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the FDA’s Accelerated Approval Program has been touted as a success, as only a small percentage of agents have been withdrawn from the market due to failure to show clinical benefit.2


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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.

Atezolizumab for Urothelial Carcinoma

On March 8, 2021, Genentech voluntarily withdrew the US indication for atezolizumab (Tecentriq) for the treatment of prior-platinum treated metastatic urothelial carcinoma.

In 2016, the FDA granted accelerated approval to atezolizumab, a PD-L1 blocking antibody, for prior-platinum treated metastatic urothelial carcinoma based on tumor response rate and duration of response data from the phase 2 IMvigor210 study (ClinicalTrials.gov: NCT02108652).

Results from a subsequent confirmatory phase 3 trial (IMvigor211; ClinicalTrials.gov: NCT02302807) showed that treatment with atezolizumab did not meet the primary endpoint of overall survival in the PD-L1 high patient population. Continued approval of this indication was contingent upon the results of IMvigor211, the original post marketing requirement (PMR) to confirm clinical benefit.

While the IMvigor130 study (ClinicalTrials.gov: NCT02807636), which was subsequently designated as the PMR, will still continue until the final analysis, the Company voluntarily withdrew the indication based on the principles of the FDA’s Accelerated Approval Program.

Six Indications Still to Be Reviewed

On March 11, the FDA announced that 6 additional indications with results from confirmatory trials that have not verified clinical benefit will be evaluated by the FDA’s Oncologic Drugs Advisory Committee.7 The meeting, which will take place on April 27-29, will review the following products, all approved through the Accelerated Approval Program:

  • Atezolizumab (Tecentriq) in combination with paclitaxel protein-bound for unresectable locally advanced or metastatic triple-negative breast cancer in patients whose tumors express PD-L1.
  • Atezolizumab (Tecentriq) for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
  • Pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
  • Pembrolizumab (Keytruda) for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
  • Pembrolizumab (Keytruda) for patients with hepatocellular carcinoma who have been previously treated with sorafenib.
  • Nivolumab (Opdivo) as a single agent for patients with hepatocellular carcinoma who have been previously treated with sorafenib.

In a statement, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said: “This public meeting of the advisory committee creates an opportunity for external oncology experts and patients with cancer to share input and perspective with the FDA. After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication.”

Additional information about the meeting can be found here.

References

1.     Food and Drug Administration Accelerated Approval Program. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program. Accessed March 10, 2021.

2.     Ribeiro TB, Buss L, Wayant C, Nobre MRC. Comparison of FDA accelerated vs regular pathway approvals for lung cancer treatments between 2006 and 2018. [published online July 24, 2020].  PLoS ONEdoi.org/10.1371/journal.pone.0236345.

3.     Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer U.S. indication. [press release]. Bristol Myers Squibb; December 29, 2020.

4. Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. [press release]. AstraZeneca; February 22, 2021.

5.     Merck provides update on Keytruda® (pembrolizumab) indication in metastatic small cell lung cancer in the US. [press release]. Kenilworth, NJ: Merck; March 1, 2021.

6.     Genentech provides update on Tecentriq U.S. indication in prior-platinum treated metastatic bladder cancer. [press release]. South San Francisco, CA: Genentech; March 8, 2021.

7.     FDA In Brief: FDA Oncologic Drugs Advisory Committee to Review Status of Six Indications Granted Accelerated Approval. U.S. Food and Drug Administration. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated. Accessed March 11, 2021.

This article originally appeared on MPR