The US Food and Drug Administration (FDA) has announced that it will not approve poziotinib (from Spectrum Pharmaceuticals) for the treatment of certain patients with nonsmall cell lung cancer (NSCLC).

The clinical data that the company had submitted was deemed insufficient for approval, and additional data including a randomized clinical trials would be needed, the agency said.

The move in not a surprise, as the FDA’s Oncological Oncologic Drugs Advisory Committee (ODAC) voted 9-4 against approval when it met to discuss the drug in September 2022, as reported at the time by Medscape Medical News.

Poziotinib was developed as a treatment for patients with previously treated locally advanced or metastatic NSCLC harboring HER2 exon 20 insertion mutations, which occur in about 2% of patients with NSCLC.

Poziotinib is a potent oral pan-HER tyrosine kinase inhibitor with activity in patients with these mutations. Clinical data from the ZENITH20 Trial reported last year showed an overall response rate of 43.8%, and the drug was described as showing “clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.”

“We continue to believe that poziotinib could present a meaningful treatment option for patients with this rare form of lung cancer, for whom other therapies have failed,” commented Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals. 

However, following multiple interactions with the FDA, “we have made the strategic decision to immediately de-prioritize the poziotinib program,” he said. This will be effective immediately, and the company is now in the process of reducing its R&D workforce by approximately 75%.

Drug Development Criticized

At the ODAC meeting, several of the panelists 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.”

The FDA panel detailed several ways in which they felt that the  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 2022.

The FDA staff contrasted a reported overall response rate for poziotinib, which was estimated at 28% [from data discussed at the meeting], 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 convenient 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 at the University of Maryland School of Medicine, 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 at the time. 

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