FDA panel votes to maintain four of six indications for checkpoint inhibitors under review

Tom Smith

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April 30, 2021

5 min read


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The Oncologic Drugs Advisory Committee voted this week to maintain four of six indications for checkpoint inhibitors that have received FDA accelerated approval.

The panel voted against maintaining a gastric cancer indication for pembrolizumab (Keytruda, Merck) and a hepatocellular carcinoma indication for nivolumab (Opdivo, Bristol Myers Squibb).


The Oncologic Drugs Advisory Committee voted to maintain four of six indications for checkpoint inhibitors that have received FDA accelerated approval.

Data were derived from
FDA. Meeting of the Oncologic Drugs Advisory Committee (virtual meeting). April 27-29, 2021.


The 3-day meeting was part of an industrywide review of drugs that have received accelerated approval, the confirmatory trials for which have not met their primary endpoints. As part of that review, four pharmaceutical companies voluntarily withdrew or announced plans to withdraw their drugs for specific indications from the market due to a lack of benefit demonstrated in confirmatory trials.

Considering those four withdrawals — but not the latest recommendations from ODAC — only 6% of accelerated approvals for oncology indications have been withdrawn since the beginning of the program, according to a press release from the FDA.

Positive votes for breast, bladder cancers

Oncologic Drugs Advisory Committee (ODAC) supported maintaining the triple-negative breast cancer and urothelial carcinoma indications of checkpoint inhibitors under review while additional trials are conducted.

The panel voted 7-2 in favor of keeping atezolizumab (Tecentriq, Genentech) plus nab-paclitaxel (Abraxane, Celgene) on the market for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors are PD-L1 positive. This combination received accelerated approval in March 2019 based on improved PFS observed in the IMpassion130 study. However, the confirmatory IMpassion131 trial did not meet its primary endpoint of PFS for the first-line treatment of patients with PD-L1-positive metastatic triple-negative breast cancer.

Despite this, panel members supported leaving the combination on the market, in part due to the lack of effective therapies for this indication. Also, representatives of Roche indicated that future confirmatory trials likely would show benefits.

The panel also voted 10-1 in favor of keeping atezolizumab on the market for the first-line treatment of adults with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and who have high tumor expression of PD-L1. The agent received accelerated approval for locally advanced or metastatic urothelial carcinoma in 2017 based on the 23.5% overall response rate observed in the intent-to-treat population of the IMvigor210 study; the indication was subsequently refined to patients with PD-L1-high tumors based on data from the ongoing IMvigor130 study. The vote reflected a near-unanimous consensus to keep atezolizumab on the market pending OS results from IMvigor130.

In a 5-3 vote, the panel favored keeping pembrolizumab on the market for its bladder cancer indication. The agent received accelerated approval in 2017 for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy based on an objective response rate of 29% in the KEYNOTE-052 study. In 2018, that indication was restricted to patients whose tumors expressed PD-L1, or for patients who are not eligible for any platinum-containing therapy regardless of PD-L1 status.

The panel voted to maintain this approval — despite that the KEYNOTE-361 trial failed to confirm clinical benefit in the first-line setting and the landscape has changed with the approval of avelumab (Bavencio; EMD Serono, Pfizer) as maintenance therapy — due to the lack of therapies that otherwise would be available for patients ineligible for platinum-based chemotherapy.

Christopher Lieu, MD

Christopher H. Lieu

Christopher H. Lieu, MD, associate director for clinical research and co-director for gastrointestinal medical oncology at University of Colorado Medicine, said he voted in favor of maintaining the approval based primarily on the unmet need among platinum-ineligible patients.

“The [KEYNOTE-052] data are compelling and strengthened by the survival benefit seen in the second-line setting,” he said. “Regarding the use of avelumab in the maintenance setting, I think this indication could be the treatment of choice in patients who are carboplatin-eligible. But, my concern is patients who are unable to receive platinum-based chemotherapy at all. If we rescind this approval, then those patients would potentially be left with no available treatment options. This does bring up the issue of reviving the indication specifically for that patient population.”

Mixed bag in HCC

The panel voted in favor of keeping on the market one of two checkpoint inhibitors indicated as monotherapy for hepatocellular carcinoma.

The panel voted 8-0 in favor of maintaining the approval of pembrolizumab for patients with hepatocellular carcinoma previously treated with sorafenib (Nexavar, Bayer), despite that the OS benefit compared with placebo did not reach the prespecified requirement for statistical significance in the confirmatory KEYNOTE-240 trial. The agent received accelerated approval for this indication in 2018 based on an ORR of 17% in the single-arm KEYNOTE-224 trial. The panel’s vote reflected concern over a lack of treatments for patients ineligible for bevacizumab (Avastin, Genentech) — approved as part of a combination with atezolizumab — and given that more data are expected soon from KEYNOTE-394.

However, in a 4-5 vote, the panel did not support maintaining the 2017 accelerated approval of nivolumab for this same patient population. Their main concerns appeared to be the low response rate of 14% in the CheckMate-040 trial and the negative confirmatory CheckMate-459 trial of nivolumab monotherapy trial vs. sorafenib in the first-line setting.

Mark Lewis

Mark A. Lewis

“This was an extremely nuanced and difficult decision,” Mark A. Lewis, MD, director of gastrointestinal medical oncology at Intermountain Healthcare, said after the vote. “One of the reasons we are gathered here today is to prevent these accelerated approvals from dangling ad infinitum. I couldn’t see any upcoming data … that are going to specifically address the risk-benefit calculus around nivolumab as monotherapy. So many other schemas are wonderful and scientifically rigorous, but they are predicated on doublet therapy, and that’s why I came down on a ‘no’ vote.”

Negative vote for gastric cancer

The panel voted 2-6 against maintaining pembrolizumab’s indication for patients with recurrent locally advanced or metastatic PD-L1-positive gastric or gastroesophageal junction adenocarcinoma who had disease progression on or after two or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy.

This 2017 accelerated approval was based on an ORR of 13.3% observed in the KEYNOTE-059 trial. However, the confirmatory second-line KEYNOTE-061 trial and first-line KEYNOTE-062 trial both failed to show OS and PFS benefits with pembrolizumab. Also, the treatment landscape has changed since the original approval, with nivolumab plus chemotherapy now approved in the first-line setting.

“I believe the accelerated approval was appropriate …. but the landscape has clearly changed,” Lieu said. “It is highly likely that by third-line therapy, patients will have received some form of immune checkpoint therapy previously. KEYNOTE-061 and -062 are troubling in terms of their lack of positive data. At this time, I don’t think the indication should continue as written; although, given the issue that patients may be in second-line therapy now without having received immunotherapy, I think there should be strong consideration given to delaying a removal of this indication, at least for several months.”

The ODAC panel votes do not guarantee the agents will be kept or removed from the market for these indications. The FDA often follows the guidance of the advisory committee, but the agency is not required to do so.

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