Multidrug regimen could be ‘curative’ option for aggressive lymphoma
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Key takeaways:
- A novel multidrug regimen targeting survival pathways in diffuse large B-cell lymphoma produced significant responses in certain subtypes.
- The regimen could be used before or instead of CAR-T.
A simultaneous, multidrug, multi-targeted treatment regimen produced remissions in patients with certain types of relapsed or refractory diffuse large B-cell lymphoma in a phase 1b/phase 2 study.
The findings, published in The New England Journal of Medicine, found 38% of the cohort had a complete response to the novel combination of venetoclax, ibrutinib, prednisone, obinutuzumab and lenalidomide (ViPOR), and tumors shrank in 54% of study participants.
“These patients usually die of their disease so there is a need for more effective therapy, and our results with ViPOR demonstrate — for the first time — that targeting multiple survival pathways is curative in a significant number of these patients,” Wyndham Wilson, MD, PhD, head of the lymphoma therapeutics section at NCI, said during a press briefing.
Background
Chemotherapy has been the standard of care for patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, curing roughly 60% of newly diagnosed individuals, according to Wilson.
However, those with relapsed or refractory DLBCL have poor prognosis.
Chimeric antigen receptor T-cell therapy has become an option for that population, but CAR-T only cures between 30% to 40% of those patients.
Prior studies have discovered genetic pathways that could be targeted for individuals with various subtypes of DLBCL.
Targeted therapies have benefited some patients, but the effects have not been durable because of other survival pathways.
“We hypothesized that multiple agents would be needed in patients with aggressive lymphoma in order to completely irradicate all evidence of disease and lead to potential cure,” Christopher J. Melani, MD, assistant research physician at NCI, said during the briefing.
Methods
Researchers evaluated an investigational regimen investigated that combined venetoclax (Venclexta; Genentech, AbbVie), ibrutinib (Imbruvica; Janssen, Pharmacyclics), prednisone, obinutuzumab (Gazyva, Genentech) and lenalidomide (Revlimid, Bristol Myers Squibb), all of which can impact survival pathways.
“In our laboratory research, we found that by combining drugs that hit two different survival pathways in a cancer cell, we get a synergistic killing,” Louis M. Staudt, MD, PhD, chief of the lymphoid malignancies branch and director of the center for cancer genomics at NCI, said during the briefing. “They trigger cell death much more efficiently when [used] together, and we found that each of the ViPOR drugs has this ability with each of the others.”
The study included adults with relapsed or refractory B-cell lymphoma in phase 1b, which researchers conducted to determine proper dosing, but only those with relapsed or refractory DLBCL could join the phase 2 expansion. Study criteria required participants had previous treatment with anthracycline therapy and received anti-CD20 antibodies.
A total of 60 adults enrolled between both phases, with 50 having DLBCL.
The DLBCL cohort (66% men; 66% white) had a median age of 61 years, 92% had stage III or IV disease, and 40% had prior CAR-T therapy. The most common DLBCL subtypes included HGBCL-DH-BCL2 (34%) and non-GCB DLBCL NOS (26%).
The ViPOR regimen differed from other therapy options in two significant ways. Instead of patients receiving continuous treatment, the regimen consisted of 2 weeks of medication and a 1-week break. Additionally, study participants only received six cycles lasting a total of 18 weeks, much shorter than other regimens, which could last years if not indefinitely, Melani said.
Researchers did this to “maximize the effectiveness of the regimen, but also minimize some of these potential additive side effects that can occur when giving multiple study agents simultaneously,” he added.
Results
Researchers observed 54% of the DLBCL cohort had an objective response to therapy and 38% had a complete response.
Complete responses only occurred in patients with HGBCL-DH-BCL2 (53% of this group) and non-GCB DLBCL NOS (62%) subtypes.
The overall study cohort had a 2-year PFS rate of 34% and 2-year OS rate of 36% at a median follow-up of 40 months.
Patients with HGBCL-DH-BCL2 had a 2-year PFS rate of 47% and those with non-GCB DLBCL NOS had a 2-year PFS rate of 39%.
In all, 78% of individuals who had a complete response and 38% who had a partial response had a 2-year response duration.
“The two subtypes that are most curable with the ViPOR regimen are the least curable with chemotherapy,” Staudt said. “I think this is important and it says the targeted therapies, by removing the survival pathways, are achieving a fundamentally different result than the toxins that we administer when we give chemotherapy.”
The results in patients with HGBCL-DH-BCL2 surprised researchers, as the regimen had primarily been designed for those with non-GCB DLBCL NOS.
Venetoclax “was particularly effective in double hit [lymphoma],” Staudt said. “This had not been noticed before, and when we combine it with another ViPOR agent, prednisone ... those were both very effective and more effective in the double hit. That is a new concept.”
The most common grade 3 or 4 adverse events included neutropenia (24% of cycles), thrombocytopenia (23%) and anemia (7%).
“ViPOR was found to be extremely well tolerated with most side effects in patients being very mild and not interfering or having a significant impact on patients’ daily life,” Melani said. “Notably, compared with other standard chemotherapy where fever and low white [blood cell] count can occur in up to 20% of cycles, ViPOR was associated with a rare incidence of febrile neutropenia occurring in only 1% of total cycles of treatment.”
CAR-T comparison
During a question-and-answer discussion, researchers examined ViPOR in comparison with CAR-T.
“We were able to essentially cure 30% of patients who had failed CAR T-cell therapy, so we already know, at least from this small number, that we can be curative in settings in which CAR-T cells are not,” Wilson said.
Wilson stated CAR-T has benefited this population, but also acknowledged some of the drawbacks of CAR-T, including the necessity for lymphodepletion, tumors needing to be under a certain level of control before treatment, needing specialized institutions to give the therapy, and the cost, which could be between $500,000 and $1 million.
Melani said ViPOR cost $180,000.
ViPOR did not prevent T-cell generation either, meaning CAR-T could be administered after if ViPOR did not work.
“If you have a patient who doesn’t go into a complete remission, we know they require alternative therapy and it really makes a lot of sense to give ViPOR first because it’s less expensive, it’s better tolerated, it’s safer,” Wilson said.
Next steps
A multicenter study has been planned to validate the results in the two DLBCL subgroups, but researchers have also started investigating whether other drugs could be added to the ViPOR regimen to make it more effective.
They are halfway through a study in which they added polatuzumab vedotin (Polivy, Genentech) and they believe they could also add bispecific T-cell engaging therapies, although that investigation has not begun yet.
“The whole idea of that is to improve the number of patients that we can cure,” Mark Roschewski, MD, clinical director of the lymphoid malignancies branch at NCI, said during the briefing.
Roschewski and colleagues believe this regimen could be an option for patients as is.
“We do already know though there are numerous groups that are actually already using it now in people that have failed other therapies,” Wilson said. “It has come to our attention that they’re also seeing positive results.”
They also believe ViPOR could be used as a front-line therapy in the future, and the treatment approach could be used in curing other cancers, too.
“It shows that they can be safely combined, and by studying the survival mechanisms that are specific for each cancer type, then we may arrive at a curative regimen,” Staudt said. “Our dream is that in our particular cancer of interest, diffuse large B-cell lymphoma, we can cure it without chemotherapy.”
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