Zipalertinib demonstrated meaningful activity in heavily pretreated NSCLC patients with EGFR exon 20 insertions post-amivantamab, achieving a 27.4% response rate with 8.5-month duration. The drug also showed promising 30% response rates in patients with uncommon non-exon 20 EGFR mutations, suggesting potential for addressing unmet needs in these difficult-to-treat populations.
Study Design & Population
- REZILIENT1: Phase 2b trial in 84 NSCLC patients with EGFR ex20ins mutations previously treated with amivantamab
- REZILIENT2 Cohort D: Phase 2b trial in 40 patients with uncommon non-ex20ins EGFR mutations
- Patients received zipalertinib 100 mg orally twice daily
- REZILIENT1 patients had median 3 prior therapy lines; 54.8% had brain metastases
- REZILIENT2 patients had median 2 prior therapy lines; 30% had brain metastases
Key Findings
- REZILIENT1 overall population (n=84): ORR 27.4%, mDOR 8.5 months, DCR 84.5%
- Prior amivantamab only subgroup (n=54): ORR 31.5%, mDOR 9.5 months, DCR 87.0%
- Brain metastases subgroup with prior amivantamab only (n=31): systemic ORR 29%
- REZILIENT2 overall population (n=40): ORR 30%, mDOR 7.75 months, DCR 70%
- Treatment-naïve REZILIENT2 patients (n=8): ORR 62.5% vs 21.9% in pretreated patients
Clinical Implications
- Provides treatment option for EGFR ex20ins patients who progress on amivantamab, addressing significant unmet need
- Demonstrates activity in uncommon EGFR mutations with limited therapeutic options
- Manageable safety profile allows for continued treatment in heavily pretreated populations
- Higher response rates in treatment-naïve patients with uncommon mutations suggest potential first-line utility
Limitations
- Single-arm trials without comparator arms limit interpretation of clinical benefit
- Relatively small patient numbers, particularly in uncommon mutation cohorts
- Safety follow-up duration not specified for long-term toxicity assessment
- REZILIENT2 data represents interim analysis with limited maturity
