Cullinan Therapeutics (CGEM) Study result summary

Background and Study Rationale

• EGFR exon 20 insertions represent 5–12% of EGFR mutations in NSCLC and respond variably to EGFR-targeted therapies.

• Zipalertinib is a selective, next-generation, irreversible EGFR inhibitor targeting exon 20 insertion mutations, with clinical activity in early studies, including CNS involvement and post-amivantamab settings.

• Previous agents like amivantamab and sunvozertinib improved PFS versus chemotherapy in randomized trials.

Study Design and Patient Population

• REZILIENT3 is a global, multicenter, randomized, controlled, open-label phase III trial evaluating zipalertinib plus chemotherapy versus chemotherapy alone in previously untreated, locally advanced or metastatic EGFR exon 20 insertion mutation NSCLC.

• 279–280 patients were enrolled: 140 received zipalertinib + chemotherapy, 139–140 received chemotherapy alone; eligibility included ECOG PS 0/1, stable brain metastases, and available archival tissue.

• Baseline characteristics were balanced: median age ~65, ~65% female, ~60% never smokers, 31–40% with brain metastases; nearly 60% of patients were enrolled outside Asia.

• The trial involved 122 sites across 24 countries and was supported by a global team of investigators and participants.

Efficacy Results

• Zipalertinib plus chemotherapy achieved a median progression-free survival (PFS) of 14.5 months versus 8.5 months for chemotherapy alone (HR: 0.50; P = 0.00015), with a 50% reduction in risk of progression or death.

• Objective response rate was 65% vs 40.3% (P < 0.0001), with a median duration of response of 14.2 vs 9.9 months.

• Subgroup analyses showed consistent PFS benefit across ECOG PS, brain metastases (HR: 0.38), sex, age, and smoking history, indicating strong intracranial activity.

• Early overall survival data showed a favorable trend (HR 0.72, P = 0.11), though not yet statistically significant, with high crossover to zipalertinib.

• Results were presented at the 2026 World Conference on Lung Cancer in a Presidential Symposium.