Venetoclax

THURSDAY, June 20, 2024 -- For patients with specific subtypes of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), treatment with venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) yields durable remission, according to a study published in the June 20 issue of the New England Journal of Medicine . Christopher Melani, M.D., from the National Cancer Institute in Bethesda, Maryland, and colleagues performed a single-center, phase 1b to 2 study of a regimen of ViPOR in relapsed or refractory DLBCL. Twenty patients were included in phase 1b, 10 with DLBCL, which assessed four dose levels of venetoclax. A phase 2 expansion was conducted in 40 patients with germinal-center B-cell (GCB) and non-GCB DLBCL. The researchers established venetoclax at a dose of 800 mg as the recommended phase 2 dose. All patients in phase 2 had toxic effects, including grade 3 or 4 neutropenia, thrombocytopenia, anemia, and febrile neutropenia (in 24, 23, 7 and 1 percent of the cycles, respectively). Overall, 54 percent of the evaluable patients with DLBCL had objective responses; complete responses occurred in 38 percent, which were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). At the end of ViPOR therapy, circulating tumor DNA was undetectable in 33 percent of the patients. Two-year progression-free and overall survival were 34 and 36 percent, respectively, with a median follow-up of 40 months. "Although the efficacy of ViPOR in specific molecular subtypes limited the subgroup of patients with DLBCL who had potentially curable disease, this very specificity provides some confidence in the generalizability of our results," the authors write. Genentech provided venetoclax and obinutuzumab and Bristol Myers Squibb-Celgene provided lenalidomide for the study.

Pictured: The National Institutes of Health's main building in Maryland/iStock, Grandbrothers Researchers from the National Institutes of Health have identified a novel, non-chemotherapy combination regimen for treating relapsed diffuse large B-cell lymphoma, reporting full remission for some patients no longer responding to standard treatments. Detailing their findings Wednesday in The New England Journal of Medicine, the NIH scientists combined five common anti-cancer agents—AbbVie and Genentech’s Vencelxta (venetoclax), Johnson & Johnson’s Imbruvica (ibrutinib), Genentech’s Gazyva (obinutuzumab), Bristol Myers Squibb’s Revlimid (lenalidomide) and the corticosteroid prednisone. The treatment combo, dubbed ViPOR, was tested in a Phase Ib/II study that included 50 patients with diffuse large B-cell lymphoma (DLBCL). Results showed that the investigational regimen “substantially” shrank tumors in 28 of 48 evaluable patients, according to the NIH. This corresponded to a 54% objective response rate. Overall, 18 patients saw their tumors completely disappear, resulting in a 38% complete response rate for ViPOR. At the end of treatment, circulating tumor DNA was undetectable in 33% of patients. After two years of follow-up, 34% of treated patients showed no signs of the disease while 36% remained alive. In terms of safety, the Phase Ib portion of the study detected a single dose-limiting case of grade 3 intracranial hemorrhage. In the Phase II portion, adverse events of note included grade 3 or 4 neutropenia, thrombocytopenia, anemia and febrile neutropenia. “DLBCL is one of the most genetically heterogeneous forms of cancer, and as a result we don't yet have the ability to identify exactly which combination of drugs would be most effective for any given patient,” Christopher Melani, from the National Cancer Institute’s Center for Cancer Research, said in a statement. Melani co-led the study. “By putting five drugs together, we believe that there will be some drug combination—either two, three, or more drugs—that will be particularly effective against the patient’s tumor,” Melani said. The NIH researchers are working on a larger Phase II study, which they plan to conduct in multiple centers. The mid-stage trial will assess the activity of ViPOR in various genetic subtypes of DLBCL. Accounting for around 25% to 30% of all non-Hodgkin lymphomas, DLBLC is the most common type of lymphoma, according to the NIH. It is typically characterized as the enlargement of lymph nodes or the rapid growth of a mass in a nodal or extranodal site. DLBCL is often aggressive, though it responds reasonably well to a regimen called R-CHOP, which consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Several pharma players are working on potentially better therapies for DLBCL to improve safety and efficacy, as well as provide patients more options in case of disease progression or treatment intolerance. Pfizer is advancing its antibody-drug conjugate Adcetris (brentuximab vedotin) for DLBCL and in March 2024 reported that it significantly improved survival in patients enrolled in the Phase III ECHELON-3 study. Roche is also targeting DLBCL with its bispecific T-cell engager Columvi (glofitamab) boosting survival in the Phase III STARGLO trial, according to an April 2024 readout. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.