Dr Peters on Combining Antiangiogenic Activity With Checkpoint Inhibition in NSCLC

"[It's] not only that you block [PD-L1], but you also make it internalized. So it's a dual blockade of the PD-1/PD-L1 pathway."

Solange Peters, MD, PhD, head of the Department of Clinical Oncology and chief of the Medical Oncology Service at Lausanne University Hospital (CHUV), as well as a full professor at the University of Lausanne, discussed the rationale behind the phase 2/3 ROSETTA Lung-02 trial (NCT06712316) evaluating the PD-L1 x VEGF-A bispecific antibody pumitamig plus chemotherapy in first-line advanced non–small cell lung cancer (NSCLC).

Combining or sequencing bevacizumab (Avastin) with checkpoint inhibitors yielded signals of efficacy, but never enough to establish the approach, Peters said. She noted that bevacizumab's 20-day half-life produces prolonged class-specific toxicities, including bleeding; massive hemoptysis and deaths in early testing kept it out of squamous disease.

In contrast, pumitamig's mechanism appears cooperative within the tumor microenvironment, Peters explained. The agent forms complexes with VEGF-A that cluster with PD-L1 and are internalized, a feature not seen with PD-L1 monospecific antibodies. According to Peters, this remodeling brings cancer cells closer to T cells, which may explain activity in tumors with low PD-L1 expression.

In data presented at the 2026 ASCO Annual Meeting, 58.3% of centrally tested patients had a PD-L1 tumor proportion score (TPS) below 1%. The confirmed objective response rate was 62.5% (95% CI, 45.8%-77.3%) overall (n = 40) and 47.6% (95% CI, 25.7%-70.2%) in patients with a TPS below 1% (n = 21).

The 2000-mg dose produced more toxicity than the 1400-mg dose, but that was not the deciding factor, Peters said. A 1500-mg flat dose, selected through pharmacokinetic/pharmacodynamic modeling, will advance to the phase 3 portion, which she described as the lowest dose delivering the best activity.

Peters added that pumitamig's half-life of roughly 4 to 6 days yields VEGF-related toxicities that are less frequently high grade than with bevacizumab. Grade 3 VEGF-related events occurred in 4.7% of patients (n = 43), including 1 bleeding event that resolved. That profile allows use in squamous disease, she said, noting that trials of the PD-1 x VEGF bispecific ivonescimab even permitted patients with a history of minor hemoptysis.