FDA Cracks Down on Dangling Accelerated Approvals in 2021, Pathway Is Scrutinized

In 2021, the FDA's crack down on accelerated approvals meant the removal of several immunotherapy indications from the US market.

In an editorial from FDA faculty members, Julia A. Beaver, MD; and Richard Pazdur, MD, they explained that in the 29 years that the accelerated approval pathway has existed, over 155 accelerated approvals for oncology drugs have been granted, but only 10 have been withdrawn due to an inability to confirm benefit of the drug in further trials.¹

An industry-wide evaluation of accelerated oncology drug approvals, where clinical benefit was not verified in subsequent confirmatory trials, called 10 immunotherapy indications into question this year.

These approvals have been dubbed “dangling” accelerated approvals. Each indication was granted an accelerated approval based on the findings from early-phase, often single-arm, studies using surrogate end points. These results were not confirmed, though, in confirmatory randomized phase 3 trials. The 10 approvals were granted between 2016 and 2019, yet their approvals withstood, oftentimes for years, after the results of confirmatory trials failed to show benefit.

Several developers responded by voluntarily withdrawing the drug from the market for the particular setting, but for other approvals, the Oncologic Drugs Advisory Committee (ODAC) was convened to debate whether continued approval was warranted for the dangling indications.

ODAC Proceedings

Voluntarily withdrawn indications included: nivolumab (Opdivo) as a treatment for patients with small cell lung cancer (SCLC) whose disease has progressed after platinumbased chemotherapy and at least 1 other line of therapy, which Bristol Myers Squibb announced in December 2020;2 durvalumab (Imfi nzi) for the treatment of adult patients with previously treated locally advanced or metastatic bladder cancer, which AstraZeneca withdrew on February 22, 2021;³ pembrolizumab (Keytruda) for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy and at least 1 other line of therapy, which was announced by Merck on March 1, 2021;⁴ and Roche’s atezolizumab (Tecentriq) for the treatment of patients with prior platinum-treated metastatic urothelial carcinoma, which was announced on March 8, 2021.⁵

The FDA announced a 3-day public meeting of the ODAC, April 27-29, 2021, to discuss and reevaluate 6 indications to determine whether their accelerated approvals should be withdrawn: atezolizumab in combination with paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1; atezolizumab as treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy; pembrolizumab as treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy; pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 expression and disease progression on or after at least 2 prior lines of therapy, including fl uoropyrimidineand platinum-containing chemotherapy, and if appropriate, HER2-targeted therapy; nivolumab as treatment of patients with hepatocellular carcinoma (HCC) with prior treatment with sorafenib (Nexavar); and pembrolizumab for the treatment of patients with HCC previously treated with sorafenib.⁶

Prior to the meeting, Arjun V. Balar, MD, director of the Genitourinary Medical Oncology Program at New York University Langone’s Perlmutter Cancer Center, told Targeted Therapies in Oncology™, “The general take-home message is: Don’t view these ODACs as an indictment against immunotherapy. It is not. It is, rather, an opportunity for us to reset our expectations about it.”

During the meeting, oncology experts, industry members, patients with cancer, and members of the committee provided evidence of the efficacy and safety profiles of the agents in each setting as well as how the treatment landscape has changed since the initial approval to determine whether there is still a place for the indication. Of the 6 indications, the committee voted to maintain 4, with the exception of nivolumab in HCC, with a 5 to 4 vote, and pembrolizumab in gastric/GEJ adenocarcinoma, with a vote of 6 to 2.⁷

“I believe the accelerated approval for pembrolizumab in the third-line setting was appropriate based on the modest response rates in KEYNOTE-059 [NCT02335411] and the clear unmet need, but the landscape… has clearly changed. It’s highly unlikely that, by third-line therapy, patients will [not] have received some form of immune checkpoint therapy previously,” said panelist Christopher H. Lieu, MD, associate director for clinical research and co-director of gastrointestinal (GI) medical oncology at the University of Colorado Medicine, when explaining his vote against pembrolizumab during the meeting.

Of note, ODAC voted unanimously in support of continued approval for pembrolizumab in HCC.

“[Patients with] HCC are sorely in need of treatment options, given the associated mortality. They need these options based on acceptability, convenience of treatment schedule, and reduced toxicities, especially in the era of the [COVID-19] pandemic,” said Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology, coleader of the GI Cancer Research Program, and codirector of GI oncology at Vanderbilt-Ingram Cancer Center, during the meeting. “Decreasing treatment options is not approached to improve community outreach, and I do not believe that discontinuation of pembrolizumab’s accelerated approval as a second-line option is in the best interest of the patient.”

Following the ODAC meetings, 3 of the indications were voluntarily withdrawn. First was the pembrolizumab indication in gastric/GEJ adenocarcinoma, which Merck removed as of July 1, 2021,8 followed by the nivolumab indication in HCC, which was announced by Bristol Myers Squibb on July 23, 2021.9 Although the committee had voted 7 to 2 in favor of continued approval for the atezolizumab regimen in TNBC, on August 27, 2021, Roche announced that the indication was being voluntarily withdrawn.¹⁰

Additionally, the FDA converted the accelerated approval for the pembrolizumab urothelial carcinoma indication to a full approval.¹¹ During the ODAC meeting, panelists had voted 5 to 3 in favor of continued approval.⁷

Later in the year, the FDA planned further ODAC meetings to discuss 3 more dangling indications. First was melphalan flufenamide (Pepaxto) for injection in combination with dexamethasone as treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.¹² However, this meeting was canceled after the indication was voluntarily removed from the US market due to a phase 3 trial showing no benefit for melphalan flufenamide in terms of overall survival.¹³ Both the approval and withdrawal of the indication occurred within this year.

Next was a joint ODAC meeting planned for December 2, 2021, to discuss panobinostat (Farydak) capsules in combination with bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent, and vincristine sulfate liposome injection (Marqibo) for intravenous infusion for adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies. However, this meeting was also canceled, and without explanation.¹⁴

Accelerated Approval Pathway in Jeopardy?

The crack down on accelerated approvals comes in line with increased scrutiny on the pathway. Both the Institute for Clinical and Economic Review and Friends of Cancer Research have written white papers suggesting potential improvements to the pathway.^15,16 Additionally, the Office of Inspector General of the US Department of Health and Human Services has pronounced its intent to reexamine FDA policies and procedures to assess how the pathway is implemented,¹⁷ especially following the controversial accelerated approval of an Alzheimer drug, aducanumab (Aduhelm). The review is expected to occur in 2023.

The FDA and others defend the use of the pathway to fill areas of significant unmet needs but concede that improvement could still be made.

_REFERENCES

_{1. Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384(18):e68. doi:10.1056/NEJMp2104846}

_{2. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. News release. Bristol Myers Squibb; December 29, 2020. Accessed November 30, 2021. https://bit.ly/2X5PVFK}

_{3. Voluntary withdrawal of Imfi nzi indication in advanced bladder cancer in the US. News release. AstraZeneca; February 22, 2021. Accessed November 30, 2021. https://bit.ly/3dPZimL}

_{4. Merck provides update on Keytruda (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. Merck; March 1, 2021. Accessed November 30, 2021. https://bit.ly/3e1ct4j}

_{5. Roche provides update on Tecentriq US indication in prior-platinum treated metastatic bladder cancer. News release. Roche; March 8, 2021. Accessed November 30, 2021. https://bit.ly/3d5kwe2}

_{6. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA; March 11, 2021. Updated March 15, 2021. Accessed November 30, 2021. https://bit.ly/3lmMneP}

_{7. Meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA. April 29, 2021. Accessed November 30, 2021. https://bit.ly/2PyhdV1}

_{8. Merck provides update on Keytruda (pembrolizumab) indication in third-line gastric cancer in the US. News release. Merck; July 1, 2021. Accessed November 30, 2021. https://bit.ly/3jO1kGM}

_{9. Bristol Myers Squibb statement on Opdivo (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma US indication. News release. Bristol Meyers Squibb; July 23, 2021. Accessed November 30, 2021. https://bit.ly/2UOBmZI}

_{10. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche; August 27, 2021. Accessed November 30, 2021. https://bit.ly/3o8HHLl}

_{11. FDA approves updated indication for Merck’s Keytruda (pembrolizumab) for treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck; August 31, 2021. Accessed November 30, 2021. https://bit.ly/2WEvhQk}

_{12. Cancelled October 28, 2021: meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA; October 22, 2021. Accessed November 30, 2021. https://bit.ly/3xGo2Fy}

_{13. Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D. News release. Oncopeptides; October 22, 2021. Accessed November 30, 2021. https://bit.ly/3m7fdAB}

_{14. Cancelled: December 2, 2021: meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA. Updated November 23, 2021. Accessed November 30, 2021. https://bit.ly/3pbFGNT}

_{15. Strengthening the accelerated approval pathway: an analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Institute for Clinical and Economic Review. April 26, 2021. Accessed November 30, 2021. https://bit.ly/3xFew5B}

_{16. Optimizing the use of accelerated approval. Friends of Cancer Research. Accessed November 30, 2021. https://bit.ly/3d7vEaI}

_{17. Review of the FDA’s accelerated approval pathway. US Department of Health and Human Services. August 2021. Accessed November 30, 2021. https://bit.ly/3xN2A20}