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An FDA advisory committee decided that the clinical benefits of the multitargeted tyrosine kinase inhibitor (TKI) poziotinib do not outweigh its risks for patients with non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations.

By a 9-4 vote, the Oncologic Drugs Advisory Committee (ODAC) gave a negative review of the data provided. Despite the ODAC outcome, a phase III confirmatory trial of poziotinib in previously treated patients is underway.

"It's clearly evident that it wasn't an easy decision for most of us," said ODAC chair Jorge Garcia, MD, of Case Western Reserve University and University Hospitals in Cleveland. "For those who voted yes, it does appear that relates to the efficacy of these agents in a patient population that is in need of active therapies. Those who voted yes were not too worried about the tolerability of this agent, based on prior experience and years of practice. Clearly, they're not concerned as to the confirmatory trials and the need for those trials to be ongoing."

"For those of us who voted no, I think the theme is, quote-unquote, 'non-meaningful difference' compared with existing agents," he added. "Clearly, we are all concerned about the not-ideal dosing and dose finding or dose optimization issues that have been noted. Certainly, the lack of a confirmatory trial that may take a long while before we know the true dose and true efficacy of the drug is an issue."

Dueling Perspectives

In separate presentations leading up to the vote, the FDA and Spectrum Pharmaceuticals offered contrasting perspectives on risk/benefit data for poziotinib. FDA clinical team leader Nicole Drezner, MD, and clinical reviewer Justin Malinou, MD, cited four areas of concern:

• A 28% response rate with second-line poziotinib does not represent a substantive improvement over currently available options
• High rates of toxicity -- driven by diarrhea, mucositis, and rash in more than 70% of patients -- requiring dose interruptions or reductions in a majority of patients
• The sponsor settled on a 16-mg dose one time a day without adequate exploration of alternatives
• A phase III confirmatory trial has yet to enroll a single patient, despite discussions with the FDA dating back to 2020, and a final analysis is not anticipated until 2026

The FDA noted that both the response rate and duration of response for poziotinib are inferior to trastuzumab deruxtecan (T-DXd, Enhertu), which should be considered an available option because it is approved, though not specifically for patients with the exon 20 insertion. Additionally, one-third of patients in the pivotal trial had not received an immune checkpoint inhibitor.

Taking the position that T-DXd should not be considered an available therapy, Spectrum chief medical officer François Lebel, MD, said the 28% response rate with poziotinib did exceed all available therapies. In some subgroups, the overall response rate reached 40%.

Most of the treatment-related toxicity is on-target toxicity and consistent with the recognized adverse-effect profile of TKIs, he added. As for dose optimization, poziotinib has been evaluated in more than 1,300 patients at doses ranging from 5 to 32 mg, said Lebel.

Mark Socinski, MD, of AdventHealth in Orlando, Florida, said NSCLC with HER2 exon 20 insertion mutations represents a large unmet need with few treatment options. He pointed out that patients with NSCLC overall have benefited from having multiple, biologically distinct TKI options. He also noted other therapies that have produced benefits similar to poziotinib, notably the oral TKI mobocertinib (Exkivity) and the KRAS inhibitor sotorasib (Lumakras), both of which had response rates of 28% in pivotal trials.

The on-target toxicity associated with poziotinib is both "predictable and manageable," he said.

"Absence of cardiac toxicity and a very low rate of ILD [interstitial lung disease] provide an option that may make it a treatment of choice in selected patients," said Socinski, a speaker for the Spectrum presentation. "Poziotinib often showed a meaningful advantage over available therapies in the second and beyond lines of treatment. Let me remind you that there are no currently approved drugs for third-line patients who have exhausted all options, including docetaxel. In this heavily pretreated setting, poziotinib showed an overall response rate of 37% and a median progression-free survival of 5.5 months."

Dose-Optimization Issue

Further confounding discussion of the dose-optimization issue, the confirmatory trial will use a different dose (8 mg twice daily) from what Spectrum has specified in its approval application (16 mg one time a day). Lebel said the 8 mg twice daily (BID) schedule was chosen during discussions with FDA as potentially having a more favorable safety profile. The FDA disputed that.

"We did not come to any formal agreement about the 8-milligram BID dose," said FDA designated federal officer She-Chia Chen, PharmD. "We told the sponsor that it would be at their own risk to move forward with this incongruent dose ... I think a lot of this speaks to the sponsor kind of rushing the development program and trying to make catch-ups, whereas the steps should have been taken slowly and methodically and appropriately, early in development."

"Frankly, it's a bit of uncharted territory," she added. "If the accelerated approval is granted, if the confirmatory trial is conducted, and if it is a positive study with this different dose, then we will be faced with a labeling challenge -- obviously a point of confusion for patients and providers."

Richard Pazdur, MD, of the FDA Oncology Center of Excellence, spoke more bluntly about the apparent disconnect between the doses.

"What this really represents is poor drug development," he said. "Obviously, before somebody launches a large phase III trial, they should have confidence in what their doses should be, and the dose optimization should occur beforehand. What would we do -- if it can accrue, and that's a big if -- if it is negative? Is that because they chose the wrong dose?"

"We have a whole program here at the FDA on dose optimization," Pazdur continued. "This just points to one of the problems that we have here when one attempts to launch a phase III study without adequately looking at what the dose is and having confidence in it. I've said it before and I'll say it again: Proceeding with a drug development program when you don't have a well-founded dose is literally building a house on quicksand."

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