FDA Issues Complete Response Letter to NDA for Poziotinib in HER2 Exon 20+ NSCLC

A complete response letter from the FDA indicated that poziotinib as a treatment for non-small cell lung cancer harboring HER2 exon 20 insertion mutations cannot be approved in its current form.

The FDA has issued a complete response letter indicating that poziotinib could not be approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations, according to a press release from Spectrum Pharmaceuticals.1

The complete response letter highlighted that additional data on the agent would need to be gathered, including those from a randomized controlled study, before receiving approval.

“While we are not surprised by the [complete response letter] given the [Oncologic Drug Advisory Committee] ODAC recommendation in September, we are disappointed,” Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, said in the press release. “After multiple interactions with the FDA since ODAC, and following careful consideration, we have made the strategic decision to immediately de-prioritize the poziotinib program. 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.”

In September 2022, poziotinib had received a 9 to 4 vote by the FDA’s ODAC against its use for the management of HER2 exon 20 insertion mutation-positive NSCLC.2 The decision was based on evidence that poziotinib did not yield notable benefit relative to its risks.

The FDA previously accepted a new drug application for poziotinib in NSCLC harboring HER2 exon 20 insertion mutations in February 2022 based on findings from the phase 2 ZENITH20 trial (NCT03318939).3 In a population of 90 patients with HER2 exon 20 insertion mutation-positive NSCLC, poziotinib yielded an overall response rate of 27.8% at a median follow-up of 9.0 months. The disease control rate was 70.0%. Moreover, tumor shrinkage was observed in 74.4% of patients in the as-treated populations and in 90.5% of those in the evaluable population.

In the ZENITH20 trial, serious treatment-related adverse effects (TRAEs) were seen in 14.4% of patients treated with poziotinib, and 12 patients permanently discontinued treatment due to TRAEs.4 Serious TRAEs seen in 1 or more patients included rash (3.3%), asthenia (2.2%), diarrhea (2.2%), dehydration (2.2%), and stomatitis (2.2%). Grade 3 or higher TRAEs included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%).


  1. Spectrum Pharmaceuticals receives complete response letter from U.S. Food and Drug Administration for poziotinib; reaffirms focus on the commercialization of ROLVEDON™ (eflapegrastim-xnst) injection. News release. Spectrum Pharmaceuticals. November 25, 2022. Accessed November 28, 2022. bit.ly/3gBrMo5
  2. Oncologic Drugs Advisory Committee (ODAC) Meeting, September 22-23, 2022 (Day 1). Streamed live September 22, 2022. Accessed November 28, 2022. https://bit.ly/3LNcW9a
  3. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News Release. Spectrum Pharmaceuticals. February 11, 2022. Accessed November 28, 2022. https://bit.ly/3oPK3yQ
  4. Le X, Cornelissen R, Garassino M, et al. Poziotinib in non-small-cell lung cancer harboring HER2 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. Published Online November 29, 2021. J Clin Oncol. doi:10.1200/JCO.21.01323