Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials.

Summary

In two prospective trials, sacituzumab tirumotecan achieved notable responses in previously treated NSCLC, with superior activity in EGFR-mutant disease (ORR up to 55%, median PFS up to 11.1 months). Safety was manageable, dominated by hematologic events, and exploratory data suggested enhanced ADC internalization in EGFR-mutant cells.

Key Findings

• Confirmed ORR 40% and median PFS 6.2 months in KL264-01 (n=43).
• EGFR-mutant subset achieved ORR 55% and median PFS 11.1 months.
• Independent phase 2 (SKB264-II-08) in EGFR-mutant NSCLC showed ORR 34% and median PFS 9.3 months (n=64).
• Hematologic toxicities were most common; diarrhea (4%) and ILD (1%) were uncommon.
• EGFR mutation increased in vitro internalization/activity of sac-TMT.

Clinical Implications

If confirmed in phase 3, sac-TMT could become a targeted option post-TKI in EGFR-mutant NSCLC. Clinicians should monitor for hematologic toxicity and remain vigilant for rare ILD.

Limitations

• Nonrandomized design; comparative effectiveness versus current standards is unknown.
• Sample sizes remain modest; longer-term survival and safety data are pending.

Future Directions

Complete ongoing randomized phase 3 trials in EGFR-mutant NSCLC; define biomarkers (e.g., TROP2 expression, EGFR context) and resistance mechanisms; assess sequencing with TKIs and combination strategies.