Second-Line Sequencing After Earlier-Generation ROS1 TKIs and the Role of Chemotherapy and Immunotherapy in ROS1-Positive Advanced Non-Small Cell Lung Cancer

The panel addresses patients who received crizotinib or entrectinib in first line rather than lorlatinib, and who are now progressing. Transitioning to lorlatinib (or repotrectinib if the specific resistance mechanism supports it) is appropriate, though the panel emphasizes that second-line responses will not match first-line outcomes, reinforcing the importance of using the most effective agent upfront.

For patients who have exhausted targeted options, platinum-pemetrexed chemotherapy remains an active and important backbone. A multi-institutional retrospective study led by Sara Waliany and Jessica Lin, enriched for ALK but informative for fusion-positive tumors broadly, demonstrated that adding chemotherapy to the ongoing targeted therapy rather than switching to chemotherapy alone was associated with doubling of median PFS (approximately 3.5 to 7 months), with the most pronounced benefit in patients with CNS metastases. This off-label approach can be supported through insurance appeal citing this published dataset and is employed at Baptist Health.

Immunotherapy monotherapy for ROS1-positive advanced NSCLC is not recommended. The IMMUNO-TARGET study showed objective response rates of approximately 17% with single-agent immunotherapy, which was substantially inferior to the greater-than-90% response rates with targeted agents, and median response duration was limited. There is also a theoretical concern, analogous to EGFR-mutated NSCLC experience, of enhanced pneumonitis risk when transitioning from a kinase inhibitor to immunotherapy. Chemoimmunotherapy combinations are not favored given the biology does not support immunotherapy responsiveness in most ROS1-positive cases.

Clinical trial enrollment is emphasized at every line of therapy, including dedicated studies for patients with ROS1 G2032R and other resistance mechanisms, as well as antibody-drug conjugate trials targeting MET or HER2 overexpression identified at progression. The panel advocates for ongoing biopsy and IHC testing at progression to identify emergent targetable alterations.