PF-07284892 + lorlatinib

PF-07284892 + lorlatinib is an **investigational combination therapy** comprising PF-07284892, a potent and selective allosteric inhibitor of **SHP2 (encoded by PTPN11)**, and lorlatinib, an approved **ALK and ROS1 tyrosine kinase inhibitor**. PF-07284892 is designed to overcome resistance mechanisms in oncogene-driven solid tumors that have developed resistance to targeted kinase inhibitors. This combination has demonstrated in preclinical studies and early-phase clinical trials the potential to restore tumor sensitivity and induce responses in patients with advanced solid tumors—such as lung cancer harboring ALK fusions, pancreatic cancer with ROS1 fusions, colorectal cancer with BRAF V600E mutations, and others—who had progressed after standard targeted therapies. Mechanistically, SHP2 inhibition blocks RAS/MAPK pathway reactivation downstream of diverse oncogenic drivers, while lorlatinib directly inhibits ALK or ROS1 kinase activity. The strategy aims for synergistic suppression of tumor growth by addressing both primary oncogenic signaling and the bypass mechanisms that drive acquired resistance[1][3][5].