Clinical Activity of Abemaciclib (LY2835219), a Cell Cycle Inhibitor Selective for CDK4 and CDK6, in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is characterized by a recurrent chromosomal translocation t(11;14) that leads to aberrant expression of Cyclin D1 which, together with cyclin dependent kinases 4 and 6 (CDK4/6), inhibits the retinoblastoma (Rb) tumor suppressor protein and thereby induces malignant proliferation. Abemaciclib, a cell cycle inhibitor selective for CDK4/6 (Gelbert et al, 2014), has shown single agent clinical activity against multiple human tumors including lung cancer and breast cancer (Shapiro et al, ASCO 2013; Goldman et al, ASCO 2014; Patnaik et al, ASCO 2014). Based on molecular pathogenesis and single agent activity in preclinical models of human MCL, abemaciclib was evaluated in a single arm Phase II study for patients with relapsed or refractory MCL.

Methods: The primary objective of this study was to estimate the disease control rate, which includes response (complete + unconfirmed complete + partial) plus stable disease, for patients who received abemaciclib for relapsed or refractory mantle cell lymphoma (MCL). Patients were scheduled to receive abemaciclib (200 mg) orally every 12 hours on Days 1 through 28 of each 28-day cycle. Eligibility criteria permitted an unlimited number of prior systemic therapies including high dose chemotherapy with stem cell transplantation, Eastern Cooperative Oncology Group (ECOG) performance status <= 2, absolute neutrophil count >= 1.5 x 10⁹/L, and platelets >= 75 x 10⁹/L. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 were used to grade adverse events. Response Criteria for Non-Hodgkin’s Lymphomas (Cheson et al, 1999) were used to assess clinical activity. Plasma samples for pharmacokinetics were performed both after a single oral dose and after multiple doses at steady state. Flow cytometry was used to isolate circulating MCL cells for evaluation of pharmacodynamic effect on Rb phosphorylation.

Results: In this Phase II study, 22 patients with relapsed or refractory MCL received single agent oral treatment with abemaciclib. Among these patients, 91% presented at initial diagnosis with Stage III or IV disease. At the time of study entry, these patients (9 female and 13 male) had a median age of 66 years (range: 53-83), 59% had ECOG performance status of 1 or 2, and all patients had constitutional B symptoms. Eighteen patients received >= 2 prior systemic therapies, and previous treatments for the overall study population included not only high dose chemotherapy with stem cell transplantation but also rituximab (96%), cyclophosphamide-based therapy (86%), cytarabine-based therapy (64%), temsirolimus (55%), and bendamustine (41%). Patients received 1-16 cycles of treatment with abemaciclib and 8 of 22 patients (36%) completed >= 6 cycles. The most common possibly related treatment-emergent adverse events across all grades included diarrhea (55%, including 9% G3/4), nausea (23%, with no G3/4), vomiting (32%, with no G3/4), fatigue (18%, with no G3/4), thrombocytopenia (55%, including 32% G3/4), neutropenia (36%, including 32% G3/4), and anemia (18%, with no G3/4). Plasma concentrations of abemaciclib were comparable to those previously observed and associated with clinical activity in patients with advanced non-hematologic malignancies. For patients with at least one post-treatment radiographic evaluation, preliminary investigator assessment indicates that single agent therapy with abemaciclib was associated with stable disease for 9 patients and partial response for 5 patients, including durable disease control (>= 6 cycles) in 8 of these 14 patients with relapsed or refractory MCL.

Conclusions: Abemaciclib, a cell cycle inhibitor, demonstrates evidence of durable disease control as a single agent for patients with relapsed or refractory MCL.