Clinical development of mechanism-based lymphoma therapies

Division Of Basic Sciences - Nci

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Abstract

We have recently a phase I/II trial of ViPOR, a multi-targeted combination regimen that blocks key survival pathways in Lymphoma. Four of the agents in ViPOR - ibrutinib, venetoclax, lenalidomide, and prednisone - were chosen based on strong synergistic toxicity in cell line models of diffuse large B cell lymphoma (DLBCL), and the fifth agent, obinutuzumab, was included to enlist the innate immune system. As we reported in the New England Journal of Medicine, 50 patients with relapsed/refractory DLBCL were treated with ViPOR, with frequent CRs (38%), including in patients with tumors that were refractory to the last therapy and in patients whose tumors relapsed following CAR-T immunotherapy (40% of patients). At 2-years, progression-free survival rate was 34%, which compares favorably to the survival rates with CAR-T. Using molecular profiling, we identified genetic subtypes of DLBCL that are most responsive to ViPOR. As predicted from our pre-clinical work, patients with non-GCB subtype of DLBCL derived significant benefit, with ViPOR inducing a 2-year progression-free survival (PFS) of 39%. Of particular note, those non-GCB patients whose tumors belonged to the MCD genetic subtype had an 83% CR rate, which confirms our previous laboratory and clinical findings that this genetic subtype is highly susceptible to inhibition of BCR signaling. Unexpectedly, patients with GCB DLBCL whose tumors had both BCL2 and MYC translocations (aka "double hit" lymphomas) had frequent CRs to ViPOR (50%), which translated into a PFS of 47%. This genetic subtype, termed EZB-DH, contrasts with another prominent GCB subtype, termed EZB-nonDH, which lacks MYC translocation and was not responsive to ViPOR, with no CRs and a 2-year PFS of only 8%. Current laboratory studies are revealing that the efficacy of ViPOR in EZB-DH is due to the inherent toxicity of MYC overexpression, which is revealed when BCL2 is inhibited by venetoclax.