FDA Denies Approval of Poziotinib for Advanced/Metastatic NSCLC With HER2 Exon 20 Insertions

The FDA issue a complete response letter (CRL) to Spectrum Pharmaceuticals, Inc. regarding the new drug application (NDA) seeking approval of poziotinib for the treatment of patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations.¹

It is the position of the FDA that the NDA for poziotinib cannot be approved in its current state. Additional data are needed from a randomized controlled study for poziotinib to be approved for this indication, according to the FDA.

This decision come on the heels a meeting of the Oncologic Drugs Advisory Committee (ODAC) during which the NDA for poziotinib was discussed. The ODAC voted 9 to 4 that the current benefits of poziotinib did not outweigh its risks for the treatment of patients with NSCLC with HER2 exon 20 insertion mutations. The data supporting the application came from the phase 2 ZENITH20 clinical trial.

"While we are not surprised by the CRL given the ODAC recommendation in September, we are disappointed. 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," said Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, in a press release. "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."

ZENITH20 is a multicenter, multicohort, open-label phase 2 study (NCT03318939) primarily evaluating objective response rate by independent review committee (IRC) in patients with advanced or metastatic NSCLC. The secondary outcomes of the study include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), safety/tolerability, and quality of life.²

Results from the study were reported in 2021 from 90 patients who had received a median of 2 prior lines of therapy. Poziotinib achieved an ORR of 27.8% (95% CI, 18.9%-38.2%) with partial response observed in 25 patients. The DCR achieved with poziotinib was 70.0% (95% CI, 59.4%-79.2%). Seventy-four percent of patients treated with poziotinib in the study had tumor reduction at a median shrinkage of 22%.

The agent showed a 5.1-month (95% CI, 4.2 to 5.5) median duration of response, and clinical benefit with poziotinib in the study was irrespective of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations.

The median PFS observed with the poziotinib in the study was 5.5 months (95% CI, 3.9-5.8) with a 5.1-month median DOR.

"We are committed to exploring potential strategic alternatives for poziotinib, including partnerships and business development opportunities, and will determine the best path forward in support of patients. We are grateful to the patients, families, and clinicians who participated in the poziotinib program and to the team members who have dedicated their time and efforts," said Riga.

Spectrum Pharmaceutical plans to de-prioritize the poziotinib development programs and shift its priority toward eflapegrastim-xnst (Rolvedon), an agent recently approved to decrease the incidence of infection with chemotherapy-induced neutropenia.

_REFERENCE:

_{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.}

_{2. 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. J Clin Oncol. 2022;40(7): 710-718. doi: 10.1200/JCO.21.01323}