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Spectrum Pharmaceuticals Inc experienced a setback in its efforts to win accelerated approval in the US of its experimental drug poziotinib for the treatment of a form of non–small cell lung cancer (NSCLC).

On Thursday, a US Food and Drug Administration (FDA) advisory panel voted 9 to 4 against recommending the oral agent, citing concerns regarding the evidence of its clinical benefits.

The majority “no” vote from the FDA’s Oncologic Drugs Advisory Committee (ODAC) focused on the following question: “Do the current benefits of poziotinib outweigh its risks for the treatment of patients with non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations?”

After weighing the evidence that the company submitted in its new drug application, most ODAC panelists did not believe the data for poziotinib met this bar.

Some members of the ODAC panel were openly critical of the approach Spectrum took in developing the drug. The FDA’s top cancer official, Richard Pazdur, MD, characterized Spectrum’s work as “poor drug development” and likened it to “building a house on quicksand.”

Although the FDA considers the recommendations of its advisory committees, the agency is not bound by them.

Under the target dates set by the mandates of the Prescription Drug User Fee Act (PDUFA), cordarone dosage form the FDA should decide within about 2 months on the application for accelerated approval of poziotinib.

“We are disappointed by the outcome of the ODAC meeting, as patients with NSCLC HER2 exon 20 insertion mutations are in need of additional effective and safe therapies,” said Tom Riga, Spectrum’s president and chief executive officer, in a statement. “We plan to carefully evaluate our options for this program as we approach the November 24, 2022, PDUFA date.”

Established Rival Drug

The FDA panel detailed several ways in which they felt the current poziotinib application fell short of the benchmarks needed for accelerated approval.

To win such a speedy clearance, a company needs to show that a treatment provides a meaningful therapeutic benefit over existing treatments. The panel argued that, so far, poziotinib appears to be inferior to a product already available for HER2-mutant NSCLC, trastuzumab deruxtecan (Enhertu) — which received accelerated approval in August.

On Thursday, the FDA staff contrasted a reported overall response rate for poziotinib, which was estimated at 28%, with the overall response rate for trastuzumab deruxtecan, which is 58%.

Harpreet Singh, MD, a director in the FDA’s oncology division, asked the panel to consider what they would do as a physician treating a patient with this mutation, given the choices that are now available.

“That’s something we’re asking the committee to consider…to think about the context of what’s available to you in the clinic,” Singh said.

Singh said she expected that patients and physicians would prefer a drug such as trastuzumab deruxtecan, which has a more established record, regardless of the fact that treatment with poziotinib is more convient because it is given as a tablet.

Singh and other staff also raised concerns about side effects of the poziotinib, including diarrhea, as well as difficulty in determining the right dose.

Katherine Scilla, MD, one of the nine ODAC panelists to vote “no,” echoed these views. Although Scilla, an oncologist who specializes in treatment of thoracic cancers, sympathized with the need for options for people with this rare form of lung cancer, she was not persuaded by the data on poziotinib that were presented to support accelerated approval.

“I’m not sure that this represents a meaningful therapeutic benefit over other agents,” she said, and she indicated that work is needed to pin down the dose. Scilla is an assistant professor at the University of Maryland School of Medicine.

In addition, if the FDA were to grant accelerated approval, a trial to confirm the drug’s benefit would be significantly delayed, given that the planned confirmatory trial has not yet begun enrolling patients, the agency staff noted in briefing materials and that it highlighted at the meeting. Given available treatment options, it could be tough to attract participants to this study.

“We’re probably not going to have answers about a confirmatory trial for many years,” Scilla said.

It could be 2026 before results of the planned trial are known, provided the study can even be completed as planned, FDA reviewer Justin Malinou, MD, said.

“The recent approval of trastuzumab deruxtecan in the same space may make it infeasible to conduct a proposed confirmatory trial,” Malinou said.

Panelist David Mitchell, who serves as the patient representative, was one of the four panelists who voted in favor of the drug.

Mitchell explained that the FDA did not ask the panel whether to give accelerated approval but rather to weigh the potential benefits and risks. When considering that question, the side effects appeared to be manageable, and the problem regarding determing the optimal dose likely could be resolved, Mitchell said.

“This drug belongs in the armamentarium of those clinicians who are trying to treat these patients that lack sufficient numbers of options,” Mitchell said. “The challenges of the confirmatory trial are important, but it didn’t overcome my overall sense that, yes, the benefits outweigh the risks.”

Challenges With Accelerated Approval

With accelerated approvals, the FDA and drugmakers essentially strike bargains that are based on educated guesses and early signals of promise. Such approvals allow patients to have greater access to treatments.

But in the meeting, FDA staff highlighted the general challenges the agency has faced with accelerated approvals of cancer drugs.

In some cases, studies intended to prove the benefit of drugs that had been granted accelerated approval have been delayed, leaving patients exposed to medicines for which benefit may never be confirmed.

“This is where we have gotten into problems with accelerated approval,” Pazdur said. “Sponsors agree to these studies, and then they come back in a year and say, ‘Oh, we don’t have sufficient accrual,’ and then we’re looking at alternative trial design.”

To illustrate these problems, Pazdur and colleagues wrote an article that was published in The New England Journal of Medicine earlier this week. In it, they discuss data that show that only half of cancer drugs that had received accelerated approvals (86 of 172) demonstrated a meaningful clinical benefit in subsequent confirmatory trials, while 12% of cancer drugs that have been approved through this pathway have been withdrawn.

In Thursday’s meeting, Pazdur said drugmakers need to plan well when seeking accelerated approvals, including having early discussions and continued dialogue with the FDA. This approach would help speed the confirmatory trials needed to know whether cancer drugs extend or improve lives.

“It’s really only fair to the patients” to get these answers as quickly as possible, Pazdur said.

Kerry Dooley Young is a freelance journalist based in Miami Beach. Follow her on Twitter @kdooleyyoung.

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