Clinical Case 2: ROS1-Positive Advanced Non-Small Cell Lung Cancer with Progression on First-Line Therapy and Solvent-Front Resistance

The second clinical case presents a patient with ROS1 fusion-positive advanced NSCLC who achieved partial response on frontline lorlatinib, maintained for 18 months, before symptomatic and radiographic progression: increasing primary tumor size, new contralateral pulmonary nodules, and brain MRI showing 3 new small intracranial lesions. Repeat NGS identifies a ROS1 G2032R mutation, which is the most common solvent-front resistance mutation to ROS1 kinase inhibitors, acting at the glycine 2032 to arginine substitution within the kinase domain binding site, analogous to T790M in EGFR-mutated NSCLC.

The panel emphasizes the importance of obtaining tissue biopsy from the progressing lesion rather than relying solely on liquid biopsy given the spatial heterogeneity of resistance. At progression, IHC should also be ordered for protein overexpression (MET, HER2) based on emerging data that amplification or overexpression of these proteins can emerge as acquired resistance mechanisms and unlock additional therapeutic options. The panel notes that protein expression status may change over the course of treatment and should not be assumed to remain stable from baseline.

NP Hernandez describes the emotional weight of these conversations, acknowledging that she has cried with patients at progression and emphasizing that establishing a genuine connection at diagnosis with team members the patient trusts makes these subsequent conversations more manageable and keeps hope intact.