Investigational Oral EGFR Inhibitor Shows Promising Efficacy in Pretreated NSCLC

An investigational oral targeted therapy, zipalertinib (CLN-081), demonstrated meaningful tumor responses and a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) containing epidermal growth factor receptor (EGFR) exon 20 insertion mutations, according to updated results from the REZILIENT1 clinical trial. The findings were presented by Helena A. Yu, M.D., of Memorial Sloan Kettering Cancer Center in New York, at the 2025 meeting of the American Society of Clinical Oncology and published in the Journal of Clinical Oncology on June 1.

Mutations in the EGFR gene are a key biomarker in lung cancer, driving excessive cell growth. EGFR mutations occur in 10–15% of NSCLC cases in the United States. Although the most frequent mutations generally respond well to existing EGFR inhibitors such as Tagrisso (osimertinib), exon 20 insertion mutations are less responsive to these treatments. A literature review published in 2022 in Targeted Oncology that that prevalence of exon 20 insertion mutations in NSCLC at any stage ranged from 0.3% to 2.2% in NSCLC overall and from 2.5% to 23.1% in EGFR-positive NSCLC

For this more challenging subset, intravenous Rybrevant (amivantamab) was FDA-approved in 2021 and has been used along with chemotherapy, but options remain limited after progression. Zipalertinib is a next-generation EGFR inhibitor being developed by Cullinan Therapeutics and Taiho Oncology to address this treatment gap and provide the convenience of an oral option.

The REZILIENT1 phase 1/2 trial enrolled 244 patients who had disease progression after platinum-based chemotherapy; some had also received prior targeted therapy, including Rybrevant. Participants were treated with zipalertinib 100 milligrams twice daily. At a median follow-up of eight months, the confirmed objective response rate (ORR) among all participants was 35.2%, with a median duration of response of 8.8 months.

ORR was defined as the percentage of patients whose tumors got smaller or disappeared completely, based on RECIST v 1.1 criteria, a standardized system used to objectively assess tumor response to treatment in solid tumors, including lung cancer.

Notably, patients with no prior targeted therapy had an ORR of 40%, while those previously treated with Rybrevant alone achieved a response rate of 30%. For patients who had received Rybrevant plus other exon 20 insertion-directed treatments, the ORR was 14.3%. Among the 68 patients whose cancer had already spread to the brain, nearly 31% saw their tumors shrink with zipalertinib. The most common side effects included anemia, lung inflammation, skin reactions, diarrhea, elevated liver enzymes and low platelet counts.

“Zipalertinib appears to help many patients with this type of lung cancer, even when other treatments have stopped working,” Yu said in a news release from Memorial Sloan Kettering. “Additionally, the side effects were mostly very manageable. This medicine could be an important new option for patients.”

To further assess survival outcomes and long-term safety, the REZILIENT1 phase 3 clinical trial is ongoing. The trial is actively recruiting patients with previously treated advanced NSCLC harboring EGFR exon 20 insertion mutations.

Zipalertinib received breakthrough therapy designation from the FDA in January 2022. The developers are likely to submit for accelerated approval in the second half of 2025.