Data presented at the IASLC World Conference on Lung Cancer (WCLC), held September 12 – 15, 2026, in Seoul, South Korea, showed that adding zipalertinib* to platinum-based chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. In the planned interim analysis of the Phase 3 REZILIENT3 trial, median PFS was 14.5 months with zipalertinib plus chemotherapy compared with 8.5 months with chemotherapy alone, corresponding to a hazard ratio (HR) of 0.50 (95% CI, 0.34–0.73; P=0.00015). The combination also showed a higher objective response rate (ORR), while overall survival (OS) remains immature.
Key Findings
- Median PFS was 14.5 months with zipalertinib plus chemotherapy versus 8.5 months with chemotherapy alone (HR, 0.50; 95% CI, 0.34–0.73; P=0.00015).
- ORR was 65.0% versus 40.3%, respectively, with median duration of response of 14.2 versus 9.9 months.
- Among patients with brain metastases at baseline, the PFS HR was 0.38.
- At the interim OS analysis, which was approximately 30% mature, the HR for death was 0.72 (95% CI, 0.42–1.23).
- Grade ≥3 adverse events occurred in 87.1% of patients receiving the combination and 54.4% receiving chemotherapy alone, with hematologic adverse events accounting for much of the difference.
EGFR Exon 20 Insertions Represent a Distinct Molecular Subtype
EGFR exon 20 insertion mutations are a heterogeneous group of alterations within the tyrosine kinase domain of EGFR. They differ structurally and clinically from the more common EGFR exon 19 deletions and L858R mutations. In a comprehensive genomic profiling study of 14,483 NSCLC specimens, Riess and colleagues identified EGFR exon 20 insertions in 263 cases, representing 1.8% of all NSCLC specimens and 12% of EGFR-mutant cases. The investigators identified 64 distinct exon 20 insertion variants, with most located between amino acid positions 766 and 775. Among five patients with available clinical outcomes after treatment with first- or second-generation EGFR TKIs, none responded.
The molecular heterogeneity of these alterations is clinically relevant because individual exon 20 insertion variants can differ in their sensitivity to EGFR-directed therapies. A systematic literature review by Burnett and colleagues, which included 78 studies, reported EGFR exon 20 insertion frequencies ranging from 0.1% to 4% across unselected NSCLC populations and from 1% to 12% among EGFR-mutant tumors. The review also found evidence of poorer outcomes compared with other EGFR mutation subtypes across several treatment settings, although the available comparative evidence was limited and heterogeneous.
Zipalertinib
Zipalertinib, previously known as CLN-081 and TAS6417, is an oral, irreversible EGFR tyrosine kinase inhibitor developed to target activating EGFR mutations, including exon 20 insertions. The molecule was selected for activity against EGFR exon 20 insertion variants while sparing wild-type EGFR. It also has activity against several uncommon EGFR alterations, although preclinical and clinical data indicate that it does not inhibit the C797S resistance mutation. The clinical development program has included the REZILIENT1, REZILIENT3, and REZILIENT4 studies. REZILIENT3 is evaluating zipalertinib in combination with platinum-based chemotherapy in the first-line setting, while other studies have evaluated the agent in previously treated disease and other treatment settings.
REZILIENT1 Established Activity in Previously Treated Disease
The Phase 1/2 REZILIENT1 study evaluated zipalertinib in patients with EGFR exon 20 insertion-positive NSCLC who had previously received platinum-based chemotherapy, with or without prior amivantamab. The published Phase 2b results included 162 patients in the primary efficacy population. Confirmed ORR was approximately 35%, with a median duration of response of 8.8 months. In patients previously treated with platinum-based chemotherapy but not amivantamab, ORR was 40%. Among patients previously treated with amivantamab without another exon 20-directed therapy, ORR was 30%.
These results supported submission of a New Drug Application to the U.S. Food and Drug Administration. On April 28, 2026, the FDA accepted the NDA for zipalertinib for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy, with or without amivantamab. The PDUFA target action date is February 27, 2027. Zipalertinib remains investigational and has not been approved by the FDA or another regulatory authority.
REZILIENT3 Evaluates Zipalertinib in the First-Line Setting
REZILIENT3 (NCT05973773) is a randomized, open-label, global Phase 3 study evaluating zipalertinib plus platinum-based chemotherapy against chemotherapy alone in patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC harboring EGFR exon 20 insertion mutations. The chemotherapy regimen consisted of pemetrexed combined with either carboplatin or cisplatin. After a six-patient safety lead-in, 279 patients were randomized: 140 to zipalertinib 100 mg twice daily plus chemotherapy and 139 to chemotherapy alone. Baseline characteristics were generally balanced between the treatment groups, including the proportion of patients with brain metastases, which was approximately 31% in each arm.
The primary endpoint was PFS assessed by blinded independent central review. At the prespecified interim analysis after 122 PFS events, median PFS was 14.5 months with zipalertinib plus chemotherapy compared with 8.5 months with chemotherapy alone. The HR for disease progression or death was 0.50 (95% CI, 0.34–0.73; P=0.00015). The PFS result was consistent across the prespecified subgroup analyses. In patients with brain metastases at baseline, the HR for progression or death was 0.38. Interpret the subgroup result in the context of the number of patients included and the interim nature of the analysis.
Tumor Response
The combination also produced a higher ORR than chemotherapy alone. ORR was 65.0% with zipalertinib plus chemotherapy compared with 40.3% with chemotherapy alone (P<0.0001). Median duration of response was 14.2 months and 9.9 months, respectively. These findings were reported at the same interim analysis used for the primary PFS endpoint.
Overall Survival Remains Immature
Overall survival was not mature at the time of the interim analysis. Approximately 30% of the planned OS events had occurred, and the HR for death was 0.72 (95% CI, 0.42–1.23). Because the confidence interval includes 1.0 and follow-up remains ongoing, the current analysis does not establish an OS difference between the treatment groups. Additional follow-up is required to characterize OS more fully.
Safety
The safety profile of zipalertinib plus chemotherapy was generally consistent with the known safety profiles of the individual treatments. Grade ≥3 adverse events occurred in 87.1% of patients receiving zipalertinib plus chemotherapy compared with 54.4% of those receiving chemotherapy alone. Grade ≥3 hematologic adverse events occurred in 58.6% and 28.7% of patients, respectively.
Grade ≥3 EGFR-related toxicities were reported infrequently. In the combination arm, grade ≥3 rash occurred in 10.7% of patients and grade ≥3 diarrhea in 1.4%. The investigators and sponsors reported no new safety signals. The higher frequency of grade ≥3 adverse events in the combination arm should be considered when interpreting the PFS results, particularly because the treatment regimen incorporates platinum-based chemotherapy.
Regulatory Status and Next Steps
The REZILIENT3 findings provide the basis for further regulatory discussions regarding zipalertinib in combination with chemotherapy as first-line treatment for EGFR exon 20 insertion-mutated advanced NSCLC. The sponsors have stated that they intend to pursue regulatory submissions based on the Phase 3 results. This potential first-line application is separate from the pending U.S. NDA for zipalertinib monotherapy following progression on platinum-based chemotherapy, with or without amivantamab. That application has a February 27, 2027 PDUFA target action date. REZILIENT3 follow-up remains ongoing, including additional assessment of OS and other exploratory endpoints.
The Evolving Treatment Landscape
The REZILIENT3 findings add to a rapidly changing treatment landscape for EGFR exon 20 insertion-mutated NSCLC. Several agents have been evaluated in this molecularly defined population, including amivantamab, mobocertinib, sunvozertinib, firmonertinib, and zipalertinib. Direct comparisons among these agents are limited, particularly in the first-line setting. Differences in trial design, patient populations, treatment regimens, CNS eligibility, response assessment, follow-up, and endpoints make cross-trial comparisons difficult.
The REZILIENT3 results therefore establish the efficacy and safety findings of zipalertinib plus chemotherapy relative to the chemotherapy control used in that study. They do not provide a direct comparison with other EGFR exon 20-directed treatment strategies. For now, the key unanswered clinical question is how the mature survival data from REZILIENT3 will develop and how the regimen will be incorporated into treatment strategies as additional first-line data become available.
Note
*Cullinan Therapeutics and Taiho Pharmaceutical (including Taiho Oncology) have a strategic collaboration focused on jointly developing and commercializing zipalertinib (previously known as CLN-081 and TAS6417), an oral, irreversible EGFR inhibitor targeting exon 20 insertion mutations in non-small cell lung cancer (NSCLC).
Clinical Trials
A Phase 1/2 Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer (REZILIENT1) – ClinicalTrials.gov ID NCT04036682
A Study of Zipalertinib in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions or Other Uncommon Mutation. (REZILIENT2) – ClinicalTrials.gov ID NCT05967689
REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (REZILIENT3) – ClinicalTrials.gov ID NCT05973773
A Study to Assess Zipalertinib Versus Placebo in Participants With Early Stage NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection (REZILIENT4) – ClinicalTrials.gov ID NCT07128199
References
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[2] Riess JW, Gandara DR, Frampton GM, Madison R, Peled N, Bufill JA, Dy GK, Ou SI, Stephens PJ, McPherson JD, Lara PN Jr, Burich RA, Ross JS, Miller VA, Ali SM, Mack PC, Schrock AB. 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. Epub 2018 Jul 5. PMID: 29981927; PMCID: PMC6764748.
[3] Heymach JV, Yu HA, Besse B, Cheng Y, Tan DS, Wei L, Wacheck V, Nishio M. REZILIENT3: randomized phase III study of first-line zipalertinib plus chemotherapy in patients with EGFR exon 20 insertion-mutated NSCLC. Future Oncol. 2025 Feb;21(5):549-556. doi: 10.1080/14796694.2025.2457294. Epub 2025 Feb 16. PMID: 39957151; PMCID: PMC11845107.
[4] Piotrowska Z, Passaro A, Nguyen D, Ruiter G, Soo RA, Ho-Fun Lee V, Velcheti V, Tan DS, Lee SH, Kim SH, Wrangle J, Yang JC, Daga H, Juan Vidal OJ, Spira AI, Fernandez-Hinojal G, Kim SW, Umemura S, Provencio Pulla M, Keeton EK, Yang ZS, Li S, Xu ZC, Jones JA, Yu HA; REZILIENT1 Investigators. Zipalertinib in Patients With Epidermal Growth Factor Receptor Exon 20 Insertion-Positive Non-Small Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy With or Without Amivantamab. J Clin Oncol. 2025 Jul 20;43(21):2387-2397. doi: 10.1200/JCO-25-00763. Epub 2025 Jun 1. PMID: 40450572.
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[7] 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. Taiho Oncology, Inc.; Taiho Pharmaceutical Co., Ltd.; Cullinan Therapeutics, Inc. U.S. Food and Drug Administration. April 28, 2026. Online. Last accessed on September 13, 2026.
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This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. Zipalertinib remains investigational and has not been approved by the U.S. Food and Drug Administration or any other regulatory authority. The REZILIENT3 efficacy and safety data discussed here are from an interim Phase 3 analysis presented at the IASLC 2026 World Conference on Lung Cancer and accompanying sponsor and IASLC reports. Overall survival remains immature, and the findings may change with additional follow-up.
Featured image: © 2026. CHA CO JOC. Used with permission.
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