FDA Panel Votes to Uphold One Accelerated Drug Approval, and Overturn Another in Treatment of Advanced Liver Cancer


Members of an FDA committee recently voted in favor of upholding Keytruda’s accelerated approval indication for the treatment of patients with advanced hepatocellular carcinoma who had previously received treatment with Nexavar. However, the committee narrowly voted against maintaining Opdivo’s accelerated approval in the same patient population.

The Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) recently convened to vote on whether two drugs — single-agent Keytruda (pembrolizumab) and single-agent Opdivo (nivolumab) — should maintain their accelerated approval indications in patients with advanced hepatocellular carcinoma who had previously received treatment with Nexavar (sorafenib).

The meeting was a part of an industry-wide review of several accelerated drug approvals that after undergoing confirmatory trials, failed to meet certain efficacy measures and were not granted full approval by the FDA.

In an 8-to-0 vote, the committee voted in favor of continuing the accelerated approval of Keytruda in this patient population.

Keytruda, an anti-PD-1-therapy, received accelerated approval in November 2018 after initial findings of the open-label phase 2 KEYNOTE-224 trial demonstrated that treatment with the drug was associated with an objective response rate (proportion of patients with complete or partial response to therapy) of 17%. A significant portion of patients (89%) who received Keytruda had responses that lasted six months or longer, and 56% of patients experienced responses that lasted one year or longer.

The continued approval of Keytruda was reliant on positive results for the phase 3 KEYNOTE-240 trial, however it failed to show significant improvements in overall survival (OS) and progression-free survival (PFS). Patients who received Keytruda (278 patients) achieved a median PFS of three months compared to 2.8 months in patients who received placebo (135 patients). Moreover, median OS in the Keytruda group was 13.9 months and 10.6 months in the placebo group.

However, patients who received Keytruda reached an objective response rate of 18.3% compared to 4.4% in those who received placebo.

“The FDA’s successful application of the accelerated approval program has been critically important to provide people with cancer earlier access to potential treatment options,” Dr. Roy Baynes, chief medical officer of Merck Research Laboratories, said in a news release. “We are encouraged by the meaningful discussion and positive votes to maintain the … liver cancer indications reviewed for Keytruda.”

During the meeting, the committee members expressed concern in upholding the accelerated approval because of a low response rate associated with single-agent Keytruda in this patient population, as well as recent FDA approval of Tecentriq (atezolizumab) with Avastin (bevacizumab) in the first-line treatment setting.

However, as Dr. Richard S. Finn, lead author of the KEYNOTE-240 trial, noted during the hearing, around 15% to 20% of patients with advanced disease are unable to receive Avastin in the first-line setting, preventing them from receiving the Avastin-Tecentriq combo.

Opdivo Fails to Receive Same Support

Although the committee voted in favor of keeping the accelerated approval for Keytruda, it voted 5-to-4 against continuing the accelerated approval of single-agent Opdivo in this patient population following treatment with Nexavar.

In 2017, the FDA granted Opdivo accelerated approval based on results of the phase 1/2 CheckMate-040 trial, in which the objective response rate was 18.2% in patients who received Opdivo. Additionally, 3.2% of patients achieved a complete response to therapy.

Results from the confirmatory phase 3 CheckMate-459 trial in 2019 failed to identify an OS benefit for Opdivo compared to Nexavar in the first-line setting of hepatocellular carcinoma. However, the study authors at the time noted a trend toward OS benefit in the Opdivo group at a median of 16.4 months compared to 14.7 months with Nexavar.

“Immunotherapy is an important next treatment option for patients who have progressed on (Nexavar) or are unable to tolerate it,” said Dr. Ian M. Waxman, development lead of gastrointestinal cancers at Bristol Myers Squibb, in a news release. “We are disappointed with today’s outcome for patients, and we will work closely with the FDA as it completes its review. Immunotherapies have changed the way we treat many forms of advanced cancer. We’re proud of the role Opdivo has played in helping to evolve the HCC treatment landscape, and we remain committed to delivering innovative therapies for HCC patients in need.”

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