Presentation Authors: Brian Kadow*, Daniel Geynisman, Philadelphia, PA, Brian Such, New Haven, CT, Stephen Boorjian, Rochester, MN, Surena Matin, Houson, TX, Edward Rampersaud, Durham, NC, Daniel McClean, Barton Milestone, Elizabeth Plimack, Matthew Zibelman, Alexander Kutikov, Marc Smaldone, David Chen, Rosalia Viterbo, Shreyas Joshi, Richard Greenberg, Eric Ross, Lois Malizzia, Thomas McGowan, Robert Uzzo, Philadelphia, PA
Introduction: Level 1 evidence shows that mTOR inhibition is associated with clinically significant reductions in tumor size in angiomyolipomas (AMLs) associated with Tuberous Sclerosis. We conducted a phase II, multi-center trial assessing the effectiveness and tolerability of everolimus (EVE) for sporadic AMLs and report the tolerability and adverse effect (AE) data here.
Methods: We conducted a prospective, phase II clinical trial in patients presenting with >3cm sporadic AMLs who were candidates for surgical or percutaneous intervention. Response was defined as â‰¥25% volumetric reduction of the AML. Baseline, 4- and 6-month volumetric analysis was performed by dynamic contrast-enhanced MRI (DCE-MRI). Patients received EVE 10mg for 4 28-day cycles, at which point EVE was discontinued in those with â‰¥25% volumetric reduction. Those with â‰¥25% volumetric reduction received two additional cycles of EVE. Dose reductions and interruptions were allowed to 5 mg QOD. AEs and patient decisions to withdraw from the trial were categorized. Conservative stopping rules were established for toxicity.
Results: We enrolled 20 patients (median age = 68) with 21 sporadic AMLs. 11/20 (55%) patients completed 4 cycles of EVE, and 7/20 (35%) completed 6 cycles. Efficacy was demonstrated, with 10/16 (62.5%) patients exhibiting â‰¥25% reduction in tumor volume at 4 months and 8/12 (66.6%) patients exhibiting â‰¥25% reduction in tumor volume at 6 months. 4/20 (20%) patients were withdrawn due to predefined toxicities, including grade 3 mucositis, grade 1 pneumonitis, grade 2 pneumonitis, and grade 2 hyperglycemia. Dose reductions were required in 6/20 (30%) patients. 2 (10%) patients required two dose reductions, and 4 (20%) patients required a single dose reduction. 19/20 (95%) of patients experienced at least one grade 2 AE during the trial. 5/20 (25%) patients had grade 3 toxicities (oral mucositis in 3 patients, hyperglycemia in 1 patient, and UTI in 1 patient) which resolved upon discontinuation or dose reduction of EVE. Of the 8/20 (40%) patients who withdrew due to personal preference, a mean of 13.75 AEs were experienced, mainly grade 1 and 2. The most common AEs during the trial included oral mucositis (70%), increased ALT (55%), hyperlipidemia (55%), increased AST (50%), anemia (50%), hyperglycemia (40%), and fatigue (40%).
Conclusions: EVE was associated with a high rate of treatment termination due to patient preference or protocol-defined AEs. Patients appear to be less willing to tolerate the side-effect profile of EVE for benign lesions such as AMLs as they be might for metastatic renal cell carcinoma.
Source of Funding: Novartis Pharmaceuticals