A study of zipalertinib monotherapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations and who have received prior therapy has met its primary endpoint of overall response rate (ORR) for Phase 2b with a consistent safety profile, according to a January 28, statement from Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics.1
Preliminary results of this Phase 1/2 clinical trial, REZILIENT 1 (NCT04036682), have been published in the Journal of Clinical Oncology.2
The study’s lead author Tan Z. Piotrowska, MD, MHS, said zipalertinib demonstrated encouraging antitumor activity and may represent an alternative treatment option for heavily pretreated patients with EGFR exon 20 insertion-mutant NSCLC. However, Dr. Piotrowska also cautioned that the study was limited by the modest number of patients treated, short duration of follow-up, and lack of uniform assessment of CNS disease, which limits conclusions about CNS activity. Additionally, said the absence of required central exon 20 insertion confirmations and the limited number of patients with far-loop and helical mutations merits studies with larger cohorts to more robustly assess zipalertinib’s activity in these subgroups, Dr. Piotrowska said.
The developing companies said full results from REZILIENT 1 will be submitted for presentation at an upcoming international medical conference. The companies also said in the statement that they plan to submit for US regulatory approval in the second half of 2025, pending discussions with the US Food and Drug Administration (FDA).
Zipalertinib was granted Breakthrough Therapy Designation by the FDA in 2022 after demonstrating promising efficacy and favorable safety profile in a Phase 1/2a study.3
According to trial data presented during the 2024 European Society for Medical Oncology Congress, treatment with zipalertinib demonstrated promising efficacy in patients with NSCLC harboring EGFR exon 20 insertion mutations who progressed on or after amivantamab, with an objective response rate (ORR) of 40% and a median progression-free survival (PFS) of 9.7 months.4
The EGFR gene was among the first epidermal growth factor receptor mutations to be identified as oncogenic drivers in non-small cell lung cancer, but the EGFR exon 20 insertion mutations have been associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis.5>
References
- 1.. News release. Taiho Pharmaceutical Co., Ltd., Taiho Oncology, Inc., and Cullinan Therapeutics, Inc. January 28, 2025.
- 2. Piotrowska Z, Tan DS, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions. Journal of Clinical Oncology.
- 3. Cullinan Oncology, Inc. January 4, 2022.
- 4. Passaro A, Yu HA, Nguyen D, et al. Safety and antitumor activity of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior amivantamab. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract 1254MO.
- 5. Vyse, S., Huang, P.H. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019).
