The FDA has accepted a New Drug Application (NDA) for zipalertinib, an oral EGFR tyrosine kinase inhibitor, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. The submission is based on Phase 2b data from the REZILIENT1 study, with a PDUFA target action date of February 27, 2027.

Clinical Takeaway

Zipalertinib demonstrated a 35% objective response rate and 8.8-month median duration of response in patients with EGFR exon 20 insertion-mutated NSCLC who progressed after platinum-based chemotherapy. The drug showed activity even in challenging subgroups, including patients with brain metastases (31% ORR) and those who had received prior amivantamab therapy (30% ORR).

Drug Profile & Mechanism

  • Mechanism: Oral EGFR tyrosine kinase inhibitor designed as a next-generation, irreversible inhibitor
  • Selectivity: Targets EGFR variants with exon 20 insertion mutations while sparing wild-type EGFR
  • Development: Discovered using Taiho Pharmaceutical’s Cysteinomix technology
  • Regulatory status: Received Breakthrough Therapy Designation in 2021
  • Development codes: CLN-081/TAS6417

Target Population

Patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy, including patients previously treated with amivantamab. Patients with EGFR exon 20 insertion mutations continue to have limited treatment options following platinum-based chemotherapy.

Study Design

  • Trial: REZILIENT1 (Phase 1/2 study; Phase 2b data, NCT04036682)
  • Design: Single-arm study evaluating zipalertinib monotherapy
  • Dosing: 100 mg twice daily oral administration
  • Population: Adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who received prior therapy
  • Assessment: Response evaluation by blinded independent central review per RECIST v1.1

Endpoints

  • Primary endpoints:
    • Objective response rate (ORR)
    • Duration of response (DOR)
  • Safety endpoint: Adverse events characterized per NCI-CTCAE v5.0

Efficacy Outcomes

  • Primary efficacy population (n=176):
    • Confirmed ORR: 35%
    • Median DOR: 8.8 months
  • Prior platinum-based chemotherapy only (n=125):
    • ORR: 40%
    • Median DOR: 8.8 months
  • Prior amivantamab without other exon 20 insertion-targeted therapy (n=30):
    • ORR: 30%
    • Median DOR: 14.7 months
  • Patients with brain metastases (n=68):
    • ORR: 31%
    • Median DOR: 8.3 months

Safety

The safety profile of zipalertinib was manageable and consistent with previously reported data. Most treatment-emergent adverse events were grade 1 or 2.

  • Most common treatment-emergent adverse events:
    • Paronychia
    • Rash
    • Anemia
    • Dermatitis acneiform
    • Diarrhea
    • Dry skin
    • Nausea
    • Stomatitis

Key Clinical Implications

✔ Addresses unmet need in EGFR exon 20 insertion mutations, representing approximately 1-2% of all NSCLC cases

✔ Demonstrates activity after amivantamab progression, providing potential sequential treatment option

✔ Demonstrates response in patients with brain metastases, a common and challenging complication in NSCLC

✔ Manageable safety profile with predominantly low-grade adverse events

✔ Oral administration offers convenience for patients requiring long-term treatment

Bottom Line

The FDA acceptance of zipalertinib’s NDA represents an important milestone for patients with EGFR exon 20 insertion-mutated NSCLC, a population with limited treatment options. The drug’s 35% response rate and manageable safety profile in the REZILIENT1 trial support its potential as an additional treatment option for patients with EGFR exon 20 insertion-mutated NSCLC. The February 27, 2027 PDUFA date sets the timeline for regulatory decision-making.

Sources:

  • Taiho Oncology, Inc., Taiho Pharmaceutical Co., Ltd., and Cullinan Therapeutics, Inc. (2026). 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. 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/