FDA Issues Complete Response Letter to Poziotinib for Metastatic NSCLC Harboring HER2 Exon 20 Mutations

The FDA has issued a complete response letter (CRL) to the new drug application (NDA) seeking the approval of poziotinib for the treatment of patients with previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations, according to an announcement from Spectrum Pharmaceuticals.¹

The CRL from the regulatory agency indicated that the poziotinib NDA cannot be approved in its present form, and Spectrum Pharmaceuticals would need to generate additional data, including a randomized controlled study, prior to approval.

In September 2022, in a 9 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted that the benefits of poziotinib do not outweigh its risks for the treatment of patients with HER2 exon 20 insertion–mutated NSCLC.² The NDA was accepted by the FDA in February 2022.³

Following the CRL, Spectrum Pharmaceuticals announced that it would de-prioritize activities in the poziotinib program, effective immediately.

“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,” Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, stated 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.”

“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.”

The NDA was supported by data from cohort 2 (n = 90) of the phase 2 ZENITH20 trial (NCT03318939), where a once-daily dose of 16 mg of poziotinib generated an objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%) in this population.⁴ The median duration of response (DOR) was 5.1 months (95% CI, 4.2-5.5), and the median progression-free survival (PFS) was 5.5 months (95% CI, 3.9-5.8).

The multicenter, multicohort, open-label, ZENITH20 trial featured 7 cohorts of patients with NSCLC. Cohort 2 included patients with previously treated NSCLC harboring HER2 exon 20 insertion mutations.

Patients in cohort 2 were required to be at least 18 years of age and have received prior treatment for locally advanced or metastatic NSCLC. Tumors were required to have HER2 exon 20 insertion mutations and measurable disease. Patients with brain metastases were permitted, although they needed to be stable, asymptomatic, and not require high-dose or increasing doses of corticosteroids.

Enrolled patients received 16 mg of oral poziotinib as part of 28-day treatment cycles that lasted up to 24 months.

ORR served as the trial’s primary end point. Secondary end points included disease control rate, DOR, PFS, safety, and tolerability. Quality of life was also assessed.

Among all patients in cohort 2, treatment-related adverse effects (TRAEs) were reported in 97.8% of patients, and rates of grade 3 and grade 4 TRAEs were 78.9% and 4.4%, respectively.

The most common TRAEs of any grade included rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%). The most frequent grade 3 or higher TRAEs included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Serious TRAEs included rash (3.3%), asthenia (2.2%), diarrhea (2.2%), dehydration (2.2%), and stomatitis (2.2%).

Grade 4 TRAEs included stomatitis, dyspnea, hypomagnesemia, hypocalcemia, and pancreatitis relapsing. One patient experienced grade 5 pneumonia.

References

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. http://bit.ly/3Vy8TkB
2. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed November 28, 2022. https://www.youtube.com/watch?v=SON2biqVX_8.
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/3gGReox
4. Le X, Cornelissen R, Garrassino 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