pf-06463922 and Pancreatic-Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Transgenic; Neutrophils; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Pyrazoles; Tumor Microenvironment

The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking.. This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months.. Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Mutation; Pancreatic Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrazoles