ViPOR Regimen Shows Durable Responses in Relapsed/Refractory DLBCL Subtypes

August 13, 2024

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Targeting multiple survival pathways simultaneously with ViPOR may be effective in specific molecular subtypes of relapsed/refractory DLBCL.

In the single-center phase 1b/2 trial, investigators sought to determine whether targeting multiple pathways with systemic agents—specifically, ViPOR—improves survival outcomes for patients with DLBCL. Some of these survival pathways include chronic active BCR, NF-κB, PI3K, BCL2, IRF4, Ikaros, and Aiolos.

A combination regimen of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid; ViPOR) demonstrated a 54% objective response rate (ORR) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to findings from a phase 1b/2 trial (NCT03223610) published in the New England Journal of Medicine.

Results showed that the ORR in 48 evaluable patients comprised a 38% complete response (CR) rate that was exclusively observed in patients with non–germinal-center B-cell (GCB) DLBCL and high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, or both. Seventy-eight percent of CRs were durable and occurred without consolidation therapy. The CR rates were 62% in patients with non-GCB DLBCL not otherwise specified (NOS; n = 8/13), 53% (n = 8/15) of patients with high-grade B-cell lymphoma-DH-BCL2, 33% (n = 1/3) of those with high-grade B-cell lymphoma-DH-BCL6, and 20% (n = 1/5) of those with T-cell histiocyte-rich LBCL.

At a median follow-up of 40 months (IQR, 32-51), the 2-year progression-free survival (PFS) and overall survival (OS) rates were 34% (95% CI, 21%-47%) and 36% (95% CI, 23%-49%), respectively.

The phase 1b portion included 20 patients with DLBCL (n = 10) and indolent lymphomas (n = 10), and 4 dose levels of venetoclax were explored in a 3+3 design to determine a recommended phase 2 dose (RP2D); the other 4 agents had fixed doses. In the phase 2 expansion portion, patients with GCB and non-GCB DLBCL were included for a total of 40 patients with DLBCL.

The 4 venetoclax dose levels were 200 mg (dose level 1), 400 mg (dose level 2), 600 mg (dose level 3), and 800 mg (dose level 4) on days 2 to 14. Ibrutinib was given at a fixed dose of 560 mg on days 1 to 14, prednisone was given at 100 mg on days 1 to 7, obinutuzumab was given at 1000 mg on days 1 to 2, and lenalidomide was given at 15 mg on days 1 to 14. Patients had a 12-day initial ramp-up to the target venetoclax dose level and were treated with allopurinol for tumor lysis syndrome (TLS) prophylaxis.

In the phase 1b portion, there was a report of a single dose-limiting grade 3 intracranial hemorrhage, determining 800 mg of venetoclax as the RP2D. The ViPOR regimen was administered every 3 weeks for 6 cycles.

To be eligible for enrollment, patients needed to be at least 18 years old and have an ECOG performance status of 0 to 2, adequate organ function, prior anthracycline therapy, and prior receipt of anti-CD20 antibodies. Those who were pregnant or breastfeeding, had active central nervous system disease, used CYP3A4 inhibitors, and who had human immunodeficiency virus infection were excluded. Prior treatment with venetoclax, ibrutinib, or lenalidomide was permitted.

Regarding baseline characteristics in the 50 patients with DLBCL overall, the median age was 61 years (range, 29-77). Ninety-two percent of patients had stage III/IV disease, and most had elevated levels of lactate dehydrogenase (86%), at least 2 extranodal disease sites (56%), and an International Prognostic Index score of at least 3 (68%). Thirty-four percent of patients had transformed lymphoma, and the median number of prior systemic therapies was 3 (range, 1-9); 40% of patients previously received CAR T-cell therapy, and 58% had refractory disease. Patients had DLBCL NOS (n = 25), which included 12 with the GCB subtype and 13 with a non-GCB subtype. Finally, 20 patients had high-grade B-cell lymphoma, which included those with MYC and BCL2 translocations (n = 17), MYC and BCL6 translocations (n = 3), and T-cell histiocyte-rich LBCL (n = 5).

Additional results showed that there was undetectable circulating tumor DNA in 33% of patients at the end of treatment. Of the 48 patients evaluable for response, the median time to response was 0.66 months (range, 0.59-4.34). No patients in the GCB DLBCL NOS subtype (n = 12) had CRs; 4 patients had partial responses (33%).

The 2-year duration of response rate was 65%, which included 78% of patients with CRs and 38% with PRs. For patients who received ViPOR as a second-line therapy, the PFS was greater than those who received it as third-line or later treatment (HR, 0.33; 95% CI, 0.17-0.66).

Four patients experienced disease relapse following a CR, and all occurred within 18 months of treatment. One patient died from COVID-19 while being in remission for 31 months after treatment.

Regarding safety, any-grade adverse effects (AEs) were reported in more than two-thirds of patients. Grade 3/4 AEs included neutropenia (24%), thrombocytopenia (23%), anemia (7%), and febrile neutropenia (1%); grade 3/4 hypokalemia was seen in 28% of patients, and 67% of any-grade hypokalemia events led to electrolyte replacement. Additional nonhematologic AEs included diarrhea (68%), nausea (45%), rash (35%), and fatigue (33%). Serious AEs were reported in 42% of patients; non-neutropenic fever was the most common serious AE.

Grade 3 atrial fibrillation was reported in 3 patients, and there was 1 major hemorrhagic event. Furthermore, 1 grade 4 case of TLS occurred, resolved, and then recurred after continued treatment.

Dose reductions occurred in 17% of patients, and dose delays occurred in 25%; 5 patients discontinued study treatment due to unacceptable toxicity or intercurrent illness.

Reference

Melani C, Lakhotia R, Pittaluga S, et al. Combination targeted therapy in relapsed diffuse large B-cell lymphoma. N Engl J Med. 2024;390(23):2143-2155. doi:10.1056/NEJMoa2401532