Zipalertinib Combo Meets PFS End Point in First-Line EGFR Exon 20 NSCLC

Zipalertinib (CLN-081/TAS6417) plus platinum-based chemotherapy met the primary end point of progression-free survival (PFS) in a planned interim analysis of the phase 3 REZILIENT3 trial (NCT05973773) in patients with previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to a news release from Taiho Oncology, Taiho Pharmaceutical, and Cullinan Therapeutics.¹

What did the REZILIENT3 interim analysis show?

In the planned interim analysis, zipalertinib plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone. The observed safety profile for the zipalertinib-based arm was manageable. Based on these data, the independent data monitoring committee recommended unblinding the study. The trial will continue to monitor efficacy and safety.

Full results from the REZILIENT3 trial will be submitted for presentation at a future international medical conference. Based on these results and pending discussions with the FDA, the developers plan to pursue US regulatory approval for the combination regimen in the first-line setting.

“The positive topline results from the planned interim analysis of REZILIENT3 further support the potential of zipalertinib to meet the high unmet medical need in patients with NSCLC harboring EGFR exon 20 insertion mutations,” said Harold Keer, MD, PhD, chief medical officer of Taiho Oncology, in the press release.¹ “We look forward to pursuing regulatory approval of zipalertinib in combination with chemotherapy in the first-line treatment setting with the goal of providing a new treatment option for this group of patients.”

What is the REZILIENT3 trial design?

REZILIENT3 is a multicenter, randomized, controlled, open-label global trial that enrolled 285 adults with previously untreated, locally advanced or metastatic nonsquamous NSCLC harboring EGFR exon 20 insertion mutations. Patients were randomly assigned to receive zipalertinib plus platinum-based chemotherapy or chemotherapy alone for four 21-day cycles.² They were permitted to have continued zipalertinib or pemetrexed in the absence of disease progression or any withdrawal criteria met.

The primary end point of the trial is to assess PFS in the zipalertinib plus chemotherapy arm vs the chemotherapy arm. Secondary end points include objective response rate, disease control rate, duration of response, and overall survival.

What is zipalertinib and how does it work?

Zipalertinib is an orally available small molecule designed to target activating mutations in EGFR and was selected for its ability to inhibit EGFR variants with exon 20 insertion mutations. It was designed as a next-generation, irreversible EGFR inhibitor for a genetically defined subset of patients with NSCLC. The agent is investigational and has not been approved by any health authority.

What is zipalertinib's regulatory history in EGFR exon 20 NSCLC?

Previously, a rolling new drug application submission for zipalertinib was completed in February 2026, supported by data from the phase 1/2 REZILIENT1 trial (NCT04036682), for patients with advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who had received prior therapy.³

According to the press release, EGFR exon 20 insertion mutations occur in up to 4% of all NSCLC cases across the world. In the US, approximately 16% of patients with NSCLC harbor EGFR mutations, with exon 20 insertions accounting for up to 12% of these mutations.

“Achieving positive results in this phase 3 trial in the first-line setting represents an important milestone for this program. We will continue to work closely with Taiho Oncology and Cullinan Therapeutics to bring zipalertinib in combination with chemotherapy to patients as soon as possible,” Fabio Benedetti, MD, global chief medical officer at Taiho Pharmaceutical, concluded.¹

References

1. Zipalertinib plus chemotherapy meets primary endpoint of progression-free survival in planned interim analysis of phase 3 REZILIENT3 trial in first-line EGFR exon 20 insertion mutation non-small cell lung cancer. News release. Taiho Oncology, Inc.; Taiho Pharmaceutical Co., Ltd.; and Cullinan Therapeutics, Inc. August 12, 2026. Accessed August 13, 2026. https://tinyurl.com/2svzvc2x
2. REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (REZILIENT3). ClinicalTrials.gov. Updated July 30, 2026. Accessed August 13, 2026. https://tinyurl.com/2a4emw87
3. Cullinan Therapeutics provides corporate update and reports fourth quarter and full year 2025 financial results. News release. Cullinan Therapeutics Inc. March 10, 2026. Accessed August 13, 2026. https://tinyurl.com/4m5wekh8