Zipalertinib, a novel EGFR exon 20 insertion tyrosine kinase inhibitor (TKI), has shown promising efficacy and a manageable safety profile in heavily pretreated non-small cell lung cancer (NSCLC) patients harboring EGFR exon 20 insertion mutations who progressed on or after amivantamab treatment. These findings, from module C of the phase 2b REZILIENT1 trial (NCT04036682), were presented at the ESMO Congress 2024.
Antonio Passaro, MD, PhD, from the European Institute of Oncology in Milan, Italy, highlighted the significance of the data, stating, "This is the first presentation to systemically characterize patients that receive previous treatment with amivantamab and received a dedicated tyrosine kinase inhibitor for [ EGFR] exon 20 insertion alteration. Zipalertinib shows promising efficacy in patients that progress in this particular setting after amivantamab."
Efficacy Results
The overall population (n = 30) achieved an objective response rate (ORR) of 40% (95% CI, 22.7%-59.4%), including a complete response (CR) in 3.3% (95% CI, 0.1%-17.2%) and partial responses (PRs) in 36.7% (95% CI, 19.9%-56.1%). Stable disease (SD) was observed in 50% of patients (95% CI, 31.3%-68.7%).
In the subgroup of patients who previously received only amivantamab (n = 18), the ORR was 50.0% (95% CI, 26.0%-74.0%), with a CR rate of 5.6% (95% CI, 0.1%-27.3%) and a PR rate of 44.4% (95% CI, 21.5%-69.2%). SD was observed in 38.9% (95% CI, 17.3%-64.3%) of these patients.
For patients who received amivantamab plus other exon 20 insertion therapy, the ORR was 25.0% (95% CI, 5.5%-57.2%), with no CRs, a PR rate of 25.0% (95% CI, 5.5%-57.2%), and SD in 66.7% (95% CI, 34.9%-90.1%).
The disease control rates (DCRs) were 90.0% (95% CI, 73.5%-97.9%), 88.9% (95% CI, 65.3%-98.6%), and 91.7% (95% CI, 61.5%-99.8%) across the overall, amivantamab-only, and amivantamab-plus-other-therapy groups, respectively.
At the data cutoff, the duration of response (DOR) was not estimable. The median progression-free survival (PFS) was 9.7 months (90% CI, 4.1-NE). Data on the efficacy in brain metastases were not available.
Safety Profile
The most common treatment-related adverse events (TRAEs) in the overall population were rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%). Grade 3 or higher TRAEs included anemia (9%), rash (7%), and pneumonitis/interstitial lung disease (7%).
Dose reductions occurred in 7% of patients, and treatment was discontinued in another 7% due to adverse events.
Trial Design
Module C of the phase 2b trial evaluated the efficacy and safety of zipalertinib in patients who had progressed on or after amivantamab treatment. Patients received 100 mg of oral zipalertinib twice daily.
Key eligibility criteria included locally advanced or metastatic NSCLC, documented EGFR exon 20 insertion, progression on or after amivantamab, and an ECOG performance status of 0 or 1. Stable/asymptomatic brain metastases were allowed.
The primary endpoints were ORR and DOR per RECIST v1.1. Secondary endpoints included safety, PFS, and DCR.
As of the data cutoff (March 29, 2024), 45 patients were enrolled. The median age was 62 years (range, 33-85), and the majority were female (76%). Patients had received a median of 3 prior systemic regimens (range, 1-6), including chemotherapy (96%), anti–PD-1/L1 therapy (44%), targeted therapy (31%), amivantamab (100%), and investigational exon 20 insertion therapy (38%). 49% had a history of brain metastases.
Regulatory Status and Future Directions
In January 2022, the FDA granted breakthrough therapy designation to zipalertinib for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have received prior platinum-based chemotherapy, based on phase 1/2a study data (NCT04036682).
Passaro noted that zipalertinib is currently being evaluated in a phase 3 trial in the first-line setting in combination with chemotherapy, compared with the standard of care.
