Interim results from the phase 3 HARMONi-2 trial reported median overall survival of 30.8 months for ivonescimab versus 22.6 months with pembrolizumab in PD-L1–positive advanced non-small cell lung cancer. The prespecified analysis signals a potential step-change in first-line targeted immunotherapy strategy in a competitive segment of the checkpoint landscape. The development centers on whether the PD-L1 targeting approach embodied by ivonescimab can translate into a durable survival benefit compared with the standard pembrolizumab comparator. Endpoint progression and subgroup consistency will likely shape the next questions for regulators and clinicians. Market and scientific attention will follow the durability of this survival signal and how treatment-related adverse events compare across arms.