May 21, 2024

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New drug Poziotinib for HER2+20ins non-small cell lung cancer submitted to FDA

New drug Poziotinib for HER2+20ins non-small cell lung cancer submitted to FDA


New drug Poziotinib for HER2+20ins non-small cell lung cancer submitted to FDA.

As a potential treatment option for previously treated locally advanced or metastatic non-small cell lung cancer patients with HER2 exon 20 insertion mutations.

Spectrum Pharmaceuticals announced on December 6 that it had submitted a new drug application (NDA) for Pozitinib to the U.S. Food and Drug Administration (FDA) for the previously treated HER2 exon 20 insertion Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutations.

The drug has obtained fast-track certification, and there is currently no FDA specifically approved treatment for this indication.


The NDA submission is based on the positive results of cohort 2 of the Phase 2 ZENITH20 trial (NCT03318939), which evaluated the safety and effectiveness of bozitinib.

The results of the study showed that the objective response rate (ORR) of the drug in this patient population was 27.8% (95% CI, 18.9%-38.2%). In addition, the median duration of response (DOR) of 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 multi-center, multi-period, open-label, phase 2 ZENITH20 trial consisted of 7 NSCLC patient cohorts.

Cohort 1 included patients with non-small cell lung cancer who had previously been treated with EGFR exon 20 insertion mutants, and cohort 2 included patients with HER2 exon 20 mutations.

Cohort 3 included patients with untreated NSCLC and EGFR exon 20 mutations, and cohort 4 still included patients with first-line NSCLC and HER2 exon 20 mutations.


Cohorts 5 to 7 recruited the following patients:

  • Patients with EGFR or HER2 exon 20 insertion mutations who have received treatment or have not received treatment;
  • NSCLC and standard EGFR mutation patients who have progressed in the first-line osimertinib (Tagrisso) treatment and have additional EGFR mutations;
  • NSCLC patients with multiple uncommon mutations in EGFR or HER2 exons 18 to 21 or extracellular or transmembrane domains.

To be eligible for cohort 2, patients must be at least 18 years of age, have previously received treatment for locally advanced or metastatic NSCLC, and have a recorded HER2 exon 20 insertion mutation.

They also need to have measurable diseases. Patients with known brain metastases can be treated if they are stable, asymptomatic and do not require high or increased doses of corticosteroids.


Patients enrolled in group 2 took orally Pozitinib at a dose of 16 mg per day during each 28-day treatment cycle in an outpatient setting for up to 24 months.

If patients experience an adverse reaction (AE), allow them to reduce the dose in 2 mg increments. A dose interruption of up to 28 days is allowed.


The primary endpoint of the trial is ORR, and key secondary endpoints include disease control rate (DCR), DOR and PFS, and safety and tolerability. The researchers also assessed the quality of life.


Between October 2017 and March 2021, a total of 90 patients participated in the trial.

The median age of these patients was 60 years (range, 25-86 years), 64.4% were female, 77.8% were white, 65.6% had never smoked, and 57.8% had an ECOG performance status of 1.

In addition, 96.7% of histology was adenocarcinoma, and 3.3% of histology was squamous cell carcinoma. It is worth noting that 25.6% of patients had stable central nervous system (CNS) metastasis when they entered the study.


In addition, the median of previous treatments was 2 (range, 1-6), 30.0% of patients had received 1 previous treatment, 31.1% had received 2 previous treatments, and 38.9% had received 3 or more previous treatments.

In addition, 96.7% had received platinum treatment before, 67.8% had received checkpoint inhibitor treatment before, 27.8% had received anti-HER2 drug treatment before, and 65.6% had received chemotherapy and checkpoint inhibitor treatment before.


Of the 90 patients receiving treatment, 25 achieved a partial response and 0 achieved a complete response.

Among 25 respondents, the median time to response was 32 days (range, 23-183). The DCR of Pozitinib in this cohort was 70.0% (95% CI, 59.4%-79.2%). In the evaluable population of 74 patients, the ORR of the drug was 35.1% (95% CI, 24.4%-47.1%), and the DCR was 82.4% (95% CI, 71.8%-90.3%).

Most patients have experienced tumor shrinkage. In addition, 37.8% (95% CI, 25.5%-50.0%) of patients had no disease progression at 6 months.


Additional analysis shows that the drug also provides benefits in different populations.

Among patients who had received 3 or more previous treatment regimens, the ORR of Pozitinib was 37.1% (95% CI, 21.5%-55.1%); in patients who received 2 or 1 courses, these rates They were 21.4% (95% CI, 8.3%-41.0%) and 22.2% (95% CI, 8.6%-42.3%), respectively.


In addition, 26.2% of patients who had undergone checkpoint suppression responded to bozitinib.

Twenty-five of these patients had previously received anti-HER2 drugs containing one or more antibodies or antibody-drug conjugates, and had all received chemotherapy before.

Three patients had previously received trastuzumab (Herceptin) and afatinib (Gilotrif); one patient received trastuzumab and neratinib (Nerlynx).


Among the 14 patients with stable CNS metastasis at the time of enrollment, the ORR of Pozitinib was 28.6%.

The median PFS of this subgroup of patients was 7.4 months. It is worth noting that after treatment with Poziotinib, one patient with two baseline brain lesions found in two or more MRI scans did not develop these two lesions. Another 9 of these patients experienced CNS stable disease.


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


The most common toxicities reported by Pozitinib included skin rash (91.1%), diarrhea (82.2%) and stomatitis (68.9%).

The most common grade 3 or higher toxicities included skin rash (48.9%), diarrhea (25.6%) and stomatitis (24.4%). Serious treatment-related AEs (TRAE) were rash (3.3%), weakness (2.2%), diarrhea (2.2%), dehydration (2.2%) and stomatitis (2.2%).


In addition, 4.4% of patients using Pozitinib developed grade 4 TRAE, including stomatitis, dyspnea, hypomagnesemia, hypocalcemia, and recurrence of pancreatitis. One patient reported grade 5 pneumonia.


Previously, in March 2021, according to cohort 3 of the ZENITH20 trial, the FDA granted fast track designation of Pozitinib for previously treated patients with HER2 exon 20 mutations. 

The results showed that the ORR of Pozitinib was 27.8% (95% CI, 18.4%-39.1%) and the DCR of newly-treated patients with metastatic NSCLC with EGFR exon 20 mutation was 86.1%.


When administered at a dose of 8 mg twice a day in cohort 5 of the trial, the ORR of Pozitinib was 31.6% (n=6/19). When administered at a daily dose of 16 mg or 12 mg, the ORR was 15.8% (n=3/19) and 15.8% (n=3/19).

When administered at a dose of 6 mg twice a day, the ORR was 5.3% (n=1/19). In addition, data from trial cohort 4 showed that the drug caused an ORR in this population of 43.8% (95% CI, 29.5%-58.8%).




Reference source: FDAApprovalSoughtforPoziotinibinHER2Exon20–MutatedNSCLC


(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.