PrECOG PrE0510 - Phase 2 Study of Platinum-Etoposide Plus Ivonescimab for Extensive-Stage Small Cell Lung Cancer

By Taofeek K. Owonikoko, MD, PhD

@teekayowo

Despite advances in treatment, small cell lung cancer (SCLC) remains an aggressive and difficult-to-treat cancer. Most patients are diagnosed with the extensive stage of the disease (ES-SCLC), where survival is often measured in months rather than years. The majority (~70%) of patients diagnosed with ES-SCLC do not live beyond three years.

The introduction of immunotherapy combined with platinum-etoposide chemotherapy marked a significant turning point in the frontline treatment for ES-SCLC. Pivotal phase 3 trials, including CASPIAN and IMpower133, showed that adding immunotherapy to chemotherapy improved progression-free survival (PFS) and overall survival (OS). These studies established chemoimmunotherapy as the standard first-line treatment. Chemoimmunotherapy also increased long-term survival, tripling three- and five-year survival rates compared with chemotherapy alone. While outcomes have improved, gains remain modest, highlighting the need for new treatment approaches.

Before the advent of immunotherapy, researchers identified angiogenesis—the process by which tumors co-opt new blood vessels to support tumor growth—as a key driver of SCLC biology. However, early clinical trials evaluating anti-angiogenic therapies failed to demonstrate durable improvements in progression-free or overall survival. Interest in this strategy has recently resurfaced following positive results from two large trials that combined anti-angiogenic agents with immunotherapy.

Ivonescimab is a novel bispecific antibody that simultaneously targets programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF). It was designed to leverage cooperative binding, a mechanism in which binding to VEGF enhances the antibody's ability to bind PD-1. The molecule was engineered to preferentially target PD-1 while maintaining activity against VEGF. Preclinical studies suggested that concurrent binding of both targets may enhance antitumor activity. An early study in China demonstrated promising efficacy and a favorable safety profile for ivonescimab when combined with platinum-etoposide chemotherapy in patients with extensive-stage SCLC.

Encouraged by these findings, we have launched PrE0510 to determine whether combining ivonescimab with carboplatin and etoposide is safe and tolerable for patients with newly diagnosed ES-SCLC outside of China. The trial aligns with the US Food and Drug Administration's Project Optimus initiative, which emphasizes dose optimization early in drug development by evaluating both safety and preliminary efficacy. We aim to identify the most appropriate dose of ivonescimab while also assessing whether the combination shows sufficient clinical activity to justify a larger, definitive phase 3 trial.

We plan to enroll 60 patients in the US with newly diagnosed ES-SCLC. They will be randomized 1:1 to receive either:

• Ivonescimab 10 mg/kg IV and chemotherapy for four cycles, followed by maintenance ivonescimab 10 mg/kg IV every 21 days; or
• Ivonescimab 20 mg/kg IV and chemotherapy for four cycles, followed by maintenance ivonescimab 20 mg/kg IV every 21 days

Participants will continue maintenance therapy until disease progression or unacceptable toxicity and will be followed for up to three years after completing study treatment.

The primary objective or PrE0510 is to identify the optimal dose of ivonescimab when combined with carboplatin and etoposide by evaluating both safety and overall response rate at each dose level. If the regimen demonstrates an acceptable safety profile and encouraging signs of efficacy, we hope to advance the strategy to a randomized phase 3 trial, with the goal of improving outcomes for patients with extensive-stage small cell lung cancer.

Learn more about PrE0510 at clinicaltrials.gov.

Dr. Owonikoko (University of Maryland/Marlene and Stewart Greenebaum Comprehensive Cancer Center) is the study chair for this trial. The co-chair is Nisha A. Mohindra, MD (Northwestern University/Robert H. Lurie Comprehensive Cancer Center).