FDA sets target date for zipalertinib for advanced lung cancer

The FDA has accepted a new drug application (NDA) for zipalertinib for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). If approved, it would be indicated for patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations whose disease has progressed on or after platinum-based chemotherapy, with or without amivantamab. The regulatory agency has set the Prescription Drug User Fee Act (PDUFA) target action date as Feb. 27, 2027.

About 77% of lung cancer cases are NSCLC, which may not cause symptoms and is often diagnosed after it has metastasized, according to the American Cancer Society. This year, about 229,410 new cases of lung cancer will be diagnosed, and there will be approximately 124,990 deaths from lung cancer.

Between 1% and 4% of NSCLC cases globally have EGFR ex20ins, which makes them the third most common EGFR mutation subtype, according to a March 2021 review paper. In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations, with insertions at exon 20 accounting for up to 12% of these mutations.

Zipalertinib is an oral small molecule designed to inhibit EGFR variants with ex20ins mutations while sparing wild-type EGFR. Zipalertinib is being developed by Taiho Oncology and its parent company, Taiho Pharmaceutical Co., worldwide, and in collaboration with Cullinan Therapeutics in the United States.

The NDA is supported by data from the phase 2b part of the REZILIENT1 clinical trial of zipalertinib monotherapy in patients with NSCLC harboring EGFR ex20ins mutations who have received prior therapy. The study met its primary endpoint of objective response rate. Study results from REZILIENT1 were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology.

In the study, zipalertinib demonstrated clinically meaningful efficacy in the primary efficacy population of 176 patients, including 51 patients who had received prior amivantamab, a bispecific monoclonal antibody that is approved as Rybrevant both as a monotherapy and in combination with other treatments for NSCLC.

The confirmed objective response rate was 35%. Median duration of response (mDOR) was 8.8 months. In patients treated after prior platinum-based chemotherapy only (125 patients), ORR was 40% with a median duration of response of 8.8 months.

In the 30 patients who had received prior amivantamab without other ex20ins-targeted therapy, zipalertinib showed a confirmed ORR of 30% and mDOR of 14.7 months. Among the 69 patients with brain metastases, the confirmed ORR was 31%, and mDOR was 8.3 months.

The safety profile of zipalertinib was manageable and consistent with previously reported data. The most common treatment-emergent adverse events were paronychia, rash, anemia, dermatitis acneiform, diarrhea, dry skin, nausea and stomatitis.