NDA Submission Completed for Zipalertinib Plus Chemotherapy in Frontline EGFR Exon 20 Insertion–Positive NSCLC

Taiho Oncology has completed a new drug application (NDA) submission to the FDA for zipalertinib in combination with platinum-based chemotherapy for the treatment of patients with previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations.¹ The application was submitted under the FDA's Real-Time Oncology Review program and will undergo a standard review period, with a Prescription Drug User Fee Act target action date to be assigned if the FDA accepts the filing.

The application is based on findings from the phase 3 REZILIENT3 trial (NCT05973773), which met its primary end point of progression-free survival (PFS) at a prespecified interim analysis. At a data cutoff of May 29, 2026, the median PFS by blinded independent central review (BICR) was 14.5 months (95% CI, 12.9-21.4) with zipalertinib plus chemotherapy (n = 140) vs 8.5 months (95% CI, 7.0-10.9) with chemotherapy alone (n = 139; HR, 0.50; 95% CI, 0.34-0.73; P = .00015).^2,3 The data were presented during a Presidential Symposium at the 2026 IASLC WCLC meeting.

The rolling submission was initiated under the Real-Time Oncology Review program in October 2026.⁴

What is the mechanism of action of zipalertinib?

Zipalertinib is an orally available, irreversible small molecule EGFR inhibitor designed to target activating EGFR mutations.¹ The agent was selected for its ability to inhibit EGFR variants with exon 20 insertions.

Zipalertinib is also under FDA review in the previously treated setting. In April 2026, the FDA accepted an NDA for zipalertinib in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or after platinum-based chemotherapy, with or without amivantamab-vmjw (Rybrevant), and set a target action date of February 27, 2027.⁵ That application is supported by data from the phase 2b portion of the phase 1/2 REZILIENT1 trial (NCT04036682). The FDA granted breakthrough therapy designation to zipalertinib in 2021 for patients with EGFR exon 20 insertion–mutant NSCLC previously treated with platinum-based chemotherapy.

How was the REZILIENT3 trial designed?

The randomized, phase 3 trial enrolled patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC with EGFR exon 20 insertion mutations identified by local testing.³ Patients were required to have measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and available archival tumor tissue; patients with stable brain metastases were permitted.

Patients were randomly assigned 1:1 to receive zipalertinib at 100 mg orally twice daily plus pemetrexed at 500 mg/m² every 3 weeks and either carboplatin dosed to an area under the curve of 5 or cisplatin at 75 mg/m² for 4 cycles, or the same pemetrexed and platinum regimen alone. Patients in the chemotherapy arm could cross over to zipalertinib monotherapy after BICR-confirmed disease progression.

PFS by BICR served as the primary end point. Secondary end points included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response, intracranial response, safety, pharmacokinetics, and patient-reported outcomes. The prespecified interim analysis was planned at 122 PFS events, with superiority declared at a 1-sided P value below .0098.

The median age was 66.5 years (range, 30-89) in the zipalertinib arm and 64.0 years (range, 27-82) in the chemotherapy arm. In the respective arms, 65.7% and 63.3% of patients were female, 58.5% and 57.6% had an ECOG performance status of 1, and 31.4% and 31.7% had brain metastases at baseline.

What data supported the NDA?

In addition to the PFS benefit, the ORR by BICR was 65.0% (95% CI, 56.49%-72.86%; n = 91 of 140) with zipalertinib plus chemotherapy vs 40.3% (95% CI, 32.06%-48.94%; n = 56 of 139) with chemotherapy alone (P < .0001). Complete responses occurred in 6.4% (n = 9 of 140) and 2.2% (n = 3 of 139) of patients, respectively. The DCR was 89.3% (95% CI, 82.94%-93.88%; n = 125 of 140) vs 81.3% (95% CI, 73.81%-87.4%; n = 113 of 139), and the median duration of response was 14.2 months (95% CI, 10.51-not estimable) vs 9.9 months (95% CI, 6.80-not estimable). The median time to response was 1.4 vs 2.6 months.

The PFS benefit was observed in patients with brain metastases at baseline (HR, 0.38; 95% CI, 0.21-0.67) and in those without brain metastases (HR, 0.62; 95% CI, 0.38-0.99).

At the interim analysis, OS data were immature, with 30% maturity; the HR for OS was 0.72 (95% CI, 0.42-1.23; P = .11082).^2,3 Follow-up for OS is ongoing.

What is the safety profile of zipalertinib plus chemotherapy?

In the safety population, any-grade treatment-related adverse effects (TRAEs) occurred in 98.6% of patients in the zipalertinib arm (n = 140) vs 88.2% of those in the chemotherapy arm (n = 136), and grade 3 or higher TRAEs occurred in 80.7% (n = 113 of 140) vs 40.4% (n = 55 of 136), respectively.³ Treatment-related serious adverse effects were reported in 37.9% vs 12.5% of patients.

Adverse effects (AEs) led to zipalertinib interruption in 82.9% of patients, dose reduction in 43.6%, and discontinuation in 17.1%.

The most common any-grade AEs in the zipalertinib arm vs the chemotherapy arm included anemia (80.7% vs 50.0%), thrombocytopenia (56.4% vs 19.9%), neutropenia (50.7% vs 40.4%), rash (45.7% vs 6.6%), nausea (44.3% vs 41.9%), constipation (32.1% vs 30.9%), paronychia (31.4% vs 0%), stomatitis (28.6% vs 7.4%), and diarrhea (27.1% vs 8.8%). Grade 3 or higher anemia (48.6% vs 12.5%), neutropenia (33.6% vs 22.1%), thrombocytopenia (30.0% vs 8.1%), and rash (10.7% vs 0%) were more frequent with the combination.

AEs with an outcome of death occurred in 13 patients (9.3%) in the zipalertinib arm and 4 patients (2.9%) in the chemotherapy arm. Treatment-related deaths occurred in 3 patients (2.1%) in the zipalertinib arm, all due to sepsis or septic shock, vs none in the chemotherapy arm.

References

1. New drug application submission completed for zipalertinib plus chemotherapy in first-line EGFR exon 20 insertion mutation non-small cell lung cancer. News release. Cullinan Therapeutics. November 12, 2026. Accessed November 13, 2026. https://investors.cullinantherapeutics.com/news-releases/news-release-details/new-drug-application-submission-completed-zipalertinib-plus
2. Tan DS. Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st line NSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). J Thorac Oncol. 2026;21(10):104265. doi:10.1016/j.jtho.2026.104265 
3. Zipalertinib REZILIENT3 results. Cullinan Therapeutics. September 14, 2026. Accessed November 13, 2026. https://investors.cullinantherapeutics.com/static-files/ff92eaaa-8992-451c-879a-36b240b6fe45
4. OncLive Staff. NDA submission is initiated for zipalertinib plus chemotherapy in frontline EGFR exon 20 insertion+ NSCLC. OncLive. October 2, 2026. Accessed November 13, 2026. https://www.onclive.com/view/nda-submission-is-initiated-for-zipalertinib-plus-chemotherapy-in-frontline-egfr-exon-20-insertion-nsclc
5. U.S. Food and Drug Administration accepts new drug application for zipalertinib for the treatment of locally advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. Taiho Oncology. April 28, 2026. Accessed November 13, 2026. https://www.taihooncology.com/us/news/us-food-and-drug-administration-accepts-new-drug-application-for-zipalertinib-for-the-treatment-of-locally-advanced-or-metastatic-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations/