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FDA keeps Jazz’s lung cancer accelerated approval in place—for now—despite failed trial and calls for withdrawal

Even when a drug’s confirmatory trial fails, the FDA may still give companies a second chance before pulling accelerated approvals. Jazz Pharmaceuticals’ lung cancer drug Zepzelca is the latest to be granted that mercy, though not without some objections.

The FDA has turned down a citizen petition by law firm Foley Hoag that had asked the agency to pull Zepzelca’s accelerated approval in previously treated small cell lung cancer (SCLC).

The decision comes after Zepzelca, when used on top of chemotherapy, failed to beat chemo alone in a phase 3 trial in patients who had progressed after one prior platinum-containing therapy. After that trial failure, the FDA says it has signed off on two other phase 3 studies as the drug’s new confirmatory trials.

It’s not unprecedented for the FDA to allow a cancer drug’s accelerated approval to remain on the market after a failed confirmatory trial, especially when another confirmatory study has been agreed upon. For example, after a phase 3 flop, Merck & Co.’s Keytruda was able to temporarily keep its accelerated approval as a second-line liver cancer treatment pending a readout from an alternative confirmatory study. In that case, the FDA had backing from an independent advisory committee.

But this practice has raised one obvious question: Just how many chances can be afforded to an accelerated approval before a withdrawal?

“[I]t is possible that any drug will eventually yield significant results,” University of California (UC), Irvine health policy experts David Benjamin, M.D., and Vinay Prasad, M.D., wrote in an article in The Lancet Oncology about Zepzelca’s case in May. The two researchers voiced concerns that the FDA hadn’t already revoked Zepzelca at that time.

As a single agent, Zepzelca won its initial approval in 2020 based on tumor response data. In the approval letter, the FDA specified that a phase 3 study dubbed ATLANTIS could serve as the confirmatory trial, with data on patient survival expected by February 2021.

In December 2020, however, Jazz reported that Zepzelca’s combination with doxorubicin failed to outdo physician’s choice of chemotherapy in second-line SCLC. At that time, Jazz was quick to note that the study tested Zepzelca at 2mg/m2, which is a lower dose than the FDA-approved 3.2mg/m2.

In its response to the withdrawal petition, FDA acknowledged that ATLANTIS could have satisfied the postmarketing requirement of a confirmatory trial and that its results aren’t adequate to verify Zepzelca’s benefit. But the agency disagreed that the drug should be pulled based on those results at this time.

“When a confirmatory trial does not meet its endpoint, it does not necessarily mean that the drug is not effective for the indication approved through accelerated approval,” the FDA said.

For Zepzelca specifically, the use of a lower dose “raises the possibility” that the main reason for the trial failure is that the drug simply didn’t achieve its intended efficacy based on the approved dose, the FDA said. Further, the addition of doxorubicin may have led to increased toxicity and hence increased discontinuation of therapy, the agency argued.

Moreover, while the FDA has recently approved new treatments in first-line SCLC, there’s still an unmet medical need in the second line, where Zepzelca is approved, the agency added.

To help seal the deal, Jazz has offered up two trials to confirm Zepzelca’s efficacy, and the FDA has signed off on them. The first one—and perhaps the more relevant one—launched in late 2021. Dubbed LAGOON, the three-arm trial will test Zepzelca monotherapy at the currently FDA-approved daily dose of 3.2mg/m2 and at 2mg/m2 in combination with chemotherapy irinotecan. Investigators will pit those study arms against physician’s choice of chemo in second-line SCLC.

But as UC Irvine’s Benjamin and Prasad noted in their article, the LAGOON trial bears an estimated primary completion date years from now—in May 2025.

“Moving forward, the oncology field should consider how many chances a drug should be given, and how long patients with cancer must wait for confirmatory survival results,” the two researchers wrote.

As for the other confirmatory study, Jazz is collaborating with Roche on a phase 3 trial called IMforte. The trial is combining Roche’s Tecentriq with Zepzelca as a maintenance therapy in patients with extensive-stage SCLC. The study’s estimated primary completion date is in September 2025.