FDA Advisory Committee to Review Fate of Keytruda, Opdivo, and Tecentriq Following Failed Confirmatory Trials

Compiled by Keke

The fates of three cancer immunotherapies will be determined this week following the failure of confirmatory trials, under the U.S. Food and Drug Administration’s (FDA) accelerated approval pathway.

The U.S. FDA Oncologic Drugs Advisory Committee will review products approved via the accelerated approval pathway for breast cancer, urologic tumors, gastric cancer, and hepatocellular carcinoma. Specifically, the advisory committee will discuss Merck’s Keytruda, Bristol-Myers Squibb’s (BMS) Opdivo, and Roche’s Tecentriq. Each of these checkpoint inhibitors has been approved under the accelerated approval pathway but requires confirmatory trials. Keytruda is approved for gastric or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, and urothelial carcinoma; Opdivo is approved as a monotherapy for hepatocellular carcinoma; and Tecentriq is approved for triple-negative breast cancer and urothelial carcinoma.

“We are committed to ensuring the integrity of the Accelerated Approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible. The program allows the U.S. FDA to approve a drug or biologic for the treatment of serious or life-threatening diseases based on surrogate endpoints that can be measured earlier than survival time, demonstrating a meaningful advantage over existing therapies. However, when confirmatory trials fail to verify clinical benefit, a reevaluation must be conducted to determine whether the approval should be withdrawn,” the advisory committee said in a statement.

Over the past five months, several checkpoint inhibitor drugs have been withdrawn for other indications. Most recently, Merck Sharp & Dohme (MSD) withdrew Keytruda for the treatment of patients with metastatic small cell lung cancer (SCLC) who had progressed after platinum-based chemotherapy and at least one prior line of therapy. Keytruda was initially approved for this indication in 2019; however, in January of this year, the company reported the results of the confirmatory Phase III KEYNOTE-604 clinical trial, which met only one of its two primary endpoints. In this study, Keytruda achieved the progression-free survival endpoint but failed to demonstrate statistical significance for the other primary survival endpoint. Following the announcement of the confirmatory trial results, MSD withdrew the indication for Keytruda.

Both AstraZeneca and Roche have withdrawn the oncology indications for their drugs following the failure of confirmatory trials. In February this year, AstraZeneca halted the use of its checkpoint inhibitor Imfinzi for the treatment of bladder cancer after announcing the failure of its confirmatory trial. The U.S. FDA had first approved Imfinzi for this indication in 2017. However, AstraZeneca failed to meet the primary endpoint of improving overall survival in patients with advanced bladder cancer who had previously received platinum-based chemotherapy in the Phase III DANUBE clinical study.

Two weeks after AstraZeneca’s move regarding Imfinzi, Roche also withdrew the indication for Tecentriq in bladder cancer. The Swiss pharmaceutical giant Roche withdrew the use of Tecentriq for previously platinum-treated metastatic urothelial carcinoma (mUC) after failing to meet its confirmatory endpoints. Tecentriq was first approved for this indication in 2016. However, in 2017, Tecentriq failed to meet its endpoints in a Phase III clinical study for second-line treatment of bladder cancer, marking the first sign of failure.

In late December 2020, Bristol-Myers Squibb (BMS) withdrew the indication for Opdivo as a treatment for small cell lung cancer (SCLC) in patients who had progressed after platinum-based chemotherapy and at least one other prior therapy. Like other checkpoint inhibitors, Opdivo failed to meet the expected primary clinical endpoints for this indication. In 2018, when Opdivo received approval for this indication, it was the first new drug approved for this use in 20 years.

The U.S. FDA’s Accelerated Approval Program allows patients with refractory cancers to access certain new therapies earlier. However, conditions of accelerated approval include post-marketing requirements to confirm the safety and efficacy of the treatment. Over the past few months, the U.S. FDA has been conducting an industry-wide evaluation of several drugs granted accelerated approval, focusing on identifying which drugs fail to meet post-marketing requirements. The FDA Oncology Center of Excellence convened advisory meetings to evaluate accelerated approvals for oncology drugs whose confirmatory trials failed to demonstrate clinical benefit. The U.S. FDA stated that during the multiple meetings held from April 27 to 29, the advisory committee would discuss each drug and determine whether continued approval for these indications is warranted and whether additional trials are necessary.

Reference Source: FDA Advisory Committee to Review Checkpoint Inhibitors Greenlit Under Accelerated Approval

Original Title: Following Indication Withdrawals, Keytruda, Opdivo, and Tecentriq to Be Reviewed by FDA Advisory Committee This Week