FDA Approval Sought for Poziotinib in HER2 Exon 20–Mutated NSCLC

A new drug application (NDA) seeking the approval of poziotinib as a potential therapeutic option for patients with previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations has been submitted to the FDA.¹

The application is supported by findings from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939), which showed that the agent elicited an objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%) in this patient population.² Moreover, the median duration of response (DOR) with the drug was 5.1 months (95% CI, 4.2-5.5), and the median progression-free survival was 5.5 months (95% CI, 3.9-5.8).

“The NDA submission for poziotinib marks an important step in achieving a first treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” Joe Turgeon, president and chief executive officer of Spectrum Pharmaceuticals, stated in a press release. “I want to thank the patients, investigators, and our internal staff who have passionately worked to achieve this important milestone in an area of high unmet medical need.”

The multicenter, multicohort, open-label, phase 2 ZENITH20 trial was comprised of 7 cohorts of patients with NSCLC. Cohort 1 enrolled patients with previously treated NSCLC and EGFR exon 20 mutations, and cohort 2 was comprised of patients with HER2 exon 20 mutations. Cohort 3 enrolled those with NSCLC and EGFR exon 20 mutations who were treatment naïve, and cohort 4 is still enrolling patients with NSCLC and HER2 exon 20 mutations who are receiving treatment in the first-line setting.

Cohorts 5 through 7 are enrolling the following patients, respectively:

• Previously treated or treatment-naïve patients with EGFR or HER2 exon 20 insertion mutations

• Patients with NSCLC and classical EGFR mutations who progressed on treatment with frontline osimertinib (Tagrisso) and developed an additional EGFR mutation
• Patients with NSCLC who had a variety of less common mutations in EGFR or HER2 exons 18 through 21 or the extracellular or transmembrane domains

To be eligible for enrollment to cohort 2, patients needed to be at least 18 years of age, had previously received treatment for locally advanced or metastatic NSCLC, and have documented HER2 exon 20 insertion mutations. They also needed to have measurable disease. Those with known brain metastases were permitted if they were stable, asymptomatic, and did not need high-dose or increasing doses of corticosteroids.

Those enrolled to cohort 2 received oral poziotinib at a once-daily dose of 16 mg in an outpatient setting during each 28-day treatment cycle for up to 24 months. If patients experienced adverse effects (AEs), they were allowed to reduce the dose in 2-mg increments. Dose interruption of up to 28 days was permitted.

The primary end point of the trial was ORR, and key secondary end points included disease control rate (DCR), DOR, and PFS, as well as safety and tolerability. Investigators also evaluated quality of life.

A total of 90 patients were enrolled to the trial between October 2017 and March 2021. The median age of these patients was 60 years (range, 25-86), 64.4% were female, 77.8% were White, 65.6% were never smokers, and 57.8% of patients had an ECOG performance status of 1. Moreover, 96.7% had a histology of adenocarcinoma and 3.3% had a histology of squamous cell carcinoma. Notably, 25.6% of patients had stable central nervous system (CNS) metastases at the time of study entry.

Additionally, the median number of prior lines of treatment was 2 (range, 1-6), with 30.0% of patients having received 1 prior line, 31.1% having received 2 prior lines, and 38.9% having received 3 or more prior lines. Moreover, 96.7% previously received platinum-based therapy, 67.8% had received a prior checkpoint inhibitor, 27.8% had previously received an anti-HER2 agent, and 65.6% previously underwent both chemotherapy and checkpoint inhibition.

Of the 90 treated patients, 25 achieved a partial response and zero achieved a complete response. In the 25 responders, the median time to response was 32 days (range, 23-183). The DCR with poziotinib in this cohort was 70.0% (95% CI, 59.4%-79.2%). In the evaluable population of 74 patients, the ORR with the agent was 35.1% (95% CI, 24.4%-47.1%) and the DCR was 82.4% (95% CI, 71.8%-90.3%). Most patients experienced tumor shrinkage. Moreover, 37.8% (95% CI, 25.5%-50.0%) of patients were free of disease progression at 6 months.

Additional analyses revealed that the agent also provided benefit across demographic subsets. The ORR with poziotinib in patients who had received 3 or more prior lines of treatment was 37.1% (95% CI, 21.5%-55.1%); in those who received 2 or 1 lines of treatment, these rates were 21.4 % (95% CI, 8.3%-41.0%) and 22.2% (95% CI, 8.6%-42.3%), respectively.

Moreover, 26.2% of patients who received prior checkpoint inhibition responded to poziotinib. Twenty-five of these patients had previously received an anti-HER2 agent with 1 or more antibodies or antibody-drug conjugates, and all previously received chemotherapy. Three patients previously received trastuzumab (Herceptin) and afatinib (Gilotrif); 1 received trastuzumab and neratinib (Nerlynx).

Among 14 patients with stable CNS metastases at the time of enrollment, poziotinib produced an ORR of 28.6%. The median PFS in this subset of patients was 7.4 months. Notably, 1 patient who had 2 baseline brain lesions was found to have an absence of both lesions on 2 or more MRI scans following treatment with poziotinib. Nine more of these patients experienced CNS stable disease.

Regarding safety, all patients experienced treatment-emergent AEs, and 97.8% of toxicities related to treatment were reported; 78.9% of these effects were grade 3 in severity and 4.4% were grade 4.

The most frequent toxicities reported with poziotinib included rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%). The most common grade 3 or higher toxicities included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Serious treatment-related AEs (TRAEs) were rash (3.3%), asthenia (2.2%), diarrhea (2.2%), dehydration (2.2%), and stomatitis (2.2%).

Moreover, 4.4% of patients experienced grade 4 TRAEs with poziotinib, these included stomatitis, dyspnea, hypomagnesemia, hypocalcemia, and pancreatitis relapsing. One patient reported grade 5 pneumonia.

Previously, in March 2021, the FDA granted a fast track designation to poziotinib for use in previously treated patients with HER2 exon 20 mutations, based on cohort 3 of the ZENITH20 trial.³ Results showed that poziotinib elicited an ORR of 27.8% (95% CI, 18.4%-39.1%) and a DCR of 86.1% in treatment-naïve patients with metastatic NSCLC who harbored EGFR exon 20 mutations.⁴

When given at a twice-daily 8-mg dose in cohort 5 of the trial, poziotinib elicited an ORR of 31.6% (n = 6/19).⁵ When given at a daily dose of 16 mg or 12 mg, the ORRs were 15.8% (n = 3/19) and 15.8% (n = 3/19), respectively. When given at a twice-daily dose of 6 mg, the ORR was 5.3% (n = 1/19). Moreover, data from cohort 4 of the trial showed that the agent elicited an ORR of 43.8% (95% CI, 29.5%-58.8%) in this population.⁶

References

1. Spectrum Pharmaceuticals submits new drug application for poziotinib. News release. Spectrum Pharmaceuticals; December 6, 2021. Accessed December 6, 2021. https://bwnews.pr/3pvmkDl
2. 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. Published online November 29, 2021. doi:10.1200/JCO.21.01323
3. FDA grants fast track designation to Spectrum Pharmaceuticals’ poziotinib. News release. Spectrum Pharmaceuticals; March 11, 2021. Accessed December 6, 2021. http://bwnews.pr/3tf1PuO
4. Sacher A, Le X, Cornelissen R, et al. Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 exon 20 mutant non-smell cell lung cancer. Presented at: ESMO TAT Virtual Congress; March 1-2, 2021; Virtual. Accessed December 6, 2021.
5. Le X, Shum E, Suga J, et al. Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutant NSCLC (ZENITH20-5). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT169.
6. Cornelissen R, Sun S, Wollner M, et al. Efficacy and safety of poziotinib in treatment-naïve NSCLC harboring HER2 exon 20 mutations: a multinational phase II study (ZENITH20-4). Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA46.