FDA Accepts NDA for Zipalertinib in EGFR Exon 20-Mutant Lung Cancer

The FDA has accepted a new drug application (NDA) for zipalertinib (CLN-081), an oral, next-generation EGFR tyrosine kinase inhibitor (TKI). The application seeks approval for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations who have previously received systemic therapy. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of February 27, 2027.¹

The regulatory submission is primarily supported by data from the phase 2b portion of the REZILIENT1 trial (NCT04036682), a multicenter, open-label study evaluating the efficacy and safety of zipalertinib in patients with relapsed or refractory EGFR ex20ins-mutated NSCLC. In the primary efficacy population (n = 176), zipalertinib administered at 100 mg twice daily demonstrated a confirmed objective response rate (ORR) of 35% and a median duration of response (mDOR) of 8.8 months. Among a subgroup of patients who had received prior platinum-based chemotherapy but no prior ex20ins-targeted therapies (n = 125), the ORR was 40% with an identical mDOR of 8.8 months.²

Clinical management of EGFR ex20ins-mutant NSCLC has historically been challenging due to the structural configuration of the mutation, which restricts the binding pocket of traditional TKIs. While amivantamab (Rybrevant) is currently a standard of care in the second-line setting, there remains a clinical need for oral options with manageable toxicity and central nervous system (CNS) activity. In REZILIENT1, zipalertinib showed activity in patients previously treated with amivantamab (n = 30), achieving a confirmed ORR of 30% and an encouraging mDOR of 14.7 months. Furthermore, in patients with baseline brain metastases (n = 68), the agent produced an ORR of 31% and a mDOR of 8.3 months, suggesting favorable intracranial penetration.¹

The safety profile observed in the REZILIENT1 trial was consistent with earlier phase findings and characterized by a relatively low rate of high-grade toxicities compared to earlier-generation exon 20 inhibitors. The most frequent treatment-emergent adverse events (TEAEs) included paronychia, rash, anemia, diarrhea, and dry skin. Treatment-related adverse events leading to permanent discontinuation occurred in 8.2% of patients, while dose reductions were required in 14.3% of the study population.²

Notably, zipalertinib is designed to selectively target mutant EGFR while sparing wild-type EGFR, a mechanism intended to mitigate off-target toxicities such as severe skin rash and gastrointestinal distress often associated with nonselective inhibition.

"Amivantamab, while being very effective, has significant EGFR- and MET-directed [AEs]. They have significant rates of rash and paronychia. I think the MET-targeting toxicities, including the edema, really are limiting for some patients," said Helena Yu, MD, thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, in an interview with Targeted Oncology.

As part of the broader clinical development program, zipalertinib is also being investigated in the frontline setting. The phase 3 REZILIENT3 trial (NCT05973773) is currently evaluating zipalertinib in combination with platinum-based chemotherapy vs chemotherapy alone for treatment-naive patients with EGFR ex20ins-mutated NSCLC. Topline results from this study are anticipated by the end of 2026.¹

If approved, zipalertinib would provide a potent oral therapeutic option for a molecularly defined subset of lung cancer patients who currently face limited salvage-line possibilities.

REFERENCES

1. 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. Cullinan Therapeutics. April 28, 2026. Accessed April 28, 2026. https://tinyurl.com/4n8ehf6e

2. Piotrowska Z, Tan DSW, Smit EF, et al. 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;43(12):1102-1114. doi:10.1200/JCO-25-00763