‘Zipalertinib’ targets the Exon 20 lung cancer mkt…presenting new trt option

Has entered the FDA review… targeting patients who have undergone chemotherapy

Competition within a ‘Rybrevant’ monotherapy market is expected

While treatment options for EGFR exon 20 insertion mutation non-small cell lung cancer (NSCLC) remain limited, the potential for a change in the therapeutic environment is being proposed as the oral targeted therapy ‘zipalertinib’ enters the U.S. regulatory approval process.

With consistent efficacy confirmed in global clinical trials and analysis of Asian patient populations amid limited existing treatments, zipalertinib is garnering attention as a competing product to ‘Rybrevant (amivantamab),’ the only approved medicine in this space.

According to industry sources on the 4th, the U.S. Food and Drug Administration (FDA) recently accepted a New Drug Application (NDA) for zipalertinib. The drug’s target population includes patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed following platinum-based chemotherapy. The goal review date under the Prescription Drug User Fee Act (PDUFA) is February 27, 2027.

Zipalertinib is a next-generation irreversible EGFR tyrosine kinase inhibitor (TKI) being co-developed by Taiho Pharmaceutical of Japan and Cullinan Therapeutics of the U.S. This drug is designed to selectively inhibit mutant EGFR while minimizing impact on wild-type (normal) EGFR.

The NDA is based on results from Part 2b of the Phase 1/2 REZILIENT1 study.

The REZILIENT1 study included 176 patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations as the primary efficacy evaluation group. The study evaluated the clinical efficacy of zipalertinib in patients whose disease progressed after platinum-based chemotherapy.

Notably, 51 of the total patients had prior experience with Rybrevant, confirming zipalertinib’s potential as a subsequent treatment option after existing targeted therapies. Patients received 100 mg of zipalertinib orally twice daily, with objective response rate (ORR) and duration of response (DOR) analyzed as primary endpoints.

Clinical results showed an ORR of 35.2% in the Zipalertinib group, with a median DOR of 8.8 months. It is noteworthy that responses were also confirmed in patients with prior Rybrevant treatment. In that specific patient group, the ORR was 30%, suggesting its viability as a follow-up treatment option.

Zipalertinib results were presented at ESMO Asia 2025, held in Singapore last year.

The efficacy in Asian patients did not differ significantly from that in the global patients.

According to a subgroup analysis presented at the ESMO Asia 2025, the ORR for the Asian patient group was 33%, similar to the 37% observed in the non-Asian group. The duration of response (DOR) was 8.3 months and 10.5 months, respectively, while progression-free survival (PFS) showed almost identical patterns at 9.5 months and 9.0 months.

In terms of overall survival (OS), the median has not yet been reached in the Asian patient group, whereas it was 24 months in the non-Asian group.

Regarding safety, the primary adverse events included paronychia, rash, dry skin, diarrhea, and stomatitis, most of which were Grades 1–2 and manageable.

Limited treatment environment…”Oral drug option is highly significant”

Janssen’s Rybrevant

The development of treatments for NSCLC with an EGFR exon 20 insertion mutation has faced significant challenges. Unlike treatments targeting Exon 19 deletions or Exon 21 L858R mutations, Exon 20 insertion mutations have diverse subtypes, making drug design structurally difficult.

Takeda’s Exkivity, which garnered high expectations as an oral targeted therapy, received conditional approval based on a 28% ORR in early trials. However, it was withdrawn from the global market after failing to prove PFS improvement in the confirmatory Phase 3 trial (EXCLAIM-2).

Poziotinib, previously developed, was also suspended after failing to meet efficacy expectations and experiencing toxicity issues in Phase 2 trials.

As a result, Janssen’s Rybrevant is now the only treatment approved in this therapeutic area. However, as an intravenous-based therapy, it has been noted for limitations regarding administration convenience and treatment persistence.

Given such a treatment gap, zipalertinib, which can be administered orally, is being evaluated as a new alternative because it offers manageable safety while increasing mutation selectivity compared to previous agents. The industry is focusing on the possibility that the Exon 20 mutation treatment landscape will transition from a monotherapy-centered environment to a more competitive one, depending on future approvals.

Professor Ross Soo of the National Cancer Centre Singapore explained, “Zipalertinib demonstrated efficacy in Asian patients equivalent to that of the global patient population,” and added, “Because it is an oral drug, it is significant in terms of patient accessibility and treatment persistence.”