Multidrug Regimen Could Change Treatment Landscape for Relapsed/Refractory DLBCL

Almost 40% of patients with relapsed/refractory lymphomas achieved complete responses (CRs) with a five-drug regimen that targeted different cancer-survival pathways, a preliminary clinical trial showed.

Overall, 54% of patients responded to the combination of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid), or ViPOR. The 38% CR rate consisted entirely of patients with non-germinal-center B-cell (non-GCB) diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphomas (HGBCL) with specific genomic rearrangements. Two-thirds of responses were ongoing at 2 years, including 78% of CRs.

Although efficacy was limited to specific molecular subtypes, the specificity provides confidence in the generalizability of the results, reported Christopher Melani, MD, of the lymphoid malignancies branch of the National Cancer Institute (NCI) in Bethesda, Maryland, and colleagues in the New England Journal of Medicine.

“Several of these patients are now out 5 years in continued remission, so we think they’re likely cured of their disease at this point in time,” Melani said during an NCI press briefing.

Individually, none of the individual drugs in the regimen has improved overall survival in large B-cell lymphoma (LBCL) in phase III trials, according to the authors of an accompanying editorial.

“The authors present compelling preclinical evidence that the drug combinations in ViPOR, especially the combination of venetoclax and lenalidomide, provide synergistic cytotoxicity in ABC [activated B-cell] LBCL,” wrote Jordan Goldstein, MD, and Ash Alizadeh, MD, PhD, both of Stanford University in California. “This rational combination of targeted therapies in relapsed or refractory LBCL represents an innovative, chemotherapy-free treatment design with curative potential.”

Though free of chemotherapy, the regimen is not free of toxic effects, particularly hematologic toxicity, although the rate of febrile neutropenia was low, they noted.

“Although the best timing of the ViPOR regimen in the management of LBCL will be better defined in future studies, the efficacy seen in patients with disease that is resistant to CAR T-cell therapy highlights its potential as a third-line option,” Goldstein and Alizadeh noted. “Levels of circulating tumor DNA provided an added early measurement of ViPOR efficacy, because all but four future progressions were predictable at the level of minimal residual disease at the end of therapy.”

The data from the trial are too limited to predict whether ViPOR might compete with CAR T-cell therapy as second-line therapy, although “the efficacy results appear promising and perhaps comparable to previous studies of CAR T-cell therapy,” they added.

Melani and other NCI scientists and clinicians participating in the press briefing agreed that ViPOR could have a role as second-line therapy or possibly even as initial treatment for aggressive LBCLs.

“Ultimately, the way things make the greatest impact is if you can use them as the first treatment,” said Mark Roschewski, MD, also of the lymphoid malignancies branch. “So in our sort of thought process on how we want to develop this regimen, or something that looks like this, ultimately we’re planning on how to move this into the upfront setting to try to make the greatest impact and cure the most patients.”

When ViPOR was given to patients who had already received CAR T-cell therapy, about 30% of patients were cured, said Wyndham Wilson, MD, PhD, head of the lymphoma therapeutics section. Giving ViPOR before CAR-T therapy increased the cure rate to 60%.

“Because this doesn’t impact your ability to get CAR-T and is less toxic, I would say, personally, that I would position this before CAR-T because we know that if you go into complete remission with this, the chances are that you’re probably cured,” said Wilson.

Melani said work has already begun toward improving on the ViPOR platform by adding, or perhaps substituting, different agents to improve efficacy. In an ongoing study, investigators will add the bi-specific antibody polatuzumab (Polivy) to the regimen.

Study Details

Upfront chemoimmunotherapy often cures DLBCL, but relapsed/refractory disease has a poor prognosis. Anti-CD19 CAR T-cell therapy has improved outcomes in relapsed/refractory DLBCL, but only 30-40% of patients are cured by the therapy, Melani and co-authors noted.

Drugs that target individual oncogenic driver pathways in DLBCL are active but rarely induce deep responses or cures, they continued. On the basis of preclinical evidence of synergy among targeted drugs in DLBCL, investigators hypothesized that simultaneously inhibiting multiple pathways could be curative in certain molecular subtypes of DLBCL.

Melani and colleagues reported findings from a phase Ib clinical trial of the ViPOR regimen in patients with relapsed/refractory B-cell lymphoma and an efficacy analysis for phase II expansion. Eligible patients had prior exposure to anthracycline-based chemotherapy and to an anti-CD20 antibody. Patients whose disease had failed CAR T-cell therapy were eligible. Patients received ViPOR every 21 days for six cycles.

Data from phase Ib and II included 60 patients, 50 with DLBCL. More than 90% had stage III or IV disease, 86% had elevated lactate dehydrogenase, 56% had at least two extranodal sites of disease, and 68% had an International Prognostic Index score ≥3 (on a scale of 0-5). A third of the DLBCL group had transformed lymphoma, and median number of prior systemic therapies was three, including 20 patients who had prior CAR T-cell therapy.

Any-grade hematologic toxicity occurred in more than two-thirds of patients, including grade 3/4 neutropenia, thrombocytopenia, and anemia in 24%, 23%, and 7% of cycles, respectively. Among nonhematologic toxicity, two-thirds of patients had hypokalemia, which was the only grade 3/4 nonhematologic adverse event (28%). Other nonhematologic toxicities included diarrhea in 68%, nausea in 45%, rash in 35%, and fatigue in 33%.

Among 48 response-evaluable patients with DLBCL, the overall response rate was 54% (n=26), including CR in 38% (n=18). Median time to response was less than a month, and 78% of responses proved durable without consolidation therapy.

Subgroup analysis showed CRs in eight of 13 (62%) of patients with non-GCB DLBCL not otherwise specified, eight of 15 (53%) with HGBCL-DH [double hit]-BCL2, one of three patients with HGBCL-DH-BCL6, and one of five patients with T-cell histiocyte-rich LBCL. None of 12 patients with GCB DLBCL had complete responses but four had partial responses.

With a median follow-up of 40 months, the 2-year progression-free survival (PFS) was 34% in all patients with DLBCL. Patients who received ViPOR in second line had significantly better PFS as compared with those who received the regimen in third line (HR 0.33, 95% CI 0.17-0.66). Four patients had systemic relapse after CR, all within 18 months after treatment. One patient died of COVID-19 while in remission 31 months after treatment.

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