Zipalertinib Achieves ORR Primary Endpoint in NSCLC Study

Patients with NSCLC with pretreated EGFR exon 20 insertion mutations achieved an ORR of 40% from zipalertinib, with a safety profile consistent with previous data on the drug.

According to phase 2b data, the phase 1/2 REZILIENT1 trial (NCT04036682) reached its primary end point of overall response rate (ORR) from zipalertinib (CLN-081) in patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, while also finding a safety profile for zipalertinib consistent with prior findings.¹

At a data cutoff of March 29, 2024, prior findings from phase 2b of REZILIENT1 presented during the 2024 ESMO Congress demonstrated that efficacy-evaluable patients who received zipalertinib (n = 30) achieved a confirmed ORR of 40.0% (95% CI, 22.7%-59.4%), including a 3.3% (95% CI, 0.1%-17.2%) complete response (CR) rate; the disease control rate (DCR) was 90.0% (95% CI, 73.5%-97.9%).² The median duration of response (DOR) was not estimable (NE), and the median progression-free survival (PFS) was 9.7 months (90% CI, 4.1-NE).

Evaluable patients who received prior amivantamab-vmjw (Rybrevant) only (n = 18) experienced a confirmed ORR of 50.0% (95% CI, 26.0%-74.0%), with a CR rate of 5.6% (95% CI, 0.1%-27.3%) and a DCR of 88.9% (95% CI, 65.3%-98.6%). Evaluable patients who received prior amivantamab and other exon 20 insertion–directed agents (n = 12) achieved a confirmed ORR of 25.0% (95% CI, 5.5%-57.2%) and a DCR of 91.7% (95% CI, 61.5%-99.8%).

Phase 2b of REZILIENT1 enrolled patients with locally advanced or metastatic NSCLC with documented EGFR exon 20 insertion mutations who experienced disease progression on or after treatment with amivantamab. Eligible patients also needed to have an ECOG performance status of 0 or 1; those with stable or asymptomatic brain metastases were permitted. All patients in phase 2b received oral zipalertinib at a dose of 100 mg twice daily.

The coprimary end points were ORR and DOR per RECIST 1.1 criteria. Secondary end points included PFS, DCR, and safety.

The median age in the overall population (n = 45) was 62 years (range, 33-85). Most patients were female (76%), had an ECOG performance status of 1 (67%), and had received prior chemotherapy (96%). The median number of prior lines of treatment was 3 (range, 1-6); prior treatments beyond amivantamab included anti–PD-L(1) agents (44%), targeted therapy not directed against exon 20 insertion mutations (31%), and investigational exon 20 insertion–directed agents (38%).

In terms of safety, any-grade treatment-related adverse effects (TRAEs) occurring in at least 10% of the overall population included rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%). In the amivantamab-only pretreated population (n = 28), these events occurred at rates of 43%, 39%, 21%, 18%, 11%, 14%, and 7%, respectively. Among patients who received prior amivantamab and other exon 20 insertion–directed agents (n = 17), these events occurred at respective rates of 29%, 29%, 29%, 24%, 24%, 18%, and 18%.

Grade 3 or higher TRAEs in the overall population included anemia (9%), rash (7%), and pneumonitis or interstitial lung disease (ILD; 7%). Seven percent of patients reduced the dose of and/or discontinued treatment with zipalertinib.

Patients who had received prior amivantamab only experienced grade 3 anemia (7%), rash (7%), and pneumonitis/ILD (11%). These events occurred at rates of 12%, 6%, and 0% among patients who had received prior amivantamab and other exon 20 insertion–directed agents. Patients who had received prior amivantamab only experienced dose reduction (7%) and discontinuation (11%); dose reduction was reported at a rate of 6% in patients who had received prior amivantamab and other exon 20 insertion–directed agents.

Complete findings from REZILIENT1 will be submitted for presentation at an upcoming international medical meeting.¹ The companies plan to submit zipalertinib for regulatory approval in the United States in the second half of 2025, pending discussions with the FDA.

References

1. Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics announce primary endpoint met in phase 2b trial of zipalertinib in patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations who have received prior therapy. News release. Taiho Pharmaceutical Co. January 28, 2025. Accessed January 29, 2025. https://www.taihooncology.com/us/news/taiho-pharmaceutical-taiho-oncology-and-cullinan-therapeutics-announce-primary-endpoint-met-in-phase-2b-trial-of-zipalertinib-in-patients-with-non-small-cell-lung-cancer-harboring-egfr-exon-20-insertion-mutations-who-have-received-prior-therapy/
2. Passaro A, Yu HA, Nguyen D, et al. Safety and anti-tumour activity of zipalertinib in NSCLC patients (pts) with EGFR exon 20 insertion (ex20ins) mutations who received prior amivantamab. Ann Oncol. 2024;35(suppl 2):S803-S804. doi:10.1016/j.annonc.2024.08.1311