Zipalertinib Demonstrates Safety, Disease Control in Heavily Pretreated EGFR Exon 20-Mutated NSCLC

Zipalertinib demonstrated a manageable safety profile and elicited disease control in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations following disease progression on or after treatment with amivantamab-vmjw (Rybrevant), according to findings from module C of the phase 2b REZILIENT1 trial (NCT04036682) presented at the 2024 ESMO Congress.

“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,” Antonio Passaro, MD, PhD, Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy, said in a presentation of the data. “Zipalertinib shows promising efficacy in patients that progress in this particular setting after amivantamab.”

Objective response rate (ORR) in the overall population (n = 30) was 40% (95% CI, 22.7%-59.4%), including 1 (3.3%; 95% CI, 0.1%-17.2%) complete response (CR), 11 (36.7%; 95% CI, 19.9%-56.1%) partial responses (PRs), and 15 (50.0%; 95% CI, 31.3%-68.7%) patients with stable disease (SD).

In the prior amivantamab-only population (n = 18), the ORR was 50.0% (95% CI, 26.0%-74.0%), including 1 CR (5.6%; 95% CI, 0.1%-27.3%), 8 PRs (44.4%; 95% CI, 21.5%-69.2%), and 7 with SD (38.9%; 95% CI, 17.3%-64.3%).

In the population of patients who previously received amivantamab plus other exon 20 insertion therapy, the ORR was 25.0% (95% CI, 5.5%-57.2%), including no CRs, 3 PRs (25.0%; 95% CI, 5.5%-57.2%), and 8 with SD (66.7%; 95% CI, 34.9%-90.1%).

“The confirmation of response was achieved regardless of the kind of biological alteration,” Passaro noted.

Disease control rates (DCRs) across all 3 respective groups 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%).

At data cutoff, duration of response (DOR) was not estimable (NE). Median progression-free survival (PFS) was 9.7 months (90% CI, 4.1-NE). Lastly, data on efficacy of brain metastases were not available.

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%). The most common grade 3 or higher TRAEs included anemia (9%), rash (7%), and pneumonitis/interstitial lung disease (7%).

In the overall population, dose reductions occurred in 3 patients (7%), with 3 patients (7%) also discontinuing treatment.

In model C of the phase 2b trial, investigators aimed to evaluate the efficacy and safety of zipalertinib–a novel irreversible and selective EGFR exon 20 insertion TKI–in patients who progressed on or after treatment with amivantamab.

Patients received 100 mg oral zipalertinib twice daily.

Key eligibility criteria included locally advanced or metastatic NSCLC, documented EGFR exon 20 insertion, progression on or after amivantamab, and ECOG performance status of 0 or 1; stable/asymptomatic brain metastases were allowed.

ORR and DOR per RECIST v1.1 served as the primary end points. Secondary end points included safety, PFS, and DCR.

At data cutoff (March 29, 2024), 45 patients were enrolled in the trial.

Median age was 62 years (range, 33-85), and the majority of patients were female (76%). Patients received a median of 3 prior systemic regimens (range, 1-6), including chemotherapy (96%), anti–PD-1/L1therapy (44%), targeted therapy (31%), amivantamab (100%), and investigational exon 20 insertion therapy (38%). In total, 49% had a history of brain metastases.

In January 2022, the FDA granted breakthrough therapy designation to zipalertinib for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations and who have received prior platinum-based chemotherapy, based on data from the phase 1/2a study (NCT04036682).

“At the present time, zipalertinib is ongoing in a phase 3 trial in the first-line setting in combination with chemotherapy, compared with the standard of care,” Passaro said.