December 10, 2023
By Catlin Nalley
Data from a Phase Ib/II study demonstrated the feasibility and curative potential of a multi-targeted therapy approach among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a recent oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9-12 in San Diego (Abstract 434).
“Frontline chemoimmunotherapy is curative in approximately 65-70 percent of patients with DLBCL,” said study author Christopher Melani, MD, Chief of the Lymphoid Malignancies Branch in the Center for Cancer Research at the National Cancer Institute, while also highlighting the poor outcomes of chemorefractory patients who have median event-free and overall survival of approximately 6 months.
“While CAR-T therapy has resulted in cure in approximately 35-40 percent of these relapsed/refractory patients, nearly two-thirds of patients relapse after or are refractory to CAR-T and have poor outcome,” he continued. “Thus, novel treatment options are needed for these relapsed/refractory patients, especially in these chemotherapy-refractory as well as post-CAR-T patients.”
Building on previous work, Melani and colleagues developed a “five-drug combination regimen (ViPOR) that targets DLBCL survival sustained by constitutive B-cell receptor (BCR) signaling (ibrutinib, lenalidomide, prednisone) and by BCL2 (venetoclax), and also enlists the innate immune system using obinutuzumab.” To maximize drug exposure and minimize toxicity, all agents were administered in non-continuous cycles for fixed duration, according to Melani.
“In the Phase Ib cohort, we tested four different dose levels of venetoclax ranging from 200 to 800 mg. Within each dose level, we gave an accelerated 12-day venetoclax ramp-up where all patients started at 20 mg on Day 2 and reached their target dose level by Day 12 of the first cycle of venetoclax,” he explained.
“In Phase II, we had an expansion cohort of 40 patients with relapsed/refractory DLBCL. Twenty each with GCB and non-GCB by immunohistochemistry and Hans algorithm. This was included for a further assessment of safety and efficacy in DLBCL.”
Of the 50 enrolled patients, 50 percent had DLBCL NOS, including 13 non-GCB and 12 GCB by IHC. The median age was 61 years and 92 percent had Stage 3/4 disease. The median prior treatments were three with 40 percent post-CAR-T patients and 58 percent refractory.
Overall, ViPOR was very well tolerated across patients of all ages, according to Melani, who noted that, as expected, hematologic adverse events were the most common. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 25 percent, 24 percent, and 7 percent of patients, respectively.
“Dose reductions and delays were relatively infrequent, in only 17 percent and 25 percent of patients, respectively, and mostly due to neutropenia or thrombocytopenia,” Melani said. “Only five patients prematurely discontinued therapy for adverse event or intercurrent illness preventing more study therapy.”
Of 48 evaluable patients, study authors observed an ORR of 54 percent and CR of 38 percent. Responses were observed across all molecular DLBCL subtypes, including a CR rate of 62 percent in non-GCB DLBCL and 53 percent in HGBCL-DH-BCL2. Among patients with GCB DLBCL without MYC rearrangement, only partial responses were observed in 33 percent with no complete responses, Melani noted.
With a median follow-up of 40 months, study authors reported a 2-year PFS of 34 percent. “Notably, in the 15 patients, or 30 percent, who received ViPOR as a second-line of systemic therapy after frontline CD20 and anthracycline, the 2-year PFS was 60 percent overall,” according to Melani. “In the 18 patients who achieved complete remission, 78 percent of remissions are ongoing at 2 years, despite this fixed duration of ViPOR of only 18 weeks without maintenance.”
Concluding his presentation, Melani reiterated that multi-targeted therapy with ViPOR is safe and feasible in R/R DLBCL patients. “Currently, multicenter, Phase II testing is in development to confirm the activity of ViPOR in relapsed/refractory CD10-negative DLBCL and HGBCL-DH-BCL2.”
Catlin Nalley is a contributing writer.