FDA’s ODAC Votes That Benefits Do Not Outweigh Risks for Poziotinib in HER Exon 20 Ins+ NSCLC


Based on the efficacy, toxicity, dose-optimization, and lack of confirmatory data for poziotinib in HER2 exon 20 insertion-positive non–small cell lung cancer, ODAC has voted that the drug has an unfavorable risk/benefit profile.

The Oncologic Drug Advisory Committee voted 9 to 4 that the current benefits of poziotinib did not outweigh its risks for the treatment of patients with non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations.1

The decision was made on day 1 of the September 22/23 ODAC Meeting by 14 voting members. The vote followed an extensive discussion about the overall risk/benefit of poziotinib 16 mg once daily with consideration of the limited response the drug has shown, short durability of response, high toxicity, inadequate dosage optimization, and the fact the confirmatory clinical trial was delayed.

A new drug application was submitted to the FDA for poziotinib as a potential treatment option for previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations. The proposed indication was supported by results from the phase 2 ZENITH20 clinical trial. The NDA was accepted by the FDA on February 11, 2022, but then raised to the ODAC.

ZENITH20 is a multicenter, multicohort, open-label phase 2 study (NCT03318939) primarily evaluating objective response rate by independent review committee (IRC) in patients with advanced or metastatic NSCLC. The secondary outcomes of the study include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), safety/tolerability, and quality of life.2

Results reported in 2021 were from 90 patients who had received a median of 2 prior lines of therapy. Poziotinib achieved an ORR of 27.8% (95% CI, 18.9%-38.2%) with partial response observed in 25 patients. The DCR achieved with poziotinib was 70.0% (95% CI, 59.4%-79.2%). Seventy-four percent of patients treated with poziotinib in the study had tumor reduction at a median shrinkage of 22%.

The agent showed a 5.1-month (95% CI, 4.2 to 5.5) median duration of response, and clinical benefit with poziotinib in the study was irrespective of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations.

The median PFS observed with the agent was 5.5 months (95% CI, 3.9-5.8) with a 5.1-month median DOR.

Safety findings from ZENITH20 showed that the grade 3 or higher treatment-related adverse events (TRAEs) observed were rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). The majority of patients in the study (76.7%) required dose reduction. Due to TRAEs, 13.3% of patients Permanently discontinued poziotinib.

“I think the bottom line from this study is that it clearly does have substantial activity in the population was studied in when you consider the alternatives that are available and the lack of oral medications that are approved for these patients. I think it's unquestionably from my clinical perspective, it's a clinically meaningful activity. We have some patients that have been on the drug for years and are doing quite well on it and are very grateful that they had this oral drug available. I think this could potentially provide an important option for patients and for healthcare providers for this important unmet need. And it's worth pointing out that if this is approved, well her two mutations occur not just in lung cancer but in more than 20 Different malignancies. One would love to see then that if this is approved If we could build on those studies and look at the activity in those other tumor types as well,” said John Heymach, MD, PhD, a medical oncologist, and chair of the Department of Thoracic-Head & Neck Med Onc, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.

Despite the results from ZENITH20, the FDA holds that better therapies are now available for patients with HER2 exon 20 insertion mutation-positive NSCLC.

Review of the Data for Poziotinib

“Poziotinib, as demonstrated by the limited response rate with poor durability observed in the primary efficacy population is not improved over available therapies, explained Nicole Drezner, MD, clinical team lead in the Division of Oncology 2 at the FDA, during the FDA presentation.

“For patients with non­–small cell lung cancer, who have received both prior platinum-based chemotherapy and an immune checkpoint inhibitor, available therapy includes docetaxel in combination with ramucirumab [Cyramza] with a benchmark or are of 23%. Anti-PD-L1 therapies are considered available therapy that is not previously received and are associated with lower ORRs with more substantial durability than what is observed with chemotherapy. Trastuzumab dereuxtecan [Enhertu], a HER2- targeting antibody drug conjugate received accelerated approval last month for the treatment of patients with HER2-mutated non-small cell lung cancer as an indication which would include the patients who comprise the primary efficacy population in this application. The drug demonstrated a response rate of 58%, with a duration of response is 8.7 months, both considerably greater than what was observed with poziotinib, Drezner added.

Comparing the data from DESTINY-Lung02 (NCT04644237) which supported the accelerated approval of trastuzumab dereuxtecan to the ZENITH20 data3, Dezner noted that the ORR observed with poziotinib was low with poor durability. Further, the safety profile of poziotinib was brought into question.

“The applicant states that the safety profile of poziotinib is similar to other drugs in class. However, in our assessment, poziotinib is more toxic than other tyrosine kinase inhibitors [TKIs] for lung cancer, especially at the 16-milligram dose. Eight of 10 patients experienced grades 3 to 4 adverse events. Similarly, over 80% of patients require a drug interruption and over 50% of patients needed a dose reduction,” said Justin N. Malinou, MD, clinical reviewer, Division of Oncology 2 Thoracic and Head and Neck Oncology Office of Oncologic Diseases at the FDA, during the FDA presentation.

Regarding dose optimization, the FDA highlighted that dose reductions occurred within the first months of treatment. Beyond the 24-week mark, most patients were receiving a 12 mg once daily dose of poziotinib.

“In FDA review of the applicant’s clinical pharmacology package, we identified significant areas of concern regarding the lack of dosage optimization. Given that the applicant has provided insufficient data over the clinically relevant dose range, we cannot determine if alternative dosages may provide acceptable efficacy and an improved toxicity profile. Therefore, we continue to assert that the applicant failed to adequately justify their proposed dosage of 16 milligrams once daily,” said Jeanne Fourie Zirkelbach, PhD, team lead, Clinical Pharmacology Division of Cancer Pharmacology 2 Office of Clinical Pharmacology at the FDA, during the FDA presentation.

Finally, the FDA originally recommended that a confirmatory trial for poziotinib start recruitment in 2020. To date, no patients have been enrolled in the confirmatory trial. The FDA noted that it would be 4 years before results from the confirmatory trial would be available.

ODAC's Discussion

With Spectrum Pharmaceuticals alluding to their success and progress with poziotinib and the FDA asserting that they are unhappy with the development of poziotinib, ODAC members carried out an in-depth discussion.

A point was raised by Spectrum Pharmaceuticals was that poziotinib showed similar dose reduction and discontinuations as other approve TKIs like mobocertinib (Exkivity) and neratinib (Nerlynx). Moreover, poziotinib had the same ORR as agents like mobocertinib. However, the FDA responded that the duration of response with mobocertinib greatly exceeded poziotinib.

The applicant also mentioned that multiple sites for the confirmatory trials have been opened and will started enrolled patients in the next few weeks. But the FDA pointed out that only 3 of the sites were in the Unites States (US) and that failure to accrue patients at US sites would results in findings that are not reflective a US population.

During the open public hearing,7 out of 8 presentations were from patients who testified that poziotinib has either helped them or a family member. The patients did mentioned toxicities but noted that they were manageable.

Joshua K. Sabari, MD, a medical oncologist and assistant professor, Department of Medicine at NYU Grossman School of Medicine, as medical director, Kimmel Pavilion 12, at NYU Langone Health stated that although trastuzumab deruxtecan is now standard for HER2 exon 20 insertion mutation-positive NSCLC, some patients are not eligible to receive it. Therefore, poziotinib may be another option, according to Sabari.

ODAC member opinions varied during the discussion. Some oncologists noted that the risk-benefit profile of poziotinib was acceptable considering that toxicities related to TKIs can be managed in the clinic. One member noted that the short duration of response observed with poziotinib in ZENITH20 could be due to toxicity.

Importantly, poziotinib is an oral agent, which means patients can take their medication in an outpatient setting. One ODAC member raised the point that if toxicities associated with poziotinib required patients to come back to the clinic, it impacts. the favorability of the risk-benefit profile.


1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. September 22, 2022. Accessed September 22, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-22-23-2022-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09222022

2. Le X, Cornelissen R, Garassino 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

3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA website. August 11, 2022. Accessed September 22, 2022. https://bit.ly/3LyWDMK

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