Promising New Data for Zipalertinib in EGFR ex20ins NSCLC

Zipalertinib (CLN-081) continues to show clinically meaningful efficacy with a manageable safety profile in patients with EGFR exon 20 insertion (ex20ins)–mutated non–small cell lung cancer (NSCLC), according to data from the phase 2b REZILIENT1 study (NCT04036682) presented at the IASLC World Conference on Lung Cancer 2025.^1,2

The confirmed objective response rate (ORR) was 27.4% with a median duration of response (DOR) of 8.5 months and a disease control rate (DCR) of 84.5%. In patients who previously received amivantamab (Rybrevant; n = 54), the ORR was 31.5%, the median DOR was 9.5 months, and the DCR was 87.0%. In those who previously received amivantamab and another ex20in-targeted therapy (n = 30), the ORR was 20.0%, the median DOR was 8.3 months, and the DCR was 80.0%. In patients with brain metastases who received only prior amivantamab, the systemic ORR was 29%.

The median progression-free survival (PFS) in the overall population was 7.3 months (95% CI, 5.3-9.7), 7.6 months (range, 5.4-9.8) in the amivantamab-alone cohort, and 5.2 months (range, 3.2-11.5) in the amivantamab plus another ex20in-targeted therapy group. The OS rates at 12 months were 59.8%, 66.1%, and 51.1%, respectively.

The findings showed that 100 mg of zipalertinib twice daily had a manageable safety profile and did not elicit any new safety signals. The most common treatment-emergent adverse events (TEAEs) were paronychia (41.7%), anemia (38.1%), rash (34.5%), nausea (28.6%), diarrhea (22.6%), dry skin (21.4%), dermatitis acneiform (21.4%), and dyspnea (20.2%). The most common grade 3 or higher TEAEs were anemia (15.5%), pneumonia (10.7%), dyspnea (6.0%), rash (3.6%), diarrhea (2.4%), and stomatitis (2.4%).

“We’re pleased to share longer-term follow-up data from the REZILIENT1 study of zipalertinib for patients with NSCLC harboring EGFR ex20ins mutations who have been previously treated with amivantamab,” Zofia Piotrowska, MD, associate professor of medicine, Harvard Medical School, and lung cancer clinical oncologist at the Mass General Cancer Center, said in a press release.¹ “Despite recent treatment advancements, a significant medical need exists for this patient population, underscoring the importance of these data.”

Mature efficacy data with at least 9 months of follow-up for the entire study population will be presented at a later date.

In an interview with Targeted Oncology, Helena Yu, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the treatment gaps that zipalertinib fills, including its potent central nervous system (CNS) penetration, highlighted by the similar response rates in patients with and without brain metastases.

Yu also highlighted that zipalertinib’s safety profile appears more tolerable than other EGFR- and MET-targeted agents like amivantamab.

"Amivantamab, while being very effective, has significant EGFR- and MET-directed [adverse events]. They have significant rates of rash and paronychia. I think the MET-targeting toxicities, including the edema, really are limiting for some patients,” Yu said in the interview.

Zipalertinib is also being evaluated in the phase 2b REZILIENT2 study (NCT05967689) assessing the agent in advanced NSCLC harboring ex20in and other uncommon mutations.³ The phase 3 REZILIENT3 study (NCT05973773) is investigating the agent in combination with standard first-line platinum-based chemotherapy vs chemotherapy alone in patients with locally advanced or metastatic NSCLC with EGFR ex20in mutations.⁴

REFERENCES:

1. Taiho Oncology and Cullinan Therapeutics present data on zipalertinib at the IASLC 2025 World Conference on Lung Cancer. News release. Taiho Oncology. September 9, 2025. Accessed September 12, 2025. https://tinyurl.com/4tptzzb3

2. Piotrowska Z, Nguyen D, Lee VHF, et al. Zipalertinib in NSCLC patients (pts) with EGFR exon 20 insertion (ex20ins) mutations who received prior amivantamab. Presented at: IASLC World Conference on Lung Cancer 2025; September 5-9, 2025; Barcelona, Spain. Abstract MA08.02.

3. A study of zipalertinib in patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertions or other uncommon mutation. (REZILIENT2). ClinicalTrials.gov. Updated August 15, 2025. Accessed September 12, 2025. https://clinicaltrials.gov/study/NCT05967689

4. REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (REZILIENT3). ClinicalTrials.gov. Updated August 1, 2025. Accessed September 12, 2025. https://clinicaltrials.gov/study/NCT05973773