Frontline Poziotinib Produces Clinically Meaningful Efficacy in NSCLC Harboring HER2 Exon 20 Insertion Mutations

Poziotinib elicited encouraging responses when given at a daily dose of 16 mg in the first-line treatment of patients with non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations, according to data from cohort 4 of the ongoing phase 2 ZENITH20 trial (NCT03318939) presented during the 2022 ESMO Targeted Anticancer Therapies Meeting.¹

Among 70 patients who received the agent, the confirmed objective response rate (ORR) was 41% (95% CI, 30%-54%). In the 58 patients determined to be evaluable, the ORR with poziotinib was 50% (95% CI, 37%-63%). The study met its primary end point, as the observed lower bound of 30% exceeded the prespecified lower bound of 20%.

Moreover, the median duration of response (DOR) was 5.7 months (range, 1.2-19.1+), and the disease control rate (DCR) was 73% (95% CI, 61%-83%) with the agent in this population. Poziotinib resulted in a median progression-free survival (PFS) of 5.6 months (range, 0.0-20.2+).

“Cohort 4 from our ZENITH20 study demonstrated positive results for treatment-naïve lung cancer patients harboring HER2 exon 20 insertion mutations,” Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, stated in a press release.² “There is currently no approved treatment for NSCLC patients with these mutations. We are encouraged by these findings and look forward to further discussions with the FDA on the regulatory path forward.”

The multicenter, multicohort, open-label phase 2 ZENITH20 trial is composed of 7 cohorts of patients with NSCLC.³ Those with previously treated NSCLC and EGFR exon 20 mutations comprise cohort 1; those with HER2 exon 20 mutations comprise cohort 2; those with treatment-naïve NSCLC and EGFR exon 20 mutations comprise cohort 3; and those with treatment-naïve NSCLC and HER2 exon 20 mutations comprise cohort 4.

Cohort 5 is enrolling previously treated or treatment-naïve patients with EGFR or HER2 exon 20 insertion mutations; cohort 6 is enrolling those with NSCLC and classical EGFR mutations who progressed on frontline osimertinib (Tagrisso) and developed an additional EGFR mutation; and cohort 7 is enrolling those with NSCLC who have a variety of less common mutations in EGFR or HER2 exons 18 through 21 or the extracellular or transmembrane domains.

In cohort 4 of the trial, poziotinib was evaluated at a once- or twice-daily dosing strategy in patients with NSCLC and HER2 exon 20 insertion mutations. The oral drug was given once daily at 16 mg for the first 48 patients, and then at a twice-daily dose of 8 mg in an additional 22 patients. Both regimens allowed for dose reductions or interruptions if patients experienced toxicity.

The primary end point was ORR per central evaluation and by independent image review committee utilizing RECIST v1.1 criteria. Key secondary end points included DCR, DOR, and PFS, as well as safety and tolerability.

Those in cohort 4 had a median age of 60 years (range, 27-88), and 37% were female. Twenty percent of the 70 total patients were still receiving treatment at the time of data cutoff, and the median duration of treatment was 4.5 months (range, < 1-21).

Additional findings presented during the meeting revealed that 73% of patients achieved disease control and experienced a clinically meaningful reduction in tumor size.

Regarding safety, 90% of those who received the once-daily dose required a dose interruption with a median of 19 days to first interruption, vs 68% of those who were given the twice-daily dose. The median time to first interruption among those who received the twice-daily dose was slightly longer, at 26 days.

Additionally, 79% and 64% of patients who received the once- and twice-daily doses of poziotinib, respectively, experienced dose reductions. The median time to first dose reduction in the once-daily dosing group was 36 days vs 33 days in the twice-daily dosing group.

Treatment-related adverse effects (TRAEs) that were grade 3 or higher were experienced by 69% of those who received poziotinib at a once-daily dose vs 68% of those who received it at a twice-daily dose. The most common TRAEs reported across the dosing groups included rash (30%), stomatitis/mucosal inflammation (19%), diarrhea (14%), paronychia (7%), and pneumonitis (3%).

Grade 4 TRAEs were experienced by 2 patients who received the twice-daily dose of poziotinib; these patients had hypokalemia and hyponatremia.

“[The] safety profile was consistent with the TKI class and tolerability, dose reductions, and interruptions were improved with [twice-daily] dosing,” study author Sophie Sun, MD, FRCPC, of the Division of Medical Oncology at British Columbia Cancer, said in the presentation on the data. “[The] incidence of grade 3 or higher pneumonitis was low.”

In December 2021, a new drug application seeking the approval of poziotinib in patients with previously treated locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations was submitted to the FDA.⁴ The application is supported by data from cohort of ZENITH20, where the agent elicited an ORR of 27.8% (95% CI, 18.9%-38.2%) in this population. Moreover, in this cohort, the median DOR with the agent was 5.1 months (95% CI, 4.2-5.5) and the median PFS was 5.5 months (95% CI, 3.9-5.8).

References

1. Sun S. Efficacy and safety of poziotinib in treatment-naïve HER2 exon 20 insertion mutated non-small cell lung cancer: ZENITH20-4. Presented at: 2022 ESMO Targeted Anticancer Therapies; March 7-8, 2022; virtual. Accessed March 7, 2022. https://bit.ly/34mVmax
2. Spectrum Pharmaceuticals presents positive data for poziotinib in first-line NSCLC patients with HER2 exon 20 insertion mutations. News release. Spectrum Pharmaceuticals; March 7, 2022. Accessed March 7, 2022. https://bit.ly/3Kswe1l
3. 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
4. Spectrum Pharmaceuticals submits new drug application for poziotinib. News release. Spectrum Pharmaceuticals; December 6, 2021. Accessed March 7, 2022. https://bwnews.pr/3pvmkDl