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FDA Rejects Poziotinib for HER2-Mutated NSCLC Following Advisory Committee's Negative Vote

• The FDA has issued a complete response letter for poziotinib, Spectrum Pharmaceuticals' pan-HER2 inhibitor, rejecting its application for HER2 exon 20 insertion-mutated non-small cell lung cancer treatment.

• The rejection follows a 9-4 vote against approval by FDA's Oncologic Drugs Advisory Committee, citing concerns over marginal efficacy, high toxicity rates, and delayed confirmatory trials.

• Phase 2 ZENITH20 study showed limited efficacy with 28% objective response rate and five-month median response duration, while 12% of patients discontinued due to adverse effects.

The U.S. Food and Drug Administration (FDA) has declined to approve poziotinib, a pan-HER2 inhibitor developed by Spectrum Pharmaceuticals for treating HER2 exon 20 insertion-mutated non-small cell lung cancer (NSCLC), issuing a complete response letter (CRL) to the company.
The regulatory setback was first disclosed by Hanmi Pharmaceuticals, the original developer of the drug, during the U.S. Thanksgiving holiday. The rejection follows a September advisory committee meeting where the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 9 to 4 against approval, determining that poziotinib's benefits did not outweigh its risks.

Clinical Trial Results and Safety Concerns

The FDA's decision was based on review of phase 2 data from the ZENITH20 study, which demonstrated limited efficacy. The trial showed an objective response rate of 28% with a median duration of response of approximately five months. Safety concerns were prominent, with 12% of patients forced to discontinue treatment due to adverse effects.
Regulatory documents highlighted multiple concerns, including:
  • Marginal efficacy in clinical trials
  • High toxicity rates
  • Questions about the selected dosing regimen
  • Delays in initiating the confirmatory PINNACLE trial

Unmet Need in HER2-Mutated NSCLC

The rejection represents a continued gap in treatment options for patients with HER2 exon 20 insertion-mutated NSCLC, an aggressive form of lung cancer. This mutation affects up to 4% of lung cancer cases, with HER2 exon 20 alterations being the most prevalent form. Despite success in treating HER2-positive breast and gastric cancers, current HER2-targeted therapies have shown disappointing results in NSCLC.

Commercial Impact and Company Background

Spectrum Pharmaceuticals had licensed worldwide rights to poziotinib from Hanmi Pharmaceuticals in 2015, excluding Korea and China. While this represents a significant setback for their oncology pipeline, the company recently achieved success with the FDA approval and launch of Rolvedon (eflapegrastim) for treating chemotherapy-induced neutropenia, entering a market valued at approximately $2 billion annually.
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Reference News

[1]
FDA rejects Spectrum's lung cancer drug poziotinib
pharmaphorum.com · Apr 23, 2025
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