Researchers have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage KRAS G12D-mutant pancreatic cancer. The combination therapy led to durable tumor elimination and significantly improved survival outcomes in preclinical models, leading to the launch of a Phase I clinical trial.
Researchers at The University of Texas MD Anderson Cancer Center have uncovered a functional role formutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage-mutant pancreatic cancer. The combination therapy led to durable tumor elimination and significantly improved survival outcomes in preclinical models, leading to the launch of a Phase I clinical trial.
Pancreatic cancer is the third leading cause of cancer death in the United States and often is diagnosed at a late stage, when treatment options are limited and the prognosis is poormutations occur in over 40% of pancreatic cancer cases, but KRAS inhibitors alone have not yielded durable responses for patients. Immunotherapy treatments also have not benefitted patients, partly due to an immunosuppressive tumor microenvironment in pancreatic tumors.
KRAS G12D inhibition depends on immune cell activation for improved, sustained treatment response in early- and late-stage tumors. In thestudy, the researchers built upon the first study by investigating the effects of a KRAS G12D inhibitor, MRTX1133, in 16 different lab models to determine its efficacy and safety in both early- and late-stage tumors.
"These studies show that KRAS inhibition works, but monotherapy delivers only a transient response, especially when dealing with late-stage tumors," Maitra said."Leveraging the immune system by combining KRAS inhibitors with immunotherapy was able to bring about the full effects of these drugs and provide the best possible survival benefits in our models."
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