Zipalertinib May Introduce Another Option to EGFR Exon 20+ NSCLC

In the phase 3 REZILIENT3 trial (NCT05973773), adding zipalertinib (CLN-081) to first-line platinum-based chemotherapy produced a statistically significant improvement in progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated, EGFR exon 20 insertion-mutant non-small cell lung cancer (NSCLC). The median PFS was 14.5 months (95% CI, 12.9-21.4) vs 8.5 months (95% CI, 7.0-10.9) in each respective arm (HR, 0.50; 95% CI, 0.34-0.73; P = .00015).¹ The objective response rate was also higher with the combination (65.0% vs 40.3%; P < .0001), along with an improved median duration of response (14.2 vs 9.9 months). These results built on earlier phase 1/2 data from the REZILIENT1 trial (NCT04036682) evaluating single-agent zipalertinib in patients previously treated with platinum-based chemotherapy.²

CancerNetwork® spoke with Helena A. Yu, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center and a REZILIENT3 study investigator, about the background that led to testing zipalertinib plus chemotherapy in the first-line setting and her key takeaways from the trial. These results were presented at the IASLC 2026 World Conference on Lung Cancer (WCLC). Based on these findings, developers initiated a new drug application submission to the FDA seeking approval for frontline zipalertinib plus chemotherapy for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations.³

Transcript:

This study focused on EGFR exon 20-positive lung cancer, which is a small subset of [NSCLC]. This is a type of lung cancer that occurs in, or is enriched in, [patients who do not smoke] and younger patients who develop lung cancer, and it’s not related to prior smoking.

The phase 1/2 study looked at zipalertinib in the later-line setting, after initial platinum-based chemotherapy. Zipalertinib is an oral exon 20 tyrosine kinase inhibitor, a pill that blocks exon 20 of EGFR, and it looked promising in that later-line setting: the overall response rate after chemotherapy was 40%, and median PFS was 9.5 months. When something in oncology looks good in the second-line setting, we like to try to move it forward, especially targeted therapies. That initial study set up the background for looking at zipalertinib with chemotherapy in the first-line setting.

More options are always better for our patients. Right now, the only available drug for [EGFR exon 20–positive disease] is amivantamab-vmjw [Rybrevant]. Sunvozertinib [Zegfrovy] has FDA approval, but it doesn’t have access in the United States right now. I think having zipalertinib as an option, either as monotherapy in the later-line setting or with chemotherapy in the first-line setting, just gives our patients more options for treatment.

I think once we have multiple available options, then we’re going to need to learn more about sequencing. We have data already that zipalertinib can be effective after amivantamab, and we would expect the converse to be true, where we could start with zipalertinib and amivantamab would be effective after, since they’re different types of EGFR exon 20 inhibitors, an antibody vs a TKI, but those are things we need to learn.

Then, I always like to highlight that EGFR-mutant lung cancers are really enriched for the development of brain metastases. More than half of these patients will develop a brain metastasis sometime during their disease course. I think that will be a helpful way to potentially distinguish between these drugs too, because if one of these drugs is better in terms of CNS penetration, that might be something that would lead us to choose that drug first over the others.

References

1. Tan DSW, Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st line mNSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). Abstract presented at: International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.
2. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in patients with epidermal growth factor receptor exon 20 insertion-positive non–small cell lung cancer previously treated with platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(21):2387-2397. doi:10.1200/JCO-25-00763
3. New drug application submission initiated for zipalertinib plus chemotherapy in first-line EGFR exon 20 insertion mutation NSCLC for review under FDA Real-Time Oncology Review program. News release. Cullinan Therapeutics Inc. October 1, 2026. Accessed October 20, 2026. https://tinyurl.com/3hryejjd