspective was published, the FDA approved a seventh PD-1/PD-L1 inhibitor, dostarlimab-gxly, for adult patients with mismatch repair–deficient recurrent or advanced endometrial cancer.]

Success of Accelerated Approval Process and Need to Discuss Dangling Approvals

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 note 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.”

They concluded: “The FDA has successfully applied accelerated approval in oncology over the past 3 decades, making innovative therapies available to patients years earlier than they would otherwise have been available. The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases.”