Zipalertinib plus platinum-based chemotherapy met the primary end point of progression-free survival (PFS) compared with chemotherapy alone at a planned interim analysis of the phase 3 REZILIENT3 trial (NCT05973773) in patients with previously untreated, locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to a news release from Taiho Oncology.1
The zipalertinib-containing arm showed a statistically significant and clinically meaningful improvement in PFS vs chemotherapy alone, and safety in this arm was described as manageable. Full data are expected to be presented at a future international medical meeting. Based on these results, an Independent Data Monitoring Committee recommended unblinding the study, and REZILIENT3 will continue to follow patients for additional efficacy and safety end points.
“Meeting the primary end point early at a planned interim analysis marks an important milestone for the REZILIENT3 study and supports the potential role of zipalertinib in the first-line treatment setting,” Jeffrey Jones, MD, MBA, chief medical officer of Cullinan Therapeutics, stated in the release.
Jones added that the topline data support confidence in zipalertinib's potential to offer patients with EGFR exon 20 insertion–mutated NSCLC a new first-line treatment option.
EGFR exon 20 insertion mutations account for up to 4% of NSCLC cases globally, representing the third most common EGFR mutation subtype, and up to 12% of NSCLC cases with an EGFR mutation in the United States.2 Platinum-based chemotherapy has remained a standard first-line option for this genetically defined population, which historically has had poorer outcomes than patients with more common EGFR mutations.2
Zipalertinib is an oral, next-generation, irreversible EGFR inhibitor designed to inhibit EGFR variants harboring exon 20 insertion mutations while sparing wild-type EGFR; the agent previously received FDA breakthrough therapy designation based on earlier monotherapy data in the pretreated setting.
REZILIENT3 is a global, multicenter, randomized, controlled, open-label phase 3 trial that enrolled adult patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC harboring EGFR exon 20 insertion mutations and at least 1 measurable lesion.2,3 Patients were randomly assigned 1:1 to receive zipalertinib plus platinum-based chemotherapy (pemetrexed plus cisplatin or carboplatin) or chemotherapy alone, stratified by ECOG performance status, presence of brain metastases, and geographic region.3 PFS by blinded independent central review served as the primary end point; secondary end points include overall survival, investigator-assessed PFS, objective response rate, duration of response, disease control rate, intracranial efficacy, and quality of life.
“The positive topline results from the planned interim analysis of REZILIENT3 further support the potential of zipalertinib to meet the high unmet medical need in patients with NSCLC harboring EGFR exon 20 insertion mutations,” Harold Keer, MD, PhD, chief medical officer of Taiho Oncology, said in the release.1 “We look forward to pursuing regulatory approval of zipalertinib in combination with chemotherapy in the first-line treatment setting with the goal of providing a new treatment option for this group of patients.”
Cullinan and Taiho intend to pursue US regulatory approval of the zipalertinib combination in the first-line setting following discussions with health authorities and full disclosure of REZILIENT3 data.1 The interim results follow separate regulatory progress for zipalertinib monotherapy in the previously treated setting: the FDA accepted a new drug application for zipalertinib in NSCLC with EGFR exon 20 insertion mutations that progressed on or after platinum-based chemotherapy, with or without amivantamab-vmjw (Rybrevant), based on phase 1/2 REZILIENT1 trial (NCT04036682) data, and assigned a Prescription Drug User Fee Act target action date of February 27, 2027.4
