ROS1+ NSCLC: Key Takeaways From Case-Based Roundtables With Dr Santos

In this interview, Edgardo Santos Castillero, MD, reflects on the key discussions from his Case-Based Roundtables with Targeted Oncology, which centered on the evolving treatment landscape for ROS1-positive non–small cell lung cancer (NSCLC).

Santos Castillero is physician lead at The Oncology Institute, Lung Cancer Center of Excellence; clinical associate professor, Charles E. Schmidt College of Medicine, Florida Atlantic University; and president, Florida Society of Clinical Oncology.

Dr Santos begins by tracing the evolution of ROS1 tyrosine kinase inhibitors (TKIs), from first-generation agents like crizotinib (Xalkori) roughly 15 years ago to newer, more potent compounds with improved toxicity profiles. He highlights updated data from the TRUST-I and TRUST-II trials presented at the AACR Annual Meeting in April, noting that the ROS1 inhibitor taletrectinib (Ibtrozi) demonstrated a median duration of response and progression-free survival approaching 50 months—outcomes he describes as clinically significant and unprecedented for this population.

A recurring theme throughout the roundtables was the challenge of generating robust phase 3 data in rare, biomarker-defined populations like ROS1 (occurring in only 1-2% of NSCLC cases), which limits both clinical trial enrollment and physicians' hands-on experience comparing sequential inhibitors. Dr Santos also discusses the favorable tolerability profile of taletrectinib, including reduced CNS effects such as dizziness and manageable, short-lived gastrointestinal toxicity compared to earlier ROS1 inhibitors.

Looking ahead, he touches on emerging investigational agents as well as the ongoing research into resistance mechanisms, such as the G2032R mutation, that inform sequencing decisions after progression on newer TKIs like taletrectinib and repotrectinib (Augtyro). Dr Santos closes with a call for expanded real-world data collection to complement clinical trial findings, given the practical limitations of studying such a rare molecular subgroup.

This conversation offers valuable insight for oncologists managing ROS1+ NSCLC, covering the latest efficacy data, safety considerations, and the future direction of targeted therapy development in this space.