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This OncLive Peer Exchange featured Drs. Julia Rotow, Ticiana Leal, Estelamari Rodriguez, and Ignacio Wistuba discussing optimal care strategies for patients with ROS1-positive non-small cell lung cancer. Key topics included comprehensive testing importance incorporating DNA and RNA next-generation sequencing to avoid missing actionable fusions, understanding that circulating tumor DNA serves as a useful adjunct but cannot replace tissue-based testing for definitive diagnosis. The discussion highlighted significant therapeutic evolution from first-generation agents like crizotinib with limited central nervous system activity to modern selective inhibitors like taletrectinib offering remarkable durability with progression-free survival exceeding 45 months. Central nervous system activity emerged as critical, allowing systemic therapy to replace radiation in many patients and significantly impacting long-term outcomes. Safety profiles differ substantially between agents, requiring clinician familiarity with unique toxicity patterns for optimal patient management. The panelists emphasized that while ROS1 fusions are rare, occurring in 1% to 2% of patients with non-small cell lung cancer, identifying these alterations transforms patient outcomes with potential for sustained disease control and excellent quality of life lasting many years.

Optimizing Care for ROS1-Positive Non-Small Cell Lung Cancer

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EP. 1: Introduction and Comprehensive Testing Strategies

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

March 30th 2026

Panelists discuss strategies for identifying and managing ROS1-positive NSCLC, focusing on comprehensive testing approaches, emerging clinical data, and factors that guide treatment decisions.

EP. 2: Circulating Tumor DNA Testing and Clinical Decision-Making

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

March 30th 2026

Panelists discuss the role of ctDNA (liquid biopsy) in clinical practice, highlighting its benefits and limitations in detecting actionable mutations, interpreting results, and guiding treatment decisions when tissue testing is insufficient.

EP. 3: Importance of Comprehensive Testing and Patient Counseling

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 6th 2026

Dr. Leal emphasizes that although actionable genomic alterations like ROS1 are rare, their clinical implications are enormous. Following National Comprehensive Cancer Network (NCCN) guidelines, these targets should be acted upon in the first-line setting as the initial targeted therapy treatment.

EP. 4: ROS1 Gene Fusion Characteristics and Therapeutic Evolution

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 6th 2026

Dr. Wistuba provides detailed information about ROS1 gene fusions, discovered in the 1980s with over 30 to 40 fusion partners identified that constitutively activate ROS1 in cells, leading to malignant properties.

EP. 5: CNS Activity and Treatment Implications

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 13th 2026

Dr. Wistuba confirms that fusion variant identification does not impact treatment selection, emphasizing that ROS1-positive versus ROS1-negative status represents the key clinical decision point.

EP. 6: Complex Genomic Reports and Future Considerations

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 13th 2026

Dr. Wistuba addresses the complexity of NGS reports that may include multiple abnormalities beyond ROS1 fusions.

EP. 7: Resistance Mechanisms and Treatment Sequencing

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 20th 2026

Dr. Wistuba explains that acquired resistance to ROS1-targeted therapies frequently involves on-target mutations, with G2032R representing the most frequently observed resistance mutation among 10 to 12 described mutations that affect the ATP binding site and reduce drug binding efficiency.

EP. 8: Safety Profiles and Toxicity Management

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 20th 2026

Dr. Rodriguez reviews historical toxicity profiles from earlier ROS1 inhibitors, noting that crizotinib and entrectinib presented novel side effects including visual field changes preventing night driving due to floaters, along with liver function test (LFT) abnormalities requiring monitoring.

EP. 9: Modern Toxicity Management and Patient Education

ByJulia Rotow, MD,Ticiana A. Leal, MD,Estelamari Rodriguez, MD, MPH,Ignacio I. Wistuba, MD

April 27th 2026

Dr. Rodriguez outlines patient education strategies emphasizing partnership from treatment initiation, as clinical trials demonstrate over half of patients require dose adjustments.