DISCUSSION
deaths, pneumonitis, hypophosphatemia, pneumonia, neutropenia, metabolic disorder, toxicity, respiratory failure, thrombocytopenia, anemia, DLBCL, GCB and non-GCB DLBCL, lymphoma, lymphoma malignancies
PNEUMOCYSTIS PNEUMONIA, PNEUMONITIS, HYPOPHOSPHATEMIA, PNEUMONIA, NEUTROPENIA, METABOLIC DISORDER, RESPIRATORY FAILURE, DISEASE, THROMBOCYTOPENIA, SOLID TUMORS, OPPORTUNISTIC INFECTION, ANEMIA, MULTIORGAN FAILURE, LYMPHOMA, COMPLICATIONS
Primary data from this phase I, first-in-human study investigating the safety, tolerability, and preliminary efficacy of SYK/FLT3 inhibitor mivavotinib, conducted in patients with advanced solid tumors or lymphoma malignancies, were previously reported [The ORR and CR rates reported here for all patients with lymphoma including those with DLBCL are clinically meaningful, given the limited treatment options and poor outcomes for these patients with relapsed or refractory disease [Meaningful response rates were observed in both GCB and non-GCB DLBCL subtypes, consistent with the findings of our initial report [Although population-level outcomes data are limited for patients with relapsed or refractory DLBCL, in the large retrospective SCHOLAR study of 636 patients, estimated objective response rates were 26% with a CR rate of 7% and a median OS of 6.3 months [CAR T-cell therapy is expected to become the new standard of care for relapsed or refractory DLBCL [Overall, safety findings were consistent with the primary analysis and toxicity was manageable despite a high proportion of patients experiencing grade ≥3 TEAEs (96% all cause, and 76% determined by the investigator as being related to mivavotinib). The most common grade ≥3 TEAEs were increased amylase, neutropenia and hypophosphatemia; other common grade ≥3 TEAEs included elevations in clinical laboratory investigations, including AST, amylase, lipase and blood creatine phosphokinase, which were largely asymptomatic and reversible upon dose reduction or discontinuation of the study drug, consistent with the initial analysis. The most common hematologic grade ≥3 TEAE was neutropenia (27%), with most of these patients receiving G-CSF support to manage it; this was largely expected due to the number of patients with bone marrow involvement at study entry. Other hematologic grade ≥3 TEAEs including anemia and thrombocytopenia occurred in 19% and 15% of patients, respectively. The most common metabolic disorder of grade ≥3 was hypophosphatemia (26%). Serious TEAEs were reported in 76% of patients; however, only 27% of patients had serious TEAEs determined by the investigator as being related to mivavotinib, and only 26% of patients had serious TEAEs that led to discontinuation. There were 39 on-study deaths among patients with lymphoma, 4 of which were considered related to mivavotinib and were due to complications from pneumocystis pneumonia, multiorgan failure, respiratory failure and disseminated varicella. The most common reasons for discontinuation were pneumonia and pneumonitis; further intervention to reduce the risk of opportunistic infection (e.g., In conclusion, the anti-tumor efficacy of mivavotinib monotherapy observed in the primary analysis of this study was confirmed in our analysis of patients with lymphoma, including an expanded cohort of patients with relapsed or refractory DLBCL, with responses that were deep and durable. These findings support SYK as a potential therapeutic target for the treatment of this population of patients. Further investigation of markers to predict response to SYK inhibition, and research into possible mivavotinib treatment combinations, are needed to develop mivavotinib further, and to provide more extensive therapy options for patients with relapsed or refractory DLBCL who have limited treatment options.