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Zipalertinib in EGFR Exon 20–Mutant Non–Small-Cell Lung Cancer: Drug Development in a Rare but Crowded Setting

*July 2023*

In the article that accompanies this editorial, Piotrowska et al3 attempt to fill that void with results from a phase I/II study of zipalertinib, an irreversible, oral EGFR TKI in patients with recurrent or metastatic NSCLC harboring EGFR ex20ins mutations. In preclinical models, zipalertinib demonstrated selective inhibition of EGFR ex20ins, with minimal activity against wild-type EGFR or human epidermal growth factor receptor 2, making it an attractive agent to maximize therapeutic efficacy while minimizing rash and diarrhea that accompanies inhibition of wild-type EGFR. This study included 73 patients enrolled internationally over a 2-year period and treated across five dose levels. In this heavily pretreated population of patients who had received a median of 2 prior systemic therapies, objective responses were observed across all dose levels, with confirmed partial responses seen in 38.4% of patients and 41% of those treated at the 100 mg oral twice a day dosing.

Does Zipalertinib Have the Potential to Emerge as a Preferred Agent for EGFR ex20ins?

To answer this question, we would have to first compare the activity of zipalertinib against other drugs in this space. Unfortunately, there are no randomized head-to-head clinical trials to answer this question. Although we currently have two FDA-approved drugs, several others are actively being evaluated in clinical trials (Table 1). A comparison of efficacy across trials reveals comparable outcomes, with response rates around 30%-40% and a median PFS in the range of 7-10 months.

In the absence of a clear efficacy advantage, as is the case here, new TKIs can still distinguish themselves by either an improved tolerability profile, intracranial activity, or both. Zipalertinib differentiates itself as a potentially better tolerated drug—in this trial, its use was associated with lower incidence of high-grade, wild-type EGFR-mediated toxicities such as rash and diarrhea, with a low rate of treatment discontinuation. The overall incidence of grade 1-2 diarrhea with zipalertinib appeared to be much lower than observed with other TKIs in this space such as mobocertinib, poziotinib, sunvozertinib, and osimertinib (Table 1). Rash was commonly observed, with an incidence of 80%, although there were no cases of grade 3 rash at the 100 mg or lower dose levels. Although the toxicity profile was reported to be tolerable, we must underscore the clinical relevance of chronic grade 2 toxicity, which can be disabling to patients over a prolonged period. Dose optimization must consider the long-term impact of these lower-grade toxicities in the context of targeted agents that do not live on the same dose response curve as cytotoxic therapy. It is also important to note that most of the patients on this trial received prior immunotherapy, with 30% receiving it as the most recent prior regimen. On the basis of our evolving knowledge around immune-related adverse events with the use of TKIs in the post immunotherapy setting,7 the attribution of adverse events is unclear. Future reports of clinical trials with TKIs after immunotherapy should attempt to report toxicity by previous therapy received as knowledge of these will be crucial to determine the appropriate sequencing strategies to maximize efficacy and minimize toxicity. Read more.