ODAC Votes Against Poziotinib for HER2 Exon 20 Insertion–Mutated NSCLC

In a 9 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee voted that the benefits of poziotinib do not outweigh its risks for the treatment of patients with HER2 exon 20 insertion–mutated non–small cell lung cancer.

In a 9 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted that the benefits of poziotinib do not outweigh its risks for the treatment of patients with HER2 exon 20 insertion–mutated non–small cell lung cancer (NSCLC).1

In explaining his decision, mirroring many of those who also voted no, Scott Waldman, MD, PhD, of Thomas Jefferson University, said, “Clearly there’s a clinical unmet need for the drug, and the drug has activity, but I don’t know that it has a meaningful improvement over other drugs that, in the real world, are available to patients right now. [The agent] has a high level of toxicities associated with it, [although] yes, they can be managed. That’s complicated by the fact that the dose of the drug has not been adequately optimized, and that uncertainty is going to be carried through into the potential confirmatory trial, which has an end point that is far away. [Moreover,] these patients are at risk for toxicity and [the trial] isn’t studying the same dose that’s seeking approval right now.”

On February 14, 2022, the FDA accepted for review a new drug application (NDA) seeking the approval of poziotinib in previously treated patients with locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations.2

The NDA is based on findings from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939), in which poziotinib, given at a once-daily dose of 16 mg, led to an objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%) in this population (n = 90).3 The median duration of response (DOR) was 5.1 months (95% CI, 4.2-5.5), and the median progression-free survival (PFS) was 5.5 months (95% CI, 3.9-5.8).

However, in the first of a 2-day public review beginning with the proposed indication for poziotinib, the FDA expressed several concerns regarding the agent’s potential approval. Specifically, the regulatory agency reviewed efficacy results that failed to show improvements over current therapy, a high rate of toxicity, inadequate dosage optimization, and delayed confirmation of benefit with the TKI.

In their rebuttal, the sponsor stated that the confirmatory phase 3 PINNACLE trial (NCT05378763) is ongoing. However, committee members emphasized concern that the availability of other agents, including docetaxel with or without ramucirumab (Cyramza), pembrolizumab (Keytruda)/nivolumab (Opdivo), and off-label fam-trastuzumab deruxtecan-nxki (Enhertu) could negatively affect enrollment. The sponsor acknowledged that the study has yet to enroll any patients, and primary results are not expected until 2026.

In explaining his decision, Anish Thomas, MD, of the National Cancer Institute, who voted ‘no’ said, “There is an unmet need for a subgroup that was first identified probably more than a decade ago now. The drug poziotinib seems to be active, and there are patients who benefit from [it]. A big advantage seems to be that it is an oral administration over available therapies, but it is somewhat offset by toxicities, as well as uncertainties around the dose itself.”

“[Although] I recognize that this is a rare patient population, and that the dose and schedule is not always straightforward, I feel like it needs to be looked at and it has not been so far in its extended development course,” Thomas added. “I also feel that given the low therapeutic index, better predictors of response to [poziotinib] should be sought.”

Regarding safety, all patients experienced adverse effects (AEs); 81% were treatment related and grade 3 or greater in severity (grade ≥3 rash, 49%; grade ≥3 diarrhea, 26%). Fatal AEs occurred in 10% of patients, and drug interruption and dose reduction occurred in 87% and 77% of patients, respectively.

Members in support of the approval argued that clinicians have experience and are comfortable managing the AEs associated with TKIs.

Ravi Madan, MD, of the NCI, concluded by saying, “I voted no. I view the poziotinib data as very compelling preliminary evidence that I look to find confirmation [of] in future trials. We’ve discussed a lot of interesting hypotheses today that this agent may be effective in patients who are not able to tolerate or not able to receive the other HER2-directed agent or may have better central nervous system penetrance. I look for confirmation of those hypotheses in the upcoming trials. [Although] we should always respect the ability of the oncologist in the clinic to manage toxicities, we must set the providers, but more importantly the patients, up for success as best as we can by getting them the best data on what doses are best tolerated.”


  1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. https://www.youtube.com/watch?v=SON2biqVX_8.
  2. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News release. Spectrum Pharmaceuticals; February 11, 2022. Accessed September 22, 2022. https://bit.ly/3gGReox
  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