The results from a phase Ib/II study of a five-drug targeted therapy regimen—venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR)—in the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) showed the treatment produced durable remissions and potential cures in patients with specific molecular DLBCL subtypes and was associated with mild to moderate adverse events. Durable complete responses were observed in patients who were heavily pretreated with chemotherapy or chimeric antigen receptor (CAR) T-cell therapy, according to the researchers at the National Institutes of Health who developed ViPOR. The study by Melani et al was published in The New England Journal of Medicine.1
DLBCL is the most common type of non-Hodgkin lymphoma in the United States and globally.2 Each year, more than 25,000–30,000 people in the United States are diagnosed with the disease.1 Although chemoimmunotherapy for DLBCL can be curative, patients with early relapsed or refractory disease have had poor outcomes with conventional treatments.
Study Methodology
The researchers enrolled 60 patients with relapsed or refractory B-cell lymphoma from February 2018 to June 2021, including 20 patients (10 with DLBCL) in phase Ib and 40 patients (all with DLBCL) in phase II. Among the 50 patients with DLBCL, the median age was 61 years, and 92% had stage III or IV disease. The median number of previous systemic therapies was three, including 20 patients who had received previous chimeric antigen receptor (CAR) T-cell therapy, and 29 patients had refractory disease.
A total of 25 patients had DLBCL–not otherwise specified, including 12 with germinal center B-cell (GCB) subtype and 13 with non-GCB subtype. A total of 20 patients had high-grade B-cell lymphoma “double hit”—including 17 with MYC and BCL2 translocations and 3 with MYC and BCL6 translocations—and 5 patients had T-cell histiocyte-rich large B-cell lymphoma.
In the phase Ib study, patients received the ViPOR regimen, with venetoclax administered at four different dose levels to determine the recommended dose for phase II. A single dose-limiting toxic effect of grade 3 intracranial hemorrhage established venetoclax at a dose of 800 mg as the recommended phase II dose.
Study Results
In the phase II expansion study, ViPOR was administered every 21 days for six cycles. Objective responses were seen in 54% of 48 evaluable patients with DLBCL, and complete responses were seen in 38%; complete responses occurred exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival rates were 34% (95% confidence interval [CI] = 21%–47%) and 36% (95% CI = 23%–49%), respectively. Toxic effects included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (23%), anemia (7%), and febrile neutropenia (1%).
“Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events,” concluded the study authors.
Clinical Significance
Christopher J. Melani, MD
“This multiagent regimen simultaneously targets multiple key survival pathways that are important for B-cell lymphoma to grow and survive,” said principal investigator Christopher J. Melani, MD, Associate Research Physician and a clinical researcher specializing in lymphoma at the Center for Cancer Research, National Cancer Institute, during a media briefing detailing the results of the ViPOR study. “We hypothesized that multiple agents would be needed in patients with aggressive lymphoma in order to completely eradicate all evidence of disease and lead to a potential cure in these patients.”
To minimize treatment adverse events in the study participants, ViPOR was administered over six cycles or 18 weeks of therapy, explained Dr. Melani. “ViPOR is given in noncontinuous cycles, so all the medications, including the four oral agents as well as the one intravenous agent [obinutuzumab], are given in 2-week cycles with a 1-week break to try to maximize the effectiveness of the regimen but also minimize some of these potentially additive side effects that can occur when you are giving multiple agents simultaneously. Additionally, unlike other targeted therapy regimens that are given indefinitely or at least for prolonged periods of time, ViPOR is given for a fixed duration of only six cycles…[with] no prolonged maintenance or consolidation built into it,” said Dr. Melani.
The simultaneous targeting of multiple survival pathways in these patients has resulted in durable remissions, with one-third of the patients alive and experiencing no evidence of disease after 2 years following therapy, and several patients potentially cured of their disease, according to Dr. Melani. “In [patients with] non-GCB DLBCL, there were 39% of patients alive and without evidence of disease at the 2-year time point, with several of these patients now out past 5 years in continued remission, so we think they are likely cured of their disease,” said Dr. Melani.
Combining Targeted Therapies
Wyndham H. Wilson, MD, PhD
Louis M. Staudt, MD, PhD
“[These results are] the culmination of more than 25 years of involvement in this area by Wyndham H. Wilson, MD, PhD [Senior Investigator, Lymphoid Malignancies Branch, Center for Cancer Research at the National Cancer Institute, and co–senior author of the ViPOR trial] and myself,” said Louis M. Staudt, MD, PhD, Chief of the Lymphoid Malignancies Branch, Center for Cancer Research at the National Cancer Institute, and the other co–senior author of the study. “We understood that this aggressive lymphoma is not one disease but several different diseases that look the same under the microscope, but that are quite different in terms of their mechanisms of malignant survival and proliferation. Using [this model], I think we’ve come up with a regimen that addresses many of the [cancer cell] survival mechanisms we’ve discovered.”
The key findings from this study, according to Dr. Staudt, could inform how to treat—and even cure—other cancer types. “The two subtypes [of DLBCL] that are most curable with the ViPOR regimen are the least curable with chemotherapy,” said Dr. Staudt. “I think this says that targeted therapies, by removing these survival pathways, are achieving a fundamentally different result than the toxins we administer when we give chemotherapy….”
He continued: “This is perhaps a proof of principle that these combinations of targeted agents could be deployed in other types of cancers. It shows that they can be safely combined, and by studying the survival mechanisms that are specific for each cancer type, we may arrive at curative regimens. Our dream is that we can cure DLBCL without chemotherapy—completely with these targeted regimens.”
Relatively Cost-Effective Therapy
The study authors noted that another advantage of treating patients with the ViPOR regimen compared with CAR T-cell therapy, the current standard of care for patients with relapsed DLBCL, is the cost: $180,000 for six cycles of the ViPOR treatment vs $500,000 to $1 million for CAR T-cell therapy.3
The researchers have developed a larger phase II study of ViPOR in multiple trial sites to confirm the activity of the five-drug regimen in patients with non-GCB DLBCL and high-grade B-cell lymphoma with MYC and BCL2 rearrangements.
DISCLOSURE: Funding for this study was provided by the National Cancer Institute, the National Institutes of Health, and others. Dr. Melani, Dr. Staudt, and Dr. Wilson reported no conflicts of interest.
REFERENCES
1. Melani C, Lakhotia R, Pittaluga S, et al: Combination targeted therapy in relapsed diffuse large B-cell lymphoma. N Engl J Med 390:2143-2155, 2024.
2. Leukemia & Lymphoma Society: Diffuse large B-cell lymphoma (DLBCL). Available at www.lls.org/research/diffuse-large-b-cell-lymphoma-dlbcl. Accessed July 18, 2024.
3. Cliff ERS, Kelkar AH, Russler-Germain DA, et al: High cost of chimeric antigen receptor T-cells: Challenges and solutions. Am Soc Clin Oncol Educ Book 43:e397912, 2023.
