December 21, 2020 — The 5-drug regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide showed a tolerable safety profile and encouraging antitumor activity with complete responses in patients with relapsed/refractory diffuse large B-cell lymphoma.
The 5-drug regimen of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid; ViPOR) showed a tolerable safety profile and encouraging antitumor activity with complete responses (CRs) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to phase 1b/2 findings that were presented during the 2020 ASH Annual Meeting and Exposition.
Results showed that of 52 evaluable patients, the best overall response was 71%, with a complete response (CR) rate of 52% and a 19% partial response (PR) rate. Specifically, in relapsed patients (n = 30), the objective response rate (ORR) was 83% with a 70% and 13% CR and PR rate, respectively. The ORR was 55% in refractory patients (n = 22), with a 27% CR rate and a 27% PR rate.
The regimen was also found to be safe without significant rates of tumor lysis syndrome (TLS) or grade 3 or higher adverse events (AEs), and hematologic AEs were common and were managed with granulocyte colony stimulating factor (G-CSF).
“ViPOR induces durable CRs without the need for maintenance therapy, and this is especially true in non-[germinal center B-cell] DLBCL, high-grade B-cell lymphoma ‘double hit’, as well as follicular lymphoma, and includes patients with refractory disease and post–CAR [T-cell therapy] patients,” said lead study author Christopher J. Melani, MD, an assistant research physician in the Lymphoid Malignancies Branch of the National Cancer Institute, in a virtual presentation during the meeting.
ViPOR is a novel targeted therapy regimen that targets key survival pathways utilized by both indolent and aggressive B-cell lymphomas, such as regulation of apoptosis (BCL-2; venetoclax), B-cell receptor signaling (BTK; ibrutinib), and NF-κB survival pathways (IRF4/SPIB; lenalidomide).
The regimen was administered in 6 cycles of a 2-weeks-on/1-week-off schedule, or 18 weeks overall, without maintenance therapy. The dosing schedule was as follows for each cycle: obinutuzumab at 100 mg intravenously on days 1 and 2, oral prednisone at 100 mg daily on days 1 to 7, oral ibrutinib at 560 mg daily on days 1 to 14, oral lenalidomide at 15 mg daily on days 1 to 14, and venetoclax per the dose-escalation schedule on days 2 to 14. Pegfilgrastim (Neulasta) was given at 6 mg subcutaneously on day 8. The first patient cohort did not receive venetoclax until cycle 2.
Following treatment, patients were monitored for surveillance through CT scans and circulating tumor DNA (ctDNA) analyses every 3 months, every 4 months, every 6 months, and once yearly in years 1, 2, 3, and 4 and 5 years after treatment, respectively.
Accrual has been completed in the dose-escalation phase of the trial. There are 4 dose levels of venetoclax: 200 mg daily on days 2 to 14 (dose level 1), 400 mg daily on days 2 to 14 (dose level 2), 600 mg daily days 2 to 14 (dose level 3), and 800 mg daily on days 2 to 14 (dose level 4). There was a ramp-up dose-escalation schedule where patients received their target dose by day 12.
Patients are currently enrolling in the dose-expansion phase (phase 2) part of the trial. The 2 cohorts will comprise 40 patients with DLBCL with both germinal center B-cell (GCB) and non-GCB (n = 20 each), and follicular lymphoma (n = 30). These cohorts will be evaluated for further efficacy and safety, Melani said in the virtual presentation.
Twenty patients have been treated on the phase 1b portion and 38 on the phase 2 portion of the trial. Twenty-three patients had indolent non-Hodgkin lymphoma and 35 had aggressive disease. Thirty-seven percent of patients in the aggressive disease–cohort had transformed lymphoma; additionally, 37% had low to low–intermediate risk disease and 63% of these patients had high-intermediate to high-risk disease.
Overall, the median age is 58 years (range, 29-83) and patients had DLBCL (34%), double-hit lymphoma (21%), T-cell/histiocyte-rich large B-cell lymphoma (5%), follicular lymphoma (36%), and marginal zone lymphoma (3%). The median number of prior therapies was 3 (range, 1-9), which included a prior agent in the ViPOR regimen (28%), transplant (12%), and/or CD19-directed CAR T-cell therapy (22%). Forty-seven percent of patients were refractory to their last line of treatment compared with 53% of patient who had relapsed.
Regarding safety, hematologic AEs were found to be the most common of all patients evaluable for safety; grade 3/4 thrombocytopenia occurred in 23% of patients, neutropenia in 22%, and anemia in 7%. Febrile neutropenia occurred as a grade 3 event in 3 patients.
G-CSF was used in 90% of cycles, and all patients now receive pegfilgrastim as prophylaxis on day 8. Dose reductions occurred in 22 patients (7% of cycles) and dose delays in 26 patients (10% of cycles).
The most common grade 3/4 non-hematologic AEs were hypokalemia (19%), increased liver function abnormalities (11%), diarrhea (7%), and atrial fibrillation/atrial flutter (5%). One case of grade 4 tumor lysis syndrome occurred in a patient with MIK-rearranged high-grade B-cell lymphoma, which resolved after drug discontinuation, made a full recovery and the patient could continue on therapy. One dose-limiting toxicity (DLT) of grade 3 intracranial hemorrhage occurred at the dose level 1.
“Otherwise, we had no other DLTs, and thus venetoclax at 800 mg was taken forward in expansion,” Melani said.
Eighty-nine percent of the 56 evaluable patients experienced tumor reduction with the ViPOR regimen. Of the 6 patients who had an increase in tumor size, all had aggressive lymphoma, 3 of whom had GCB DLBCL.
In the 31 evaluable patients with aggressive non-Hodgkin lymphoma, the ORR was 55%, which comprised a 35% CR rate and a 19% PR rate. The ORR was 71% in relapsed patients (n = 14), which included a 50% CR rate and a 21% PR rate. In the refractory group with aggressive disease (n = 17), the ORR was 41% with a 24% CR rate and an 18% PR rate.
Responses were higher in patients with non-GCB DLBCL (n = 14), with an ORR of 64% that comprised a 57% CR rate and a 7% PR rate, compared with a 47% ORR, 18% CR rate, and 29% PR rate in patients with GCB DLBCL (n = 17), respectively.
In those with indolent lymphoma (n = 21), the ORR was 95% and 76% and 19% of patients achieved a CR and PR, respectively. In the group of relapsed patients with indolent disease (n = 16), the ORR was 94% with an 88% CR rate and 6% PR rate; these rates were 100%, 40%, and 60% in those with refractory indolent disease (n = 5).
Thirty of the 41 total responses (73%) are ongoing, which include 81% of the 27 CRs and 57% of the 8 PRs. Overall, the median time to response was 0.79 months (95% CI, 0.66-1.35) and the median duration of response has not been reached.
At a median follow-up of 14.7 months, the 1-year progression-free survival (PFS) rate was 32.8% with the ViPOR regimen in patients with aggressive non-Hodgkin lymphoma. When stratified by DLBCL subtype, these rates were 43.8% and 23.3% in non-GCB DLBCL and GCB DLBCL, respectively (2-sided P = 0.85; 1-sided P = .042). In those with indolent disease, the 1-year PFS rate was 69.2%.
Molecular and ctDNA analyses are ongoing to determine the rate of minimal residual disease negativity as well as response in the DLBCL genetic subtypes. Additional targeted agents are also being added to ViPOR to improve responses in the more resistant tumors, including GCB DLBCL and transformed lymphomas, Melani concluded.