Discussion
tumor, high-grade astrocytoma, DLBCL, malignancies, glioblastoma, tumors
TUMOR, THROMBOCYTOPENIA, MINOR, SOLID TUMORS, DISEASE, BRAIN TUMOR, ADVANCED CANCER, MALIGNANCIES, GLIOBLASTOMA, TUMORS, DIFFUSE ASTROCYTOMA
Effective new treatments for patients with advanced malignancies are urgently needed, particularly for those patients who have tumor types with limited treatment options or whose tumors are refractory to currently available therapies. BET inhibitors have a mechanism of action that differs from existing marketed drugs, and have demonstrated anticancer activity across a broad range of tumor types in preclinical models and patients with various solid and hematological malignanciesTrotabresib is a next-generation BET inhibitor with properties that provide potent and selective inhibition of BRD family proteins, as well as a PK profile that allowed evaluation of a range of dosing schedules in part A. Preliminary results of this study were encouraging, with trotabresib showing high oral bioavailability and a comparatively long tLonger follow-up of the dose escalation (part A) and data from parts B and C confirmed that trotabresib was generally very well tolerated in heavily pretreated patients with advanced, unresectable solid tumors and R/R DLBCL. Most TRAEs were mild or moderate and were easily manageable with dose modifications and/or treatment interruption. The most frequent grade 3/4 TRAE was thrombocytopenia, which is a class effect of BET inhibitorsBiomarker analysis using blood levels of The preliminary efficacy of trotabresib monotherapy in patients with heavily pretreated advanced solid tumors and R/R DLBCL was supportive of antitumor activity, with one CR and one PR reported in part A (ORR 2.9%; 95% CI, 0.4–10.1), two CRs and one PR in part B (ORR 13.0; 95% CI, 2.8–33.6), and one minor response per Response Assessment in Neuro-Oncology (RANO) criteria in part C (ORR 0.0; 95% CI, 0.0–8.6). The longer follow-up of patients enrolled in part A allowed further characterization of responses in this cohort, with the patient with a CR having sustained response for 19 cycles. A total of five patients in part A remained on treatment for ≥24 cycles, including a patient who received 38 cycles of treatment and a patient who remains on treatment at cycle 53, corresponding to treatment durations of 3 and 4 years, respectively. One patient with high-grade astrocytoma in part C has a minor antitumoral response that is ongoing at cycle 34, and a further seven patients with advanced solid tumors in part C completed ≥1 year of treatment. These data suggest that trotabresib monotherapy may provide long-lasting disease control in some patients, and demonstrate the long-term efficacy and good tolerability of intermittent dosing of trotabresib even in patients with advanced, progressive disease. Importantly, the durable CR in a patient with progressive diffuse astrocytoma and the minor radiographic response in a patient with high-grade astrocytoma, a tumor type with typically poor outcomes and limited effective treatment options, illustrate the ability of trotabresib to penetrate brain tumor tissueEvaluation of the effects of food on trotabresib PK showed generally comparable exposure and plasma concentrations between fed and fasted patients, with a similar tAs this exploratory phase I first-in-human trial was designed to evaluate trotabresib in patients with advanced cancers for whom no standard therapy was available, as well as to guide dose selection for subsequent studies, it is subject to a number of limitations. Thus, its results should be interpreted with care in the absence of an adequately powered randomized controlled trial.In summary, the results from this study demonstrated a tolerable safety profile during long-term treatment, a long tThe results reported here demonstrate the preliminary anticancer properties of trotabresib monotherapy across a range of heavily pretreated advanced solid tumors and in R/R DLBCL, supporting further investigation of its use in combination with other anticancer agents. Based on the responses observed in this study, a clinical trial has been initiated to investigate trotabresib in combination with temozolomide in patients with newly diagnosed glioblastoma (NCT04324840)