In a phase 1b/2 study of patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL), the ViPOR regimen [venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide] led to complete responses (CRs), with no unexpected toxicities, according to findings presented by Christopher Melani, MD, Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

“Targeted agents can disrupt key survival pathways in NHL such as regulation of apoptosis (BCL2: venetoclax), B-cell receptor signaling (BTK: ibrutinib), and NF-κB survival pathways (IRF4/SPIB: lenalidomide). These agents are active as monotherapy but fail to induce deep responses and require continuous therapy,” wrote Dr Melani and colleagues, who hypothesized that combining agents that target multiple survival pathways with time-limited cyclic dosing would increase efficacy while limiting toxicities.

Patients with relapsed/refractory B-cell NHL who had adequate organ function were eligible to participate in the study. Using a phase 11 “3+3” design, researchers were able to determine the maximum tolerated dose (MTD) as 4 dose-levels of dose-escalated venetoclax (200 mg, 400 mg, 600 mg, and 800 mg) days 2 to 14 (starts cycle 2 for day 1) in combination with fixed-dose ibrutinib 560 mg days 1 to 14, prednisone 100mg days 1 to 7, obinutuzumab 1000 mg IV days 1 and 2, and lenalidomide 15 mg days 1 to 14.

ViPOR was given for up to 6 cycles every 21-days without maintenance, however, tumor lysis syndrome and pneumocystis jiroveci pneumonia prophylaxis were given to all patients, as well as venous thromboembolism prophylaxis and G-CSF at the discretion of investigators. After cycles 1, 2, 4, and 6, baseline CT, PET, bone marrow, and tumor biopsy was performed along with CT scans; PET scans were also given after cycle 6 or suspected CR.

A total of 53 patients were enrolled and treated, including 17 patients in the dose-escalation phase , 36 in the dose-expansion phase. Approximately 90% had stage III/IV disease, 23 had the diffuse large B-cell lymphoma (DLBCL) subtype, 19 had follicular lymphoma (FL), 9 had high-grade B-cell lymphoma (HGBCL), and 2 had marginal zone lymphoma; of 32 patients with aggressive disease, 34% transformed from indolent NHL.

Among the 53 patients, 51 completed 1 cycle of therapy with restaging CT, tumor reduction occurred in 90% of patients over.  Of the 44 patients no longer receiving therapy, 43 patients were evaluable for response, the objective response rate (OR) was 70%, the CR was 49%. Responses were seen across all DLs and NHL subtypes. In 27 patients with aggressive NHL, the ORR was 56% with 37% CR.  

In patients with non-germinal center B-cell (non-GCB) DLBCL, ORR and CR rates were 62% (8/13) and 54% (7/13), respectively ; patients with GCB DLBCL had a 21% (3/14) CR rate. Among the 16 patients with indolent NHL, ORR was 94% and CR was 69%. In refractory patients, the ORR and CR rate was 52% (11/21) and 29% (6/21), and 86% (19/22) and 68% (15/22) in relapsed patients, respectively.

Patients who did not respond to previous CAR-T therapy and completed ViPOR had an ORR and CR of 40% and 30%, respectively. The median PFS and OS was 9 months and not reached (NR);  in indolent NHL patients, it was 20 months and NR, 3 months and 13 months in GCB, and 7 months and 13 months in non-GCB DLBCL. 5 relapsed after CR, including 2 non-GCB at 3 and 6 months, 1 HGBCL at 5 months, 1 FL at 6 months, and 1 marginal zone lymphoma at 16 months.

One dose-limiting toxicity (DLT), grade 3 intracranial hemorrhage, occurred at dose level 1 with concomitant enoxaparin and aspirin. Adverse events (AEs) included hematologic AEs such as thrombocytopenia (23%), neutropenia (23%), and anemia (7%), and the majority of non-hematologic AEs were grade 1/2, including, diarrhea (67%), hypokalemia (56%), nausea (52%), and rash (42%). Hypokalemia (19%), diarrhea (8%), and a.fib/flutter (6%) were among the most common grade 3/4 non-hematologic AEs.

Grade 4 tumor lysis syndrome occurred in 1 patient with HGBCL after the first venetoclax dose but was treated without further complications.

“ViPOR is safe without unexpected toxicities observed. Most common AEs were hematologic with rare febrile neutropenia and no severe infections observed when given with G-CSF prophylaxis. ViPOR induces durable CRs without maintenance therapy, including refractory and post CAR-T patients,” concluded Dr Melani et al.—Alexandra Graziano

Melani O, Lakhotia R, Pittaluga S. Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide) in Relapsed/Refractory B-Cell Lymphoma: Safety, Efficacy and Molecular Analysis. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 598.