Capmatinib and Lorlatinib

Capmatinib and lorlatinib is a combination therapy used in the treatment of non-small cell lung cancer (NSCLC). This combination specifically targets two distinct oncogenic drivers: 1. Lorlatinib is a potent ALK tyrosine kinase inhibitor (TKI) that targets the anaplastic lymphoma kinase (ALK) gene alterations. 2. Capmatinib is a selective MET tyrosine kinase inhibitor that targets c-Met (hepatocyte growth factor receptor). The combination has shown particular efficacy in ROS1-rearranged NSCLC with acquired MET amplification as a resistance mechanism. Both drugs have CNS-penetrant properties, making them effective for treating brain metastases, which are common in advanced NSCLC[1][2]. In clinical cases, this combination has demonstrated both intracranial and extracranial responses in patients who developed resistance to sequential ROS1 inhibitor therapy due to MET amplification[1][2]. ## Mechanisms of Action The combination works through dual inhibition: - Lorlatinib inhibits ALK, including ALK that has become resistant to other ALK inhibitors - Capmatinib inhibits c-Met (HGFR), blocking aberrant signaling pathways that drive cancer growth This dual targeting approach helps overcome resistance mechanisms that develop with single-agent therapy[1][2][4]. ## Clinical Evidence In a reported case of ROS1-rearranged lung adenocarcinoma with acquired MET amplification after sequential treatment with ROS1 inhibitors, the combination of lorlatinib (50 mg daily) and capmatinib (400 mg twice daily) induced: - Rapid clinical improvement within 2 weeks - 69% reduction in target tumor lesions - Shrinkage of numerous parenchymal CNS metastases (43% reduction in dominant left temporal lobe lesion) - Intracranial and extracranial partial responses per RECIST v1.1 criteria - Duration of benefit was 32 weeks until disease progression[1] ## Side Effects Common adverse events reported with this combination include: - Grade 1 lower extremity edema - Grade 1 nausea (predominantly attributed to capmatinib) - Grade 2 hyperlipidemia (attributed to lorlatinib)[1] For lorlatinib alone, common side effects include hyperlipidemia (66-72%), with a quarter of patients experiencing grade 3-4 events, and weight gain (44% at 5 years)[7]. ## Development Status This combination is being investigated for use in NSCLC patients with specific genetic alterations, particularly those with ROS1-rearrangements who have developed MET amplification as a resistance mechanism to prior targeted therapies[1][2].