Created in 1992, the Food and Drug Administration’s Accelerated Approval Program allows for earlier approval of drugs intended to treat serious conditions or fill unmet needs.1 Through this pathway, approval is based on a surrogate endpoint that is thought to predict clinical benefit. These outcomes may include laboratory measurements, radiographic images, or any other measures that demonstrate an advantage over other therapies and can be evaluated sooner than survival.
Following accelerated approval, manufacturers are required to conduct confirmatory trials, also known as a phase 4 studies, to prove clinical benefit.1 If a confirmatory trial does not meet the endpoint established as the postmarketing requirement, the Agency can take steps to remove the drug or indication.
For oncology drugs, the FDA’s Accelerated Approval Program has been touted as a success, as only a small percentage of agents have been withdrawn from the market due to failure to show clinical benefit.2
Recently, several companies announced indication withdrawals following an industry-wide evaluation of accelerated approvals in oncology. In all of these cases, the confirmatory trials did not confirm clinical benefit.
Nivolumab for Small Cell Lung Cancer
Closing out 2020, Bristol Myers Squibb announced their decision to withdraw the indication for nivolumab (Opdivo) for the treatment of patients with small cell lung cancer (SCLC) whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy.3
In 2018, the FDA granted accelerated approval to nivolumab, a programmed death receptor-1 (PD-L1) blocking antibody, for SCLC based on data from the phase 1/2 CheckMate 032 trial (ClinicalTrials.gov: NCT01928394), which showed promising response rates and duration of response.
Subsequent confirmatory studies (CheckMate 451 [ClinicalTrials.gov: NCT02538666 and CheckMate 331 [ClinicalTrials.gov: NCT02481830) in different treatment settings showed that nivolumab failed to meet the primary endpoints of overall survival in patients with SCLC.
Durvalumab for Urothelial Carcinoma
On February 22, 2021, AstraZeneca decided to withdraw the indication for durvalumab (Imfinzi) in the United States (US) for the treatment of locally advanced or metastatic urothelial carcinoma in previously treated adults, following a meeting with the FDA.4
In 2017, the FDA granted accelerated approval to durvalumab, a PD-L1 blocking antibody, for locally advanced or metastatic bladder cancer based on data from a phase 1/2 study (ClinicalTrials.gov: NCT01693562), which showed promising tumor response rates and duration of response.
However, results from the subsequent confirmatory phase 3 DANUBE trial (ClinicalTrials.gov: NCT02516241) evaluating durvalumab as a first-line treatment in a metastatic bladder cancer setting showed that it did not meet the primary endpoints in 2020.
Pembrolizumab for Small Cell Lung Cancer
On March 1, 2021, Merck voluntarily withdrew the US indication for pembrolizumab (Keytruda) for the treatment of patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy.
In June 2019, the FDA granted accelerated approval to pembrolizumab, a PD-L1 blocking antibody, for metastatic SCLC based on data from the KEYNOTE-158 (ClinicalTrials.gov: NCT02628067) and KEYNOTE-028 (ClinicalTrials.gov: NCT02054806) trials, which showed positive tumor response rates and durable responses.
Findings from a subsequent confirmatory phase 3 trial (KEYNOTE-604; ClinicalTrials.gov: NCT03066778) showed that the study met one of its primary endpoints, progression-free survival, but did not reach statistical significance for the other, overall survival. Continued approval of the indication was contingent upon establishing the superiority of pembrolizumab as determined by overall survival.