Discussion
tumor, cancers, TEEs, cancer, pleomorphic adenoma, tumors, MTAP loss
TUMOR, CANCERS, CANCER, DISEASE, ADVANCED CANCER, PERIVASCULAR EPITHELIOID CELL TUMOR, DELETION, PLEOMORPHIC ADENOMA, TUMOR GROWTH, TUMORS, DISEASE CHARACTERISTIC
GSK3368715 is a first-in-class type I PRMT inhibitor that exhibited strong anticancer activity in preclinical studies. Despite this encouraging finding, and early evidence in the current study of target engagement in peripheral blood at doses of 200 mg, the study was paused due to concern over a higher-than-expected rate of TEEs and limited clinical activity as manifested by disease stability in 29% of patients. These results should be interpreted with caution, considering that only 5/31 (16%) participants had treatment for 3–6 months, and only 1 participant had treatment beyond 6 months. Taken together, the lack of observed clinical efficacy, the cumulative incidence of TEEs over a relatively short period of time, and limited and variable target engagement in the tumor at lower doses (100 mg) led to a comprehensive risk/benefit analysis and early study termination.The expected rate of TEEs in a population of patients with advanced cancer treated in Phase I studies has been previously described [Efficacy in this unselected patient population was limited and no clear trend regarding treatment response and disease characteristics was apparent. Efficacy may have been influenced by the incidence of TEEs and low target engagement in tumor. In a subset of in vivo preclinical xenograft models, a 40–60% decrease in ADMA-hnRNP-A1 measured by IHC in tumors was associated with 80–100% tumor growth inhibition. Thus, a response would have been expected at the 200-mg dose level. While the incidence of TEEs precluded evaluation of target engagement and efficacy at 200 mg which may have confirmed a relationship between dose level and efficacy, limited tumor target engagement at 100 mg suggested an association with the lack of efficacy at this dose level. Additionally, some tumor types with frequent MTAP gene deletion were included in part 1, but MTAP loss was not required for enrollment. Only 6 patients in the study had MTAP gene deletion and of those, 4 had progressive disease with treatment exposure ranging from 15 days to 37 days and 2 achieved stable disease. The two patients who achieved stable disease included the patient with a primary diagnosis of pleomorphic adenoma who had 224 days of exposure to GSK3368715 100-mg and a patient who had a uterine perivascular epithelioid cell tumor and 57 days of treatment exposure at the 200-mg dose level. Due to the small number of patients with MTAP loss included in the study and limited exposure to treatment, no conclusions can be made regarding efficacy in this specific patient population.Despite the findings in this study, additional investigation of PRMT inhibition remains warranted regarding, both the interplay between type I and type II PRMT (PRMT5) inhibition and the respective utility of targeting each individually for the treatment of cancer. Preclinical studies suggest a synthetic lethal relationship between PRMT5 and loss of type I PRMT function [With respect to PRMT5, overexpression has been linked with multiple hematopoietic and solid cancers, and several selective PRMT5 inhibitors have recently been studied in Phase 1/2 trials, particularly to target tumor dependencies on PRMT5 functioning as a splicing regulator [Overall, in the current study, which targeted type 1 PRMT in isolation, heterogeneity of the study population may be contributing to the study results.