NDA Submission Initiated for Zipalertinib Combo in EGFR Exon 20+ NSCLC

Submission of a new drug application (NDA) for zipalertinib (CLN-081; TAS6417) in combination with platinum-based chemotherapy has been initiated under the FDA's Real-Time Oncology Review (RTOR) program for previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations. Completion of the NDA submission is expected by year-end 2026.¹

The RTOR program allows sponsors to submit clinical data ahead of the complete application, facilitating earlier review of efficacy and safety results. The submission process was initiated after agreement with the FDA.

REZILIENT3 Data Support the Submission

The NDA is based on findings from the phase 3 REZILIENT3 trial (NCT05973773),² which met its primary end point with a statistically significant and clinically meaningful improvement in median progression-free survival (PFS) with zipalertinib plus chemotherapy vs chemotherapy alone.¹ The results were presented during a Presidential Symposium at the International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer (WCLC).

Median PFS by blinded independent central review was 14.5 months with zipalertinib plus platinum-pemetrexed chemotherapy vs 8.5 months with chemotherapy alone (HR, 0.50; 95% CI, 0.34-0.73; P = .00015), representing a 50% reduction in the risk of progression or death.³ The PFS benefit was consistent across subgroups, including patients with brain metastases (HR, 0.38).

The objective response rate was 65.0% with the combination vs 40.3% with chemotherapy alone (P < .0001), and median duration of response was 14.2 months vs 9.9 months, respectively.³ At an interim overall survival (OS) analysis conducted at 30% maturity, the HR for death was 0.72 (95% CI, 0.42-1.23), and follow-up is ongoing.

In a news release, Daniel S.W. Tan, professor, National Cancer Centre Singapore and Duke-NUS Medical School, said the addition of zipalertinib to platinum-based chemotherapy produced a "statistically significant and clinically meaningful 6-month improvement" in PFS, and that the higher response rate supports its potential as a first-line approach

Study Design

REZILIENT3 randomly assigned 279 patients 1:1 to platinum-pemetrexed chemotherapy with zipalertinib at 100 mg twice daily (n = 140) or chemotherapy alone (n = 139). Patients had previously untreated, advanced NSCLC harboring EGFR ex20ins mutations, and those with untreated, asymptomatic brain metastases up to 2 cm were eligible.Patients in the chemotherapy arm could cross over to zipalertinib after disease progression.

A safety lead-in (part A) determined the recommended zipalertinib dose before the randomized portion (part B), with carboplatin or cisplatin given for 4 cycles of 21 days.² Primary end points are PFS by blinded independent central review and the rate and severity of treatment-emergent adverse events (AEs), and OS is a secondary end point.

Safety Profile

The AE profile of the combination was generally consistent with the known safety profiles of the individual agents. Grade 3 or higher AEs occurred in 87.1% of patients receiving zipalertinib plus chemotherapy vs 54.4% of those receiving chemotherapy alone, driven primarily by hematologic events. Grade 3 or higher EGFR-related toxicities occurred only in the combination arm, including rash in 10.7% of patients and diarrhea in 1.4%. No new safety signals were observed.³

Regulatory History and Pipeline Context

Zipalertinib holds FDA breakthrough therapy designation for locally advanced or metastatic EGFR ex20ins NSCLC previously treated with platinum-based chemotherapy.¹ The designation was granted in January 2022 based on data from the phase 1/2a REZILIENT1 trial (NCT04036682).⁴

A separate NDA seeking accelerated approval for zipalertinib monotherapy in that previously treated setting remains under FDA review, with a Prescription Drug User Fee Act target action date of February 27, 2027.¹ The FDA accepted that application in April 2026.⁵

About Zipalertinib

Zipalertinib is an orally available, irreversible, next-generation EGFR inhibitor designed to target activating EGFR mutations and selected for its ability to inhibit EGFR variants with exon 20 insertions.¹ The agent is investigational and has not been approved by any health authority. Taiho Oncology and its parent company, Taiho Pharmaceutical, are developing zipalertinib in collaboration with Cullinan Therapeutics in the US.

EGFR Exon 20 Insertions in NSCLC

Up to 4% of NSCLC cases worldwide harbor EGFR ex20ins mutations.⁶ In the US, approximately 16% of patients with NSCLC have EGFR mutations, with exon 20 insertions accounting for up to 12% of these.⁷

REFERENCES

1. 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 2, 2026. https://tinyurl.com/42r7e5p4

2. REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors). ClinicalTrials.gov. Accessed October 2, 2026. https://clinicaltrials.gov/study/NCT05973773

3. Zipalertinib plus chemotherapy significantly extends progression-free survival in first-line EGFR exon 20 insertion-positive NSCLC. News release. International Association for the Study of Lung Cancer. September 14, 2026. Accessed October 2, 2026. https://tinyurl.com/d9xmhma6

4. REZILIENT1 trial finds zipalertinib meets primary end point in EGFR+ NSCLC. Targeted Oncology. January 29, 2025. Accessed October 2, 2026. https://tinyurl.com/2hkmkxmc

5. FDA accepts NDA for zipalertinib in EGFR exon 20-mutant lung cancer. Targeted Oncology. April 28, 2026. Accessed October 2, 2026. https://tinyurl.com/4mcmyvh3

6. Burnett H, Emich H, Carroll C, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non–small cell lung cancer: a systematic literature review. PLoS One. 2021 Mar 8;16(3):e0247620. doi: 10.1371/journal.pone.0247620.

7. Riess JW, Gandara DR, Frampton GM, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018 Oct;13(10):1560-1568. doi: 10.1016/j.jtho.2018.06.019.