Abstract
Aberrant activation of the PI3K/AKT/mTOR pathway has been implicated in promoting lymphoma cell growth and survival. Several agents targeting this pathway at the PI3K or mTOR levels have demonstrated clinical activity in a variety of lymphoma subtypes. However, there has been no clinical data with AKT inhibitors in lymphoma. MK-2206 is the first oral non-ATP competitive allosteric inhibitor of AKT 1, 2, and 3 which entered clinical development. MK-2206 demonstrated AKT inhibition and antiproliferative activity as single agent and in combination with other agents in multiple human cancer cell lines. MK-2006 synergized antitumor effects of chemotherapeutic agents in vivo and in vitro. To investigate the potential therapeutic value of targeting AKT in lymphoma, we conducted a phase II study of MK2206 in patients with relapsed or refractory lymphoma. Eligible patients were required to have lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma that have relapsed or been refractory after at least one treatment regimen, have no curative option available and have adequate organ functions. MK-2206 (200 mg) was given orally, once per week, in 28-day cycles for a maximum of 12 cycles. In the absences of limiting toxicity, MK2206 dose could be increased to 300 mg. Serum cytokines levels are measured in consenting patients on days 1, 8 and 22 of the first cycle. A total of 59 patients were enrolled including 25 patients with classical Hodgkin lymphoma. The median number of prior treatment regimen was 4 (range, 1-10). Based on intent-to-treat analysis, objective responses were observed in 8 (14%) patients, with 29 (49%) patients demonstrating reduction in their tumor measurements (Figure). The median response duration was 5.8 months. In the 25 patients with classical Hodgkin lymphoma, the response rate was 20%. Treatment was well tolerated, with skin rash being the most common toxicity (Any grade: 53%, Grade 3: 15%). Grade 3 or 4 hyperglycemia was observed in 5%, and neutropenia in 2%. There was no grade 3 or 4 thrombocytopenia. Collectively, the study showed that the AKT inhibitor MK2206 can induce responses in classical Hodgkin lymphoma and indolent lymphoma. The single agent activity, however, seems to be low against large B-cell lymphoma, T-cell lymphoma or mantle cell lymphoma. The possible mechanism of resistance to the treatment with AKT inhibitors may include suboptimal inhibition of AKT phosphorylation at low concentrations or development of alternative survival pathway. Future studies should aim at optimizing the dose and schedule of MK2206, and exploring mechanism-based combination strategies.
Figure 1 Figure 1.
Disclosures
No relevant conflicts of interest to declare.
Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma