The FDA’s Oncologic Drugs Advisory Committee (ODAC) is poised to move forward this week with a public review of 6 indications for immune checkpoint inhibitors (ICIs) granted under the agency’s accelerated approval process that later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.
Experts and patients will be able to testify during the hearings on April 27 to 29 involving indications for PD-1/PD-L1–directed ICIs currently being used to treat patients with triple-negative breast cancer (TNBC), metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC). Based on the testimony, ODAC will consider whether the approvals should be withdrawn and whether additional trials should be conducted.1
The hearings, which are scheduled to be conducted virtually and broadcast via live webcast, will involve 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab (Keytruda), and 1 for nivolumab (Opdivo). Specifically, findings concerning these indications will be reviewed (Table1-20):
- Atezolizumab―in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic TNBC; and as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy
- Pembrolizumab―as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy; for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy; and for patients with HCC who have been previously treated with sorafenib (Nexavar)
- Nivolumab―as a single agent for patients with HCC who previously received sorafenib
The indications that will be discussed are among 10 accelerated approvals for ICIs that were left “dangling” with continued marketing authorization despite not meeting the objectives of confirmatory studies, according to Julia A. Beaver, MD, and Richard Pazdur, MD, of the FDA’s Oncology Center of Excellence (OCE), who explained the rationale for the review in an article in the New England Journal of Medicine.21 Beaver is chief of medical oncology for the OCE and Pazdur is OCE director and a 2019 Giants of Cancer Care® award winner for Community Outreach.
Of those 10 indications, 9 were approved as a result of findings from single-arm trials based on response rates and on the duration of responses, the authors noted. “Seven of these showed response rates of 10 to 20%, but the approvals were granted because of the responses’ prolonged duration—in some cases many years—and the lack of other available therapies,” Beaver and Pazdur wrote.
However, response rates in single-arm trials of ICIs have not always been predictive of an overall survival benefit. When trials fail to confirm benefits of a therapy, Beaver and Pazdur noted, “the medical need and available therapies should be reassessed to determine whether the conditions for accelerated approval still exist.”
After discussions with the FDA, pharmaceutical companies voluntarily withdrew 4 of the 10 “dangling” indications. These decisions reflected a treatment landscape that had changed since the initial approvals to include competitor drugs that had received regular marketing authorization for the same tumor type, the FDA officials said.
As part of these withdrawals, Bristol Myers Squibb and Merck said they will discontinue indications for nivolumab and pembrolizumab, respectively, for patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy; AstraZeneca will withdraw an indication for durvalumab (Imfinzi) for patients with locally advanced or mUC that has progressed after chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and Genentech will halt an indication for atezolizumab for patients with mUC previously treated with platinum-based chemotherapy.
Accelerated Approvals Boost Oncology
Although questions are currently being raised about the ICI indications, the use of the accelerated approval process has been a boon for the development of oncology drugs, Beaver and Pazdur said. In all, 85% of drugs approved through this pathway have been for oncology indications.
Moreover, they said, the accelerated approval pathway has helped make the PD-1/PD-L1 antibodies the most rapidly developed therapeutic class in history. Of the first 76 approvals granted for these drugs, 35 were accelerated.
Despite this level of activity, only 10 of the more than 155 accelerated approvals given for oncology drugs have been subsequently withdrawn, including the 4 for ICIs that were recently removed from the marketplace. “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,” Beaver and Pazdur said.21
Other indications for the ICIs under review are not affected by the hearings or the announced withdrawals.
- FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 15, 2021. Accessed April 1, 2021. https://bit.ly/3cgG1bm
- FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed March 18, 2021. http://bit.ly/2PaK552
- Roche provides update on Phase III study of Tecentriq in combination with paclitaxel for people with metastatic triple-negative breast cancer. News release. Roche. August 6, 2020. Accessed March 18, 2021. http://bit.ly/30VWtZp
- Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1147-S1148. doi:10.1016/j.annonc.2020.08.2243
- FDA grants Roche’s Tecentriq (atezolizumab) accelerated approval as initial treatment for certain people with advanced bladder cancer. News release. April 18, 2017. Accessed March 18, 2021. http://bit.ly/3s1lJcx
- Tecentriq. Prescribing information. Genentech; 2017. Accessed April 1, 2021. https://bit.ly/3fvAfGj
- FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. Updated July 5, 2018. Accessed March 18, 2021. https://bit.ly/3c2imNf
- Roche provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer. News release. Roche. May 10, 2017. https://bit.ly/3eRialL
- Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757. doi:10.1016/S0140-6736(17)33297-X
- FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. Updated December 14, 2018. Accessed March 18, 2021. https://bit.ly/2P1MuPD
- Phase 3 study of Keytruda (pembrolizumab) in previously treated patients with advanced hepatocellular carcinoma. News release. Merck. February 19, 2019. Accessed March 18, 2021. https://bit.ly/3cQxgVO
- Finn RS, Ryoo BK, Merle P, et al; KEYNOTE-240 Investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307
- Pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. FDA. Updated May 19, 2017. Accessed March 18, 2021. https://bit.ly/3eTrkOq
- Merck provides update on phase 3 KEYNOTE-361 trial evaluating Keytruda (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. News release. Merck. June 9, 2020. Accessed March 18, 2021. https://bit.ly/3qY5tYB
- Alva A, Csőszi T, Ozguroglu M, et al. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol. 2020;31(suppl 4):S1155. doi:10.1016/j.annonc.2020.08.2252
- FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. FDA. September 22, 2017. Accessed March 18, 2021. https://bit.ly/3bWzwM6
- Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370
- FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. Updated September 25, 2017. Accessed March 18, 2021. https://bit.ly/30WxV2x
- Bristol-Myers Squibb announces results from CheckMate -459 study evaluating Opdivo (nivolumab) as a first-line treatment for patients with unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb Company. June 24, 2019. Accessed March 18, 2021. https://bit.ly/38YhhDY
- Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30(suppl 5):V874-V875. doi:10.1093/annonc/mdz394.029
- Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. Published online April 21, 2021. doi:10.1056/NEJMp2104846