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A new SHP2 inhibitor overcomes resistance mediated by bypass signaling pathway activation in diverse tumor models, ranging from ALK-fusuon positive lung cancer to ROS1 fusion-positive pancreatic cancer
Many cancer patients develop resistance to targeted therapies through bypass signaling pathway activation, thus authors of a new study recently published in Cancer Discovery designed a novel allosteric SHP2 inhibitor, PF-07284892, to overcome that resistance when combined with inhibitors of various oncogenic drivers.
The new study distinguishes itself from prior drug development programs by leveraging early introduction of combination therapy in a phase I trial. As opposed to treating patients with a SHP2 inhibitor alone in dose escalation, each patient with an oncogene-driven cancer was permitted the addition of matched targeted therapy. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion–positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial, then the study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA reductions and extended the duration of overall clinical benefit for four patients treated at the first dose level. «We are not aware of another trial in which the first patients in dose escalation had access to rational combination treatments instituted immediately upon monotherapy progression. This phase I study is ongoing and will more fully evaluate up-front combination therapy safety and efficacy at higher doses in patients with prior progression on appropriate targeted treatment», authors conclude.