Twice Daily Poziotinib Helps Lesson Toxicity in EGFR or HER2 exon 20-Positive NSCLC

Xiuning Le, MD, PhD

Patients with EGFR and HER2 exon 20 mutant non–small cell lung cancer (NSCLC) are populations of unmet medical need, as no FDA-approved therapies exist to target their unique tumors. 

Poziotinib is a tyrosine kinase inhibitor (TKI) that targets EGFR and HER2 exon 20 mutations. Poziotinib was granted a fast tract designation by the FDA in March of 2021. The ongoing prospective multi-cohort ZENITH20 study (NCT03318939) aims to determine if the agent could be an effective treatment for NSCLC with EGFR or HER2 exon 20 insertion mutations.

Results from a cohort the study were previously reported during the ESMO Virtual Congress 2020. The cohort was comprised of previously-treated patients with advanced NSCLC and HER2 exon 20 insertion mutations. The patients received poziotinib 16 mg orally once daily and were evaluated for the primary end point of objective response rate (ORR). The secondary end points were disease control rate, duration of response, progression-free survival, and safety.

According to a presentation given by Mark Socinski, MD, executive director of Thoracic Cancer, and medical oncologist at Advent Health Cancer Institute, poziotinib achieved an ORR of 35.1% (95% CI, 24.4-47.1%) in 74 evaluable patients and an ORR of 27.8% (95% CI, 18.9-38.2%) in the overall population of 90 patients. The median DOR overall was 5.1 months (range, 1-12.3+ months), and 3 patients were continuing treatment at the time of data cutoff. The DCR observed in the cohort was 70%. Poziotinib also showed a median PFS of 5.5 months. The trial has already met its primary end point.

ZENITH20 had an aim to enroll approximately 603 patients across 7 cohorts. In each cohort, patients will receive poziotinib at different dose levels. Assessment for cohorts 1 through 5 have been completed, and in the remaining 2 cohorts, patients with acquired EGFR mutation who progressed while on treatment with first-line osimertinib (Tagrisso), and those with EGFR or HER2 activating mutations will be evaluated on treatment with poziotinib.

In an interview with Targeted Oncology, Xiuning Le, MD, PhD, a medical oncologist at the University of Texas MD Anderson Cancer Center, discuss the findings from cohort 5 of the ZENITH20 study including the strategy of splitting the dose in half to reduce adverse events (AEs) associated with poziotinib.

TARGETED ONCOLOGY: Can you give some background on this study and provide the rationale for using poziotinib in these patients?

LE: Poziotinib is a small molecule inhibitor of the ErbB family, including EGFR and HER2. Poziotinib is particularly potent for exon 20 insertions for which we don't actually have any FDA approved drug, which is a big medical need for lung cancer patients.

During this year's AACR, we were particularly focused on the cohort 5 patient population. Those patients from the molecular perspective, they're similar to cohort 1-4. In cohort 5, we allowed patients with EGFR exon 20, and HER2 exon 20 advanced metastatic lung cancer.

The unique part of the design is the dosing of poziotinib itself. From prior cohorts, we know poziotinib is an active drug. We also learned that poziotinib has intrinsic drug side effects. The most prominent ones are the rash and diarrhea which impacts patient quality of life. So, this cohort 5 was designed to evaluate which dosing will results in fewers AEs while preserving or even enhancing treatment efficacy, so that patient quality of life can be improved. That's why the dosing regimen was split. Instead of going for 16 milligrams every day, going to 8 milligrams twice a day, so that the totality of the dose is the same, but the toxicity can be decreased that way.

What were the results from this analysis?

We presented the preliminary results from cohort 5, comparing the same dose level, but comparing the daily dosing versus the twice a day dosing or BID. The first part of the presentation, we focus on the toxicities like rash and diarrhea. What we have shown here is in the initial 20 to 30 patients per group, we find that BID dosing decreases the high-grade rash and diarrhea by almost 50%. At each of the dose levels, if you compare the daily to the BID dosing.

For the second part of the presentation, we were also able to show very preliminary data on the efficacy. We can only look at the first 19 patients, that's the predefined evaluation point. What we have seen here is that giving 8 milligrams twice a day enhances the efficacy compared to 16 milligrams daily. It’s very early data, but it’s encouraging.

Looking forward to maybe a phase 3 trial, what end points are you going to be exploring in terms of efficacy for this study?

I think going forward, we're going to focus on 8 milligrams of BID because it is more tolerable and potentially enhances efficacy. We're still going to be looking at both response rates and also duration of response, and PFS.

As poziotinib moves further along for the treatment of these patients, how do you see it potentially changing the landscape?

As of now in EGFR exon 20 and HER2 exon 20 advanced lung cancer, we still don't have an FDA-approved drug. This is really a great need. We need to target this oncogene because it's an established oncogenic driver, no different from the other drivers. We have to design and utilize all the medical tools we have. We're not excluding chemotherapy or immunotherapy, but small molecule TKIs should be an important part of the treatment. From what the data from poziotinib have shown in the HER2 exon 20-positive population, the study has met the initial primary end point. Currently, the FDA is waiting to consider it. So, we're hoping to bring more options to the patients from the oncologist standpoint.

What other biomarker-driven lung cancer research are you working on? 

We presented another EGFR-positive lung cancer poster during AACR. It's about a CD73 inhibitor with osimertinib (Tagrisso). There is a novel agent of a CD73 antibody in combination with osimertinib. We found the combination to be safe and that in patients who benefit from this combination, the duration can be quite long. This is very interesting because a CD73 antibody is an immunomodulating agent. Lately, in one of our own studies, we've shown that EGFR-positive tumors, particularly upregulate CD73, to create an immune barrier. So, to me this particular abstract is interesting showing the safety and preliminary clinical efficacy. I'm excited about those particular agents being reported as well.

^References:

^{Socinski MA, Cornelissen R, Garassino MC, et al. LBA60 - ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Ann Oncol. 2020;31 (suppl_4): S1142-S1215. doi: 10.1016/annonc/annonc325}