Cabozantinib overcomes ROS1 L2086F NSCLC resistance to lorlatinib: A case report

ROS1 rearrangement a distinct molecular subtype of non-small cell lung cancer that is amenable to targeted therapeutic interventions. Despite the availability of effective targeted therapies, the development of acquired resistance to later-line inhibitors, particularly lorlatinib, remains an inevitable, and clinically significant challenge. The emergence of the ROS1 L2086F mutation as a mechanism of lorlatinib resistance further complicates treatment, with limited therapeutic options available post-resistance. This case report evaluates the potential efficacy of cabozantinib, a multi-targeted kinase inhibitor, as a salvage therapy in this specific and challenging clinical context.

A 63-year-old, nonsmoking female presented with cough and expectoration.

The patient was diagnosed with left lower lobe lung adenocarcinoma (cT2N2M1, stage IV), characterized by a CD74-ROS1 fusion mutation. Following disease progression on lorlatinib, next-generation sequencing analysis of pleural effusion identified an acquired ROS1 L2086F resistance mutation, accompanied by a concurrent mTOR mutation and FGFR3 gene amplification.

The patient underwent sequential targeted therapy with first-line crizotinib, second-line lorlatinib, and third-line cabozantinib.

The patient demonstrated a progression-free survival (PFS) of 47 months with first-line crizotinib (PFS1) and 11 months with second-line lorlatinib (PFS2). Upon detection of the L2086F mutation, third-line cabozantinib achieved a clinically significant PFS of 12 months (PFS3), accompanied by disease stabilization and symptomatic relief. The overall survival from initial diagnosis was 73 months.

This case highlights the clinical efficacy of cabozantinib in overcoming lorlatinib resistance mediated by the ROS1 L2086F mutation, resulting in durable clinical benefits surpassing those of conventional chemotherapy. These findings emphasize the critical role of repeated, comprehensive genomic profiling in managing refractory ROS1-positive non-small cell lung cancer and establish cabozantinib as a viable therapeutic option in this specific resistance context.