Background
Randomised, open-label phase 3, 62 sites in China. N=498. Age 18-75, locally advanced/metastatic non-squamous NSCLC with EGFR exon 19 del or L858R, progressed on/after EGFR-TKI. Ruzaltatug rezetecan is a HER3-directed ADC.
Results
Interventions and follow up: Arm A: ruzaltatug rezetecan 8.0 mg/kg IV q3w (n=250)
Arm B: pemetrexed 500 mg/m2 + carboplatin (AUC 5) or cisplatin 75 mg/m2 x4, then pemetrexed maintenance (n=248)
Primary endpoint: PFS by BICR (ITT)
mFollow up: 7.7 mo (interim)
Results: PFS (BICR): 8.3 vs 5.4 mo, HR 0.47 (95% CI 0.36-0.60), P<.0001 (one-sided)
OS: NR
Arm B: pemetrexed 500 mg/m2 + carboplatin (AUC 5) or cisplatin 75 mg/m2 x4, then pemetrexed maintenance (n=248)
Primary endpoint: PFS by BICR (ITT)
mFollow up: 7.7 mo (interim)
Results: PFS (BICR): 8.3 vs 5.4 mo, HR 0.47 (95% CI 0.36-0.60), P<.0001 (one-sided)
OS: NR
Adverse events
Grade ≥3 TRAE: 41% vs 39%
Hematologic: neutrophil count decreased G≥3 26% vs 19%, WBC decreased 12% vs 12%, anemia 6% vs 11%
Discontinuation (TRAE): 1% vs 1%
Deaths: 1 possibly treatment-related (unknown cause) in ADC arm
Hematologic: neutrophil count decreased G≥3 26% vs 19%, WBC decreased 12% vs 12%, anemia 6% vs 11%
Discontinuation (TRAE): 1% vs 1%
Deaths: 1 possibly treatment-related (unknown cause) in ADC arm
Conclusions
Ruzaltatug rezetecan significantly prolonged PFS vs chemotherapy with similar grade ≥3 TRAE rates in EGFR-TKI-resistant EGFR-mutated NSCLC.
Key Limitations
Interim PFS analysis with short follow-up (7.7 mo); OS immature; open-label; China-only; prior TKI generation mixed (stratified); no head-to-head vs other HER3/TROP2 ADCs.
Clinical Context
Platinum-pemetrexed remains the reference chemotherapy comparator after EGFR-TKI progression. This is a further HER3-directed ADC phase 3 positive on PFS; regulatory status not established in the publication.
