Combination Targeted Therapy Yields Long-Lasting Remissions in Resistant Aggressive B-Cell Lymphoma

TOPLINE
Researchers at the National Institutes of Health (NIH) have developed a non-chemotherapy treatment regimen achieving full remissions in some patients with aggressive B-cell lymphoma that has recurred or is unresponsive to standard treatments. The five-drug combination targets multiple molecular pathways that diffuse large B-cell lymphoma (DLBCL) tumors use to survive.

KEY FACTS
In a clinical trial conducted at NIH’s National Cancer Institute (NCI), researchers tested a combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) on 50 patients with DLBCL, the most common type of lymphoma. The treatment significantly shrank tumors in 26 of 48 evaluable patients (54%), with 18 of those patients (38%) experiencing complete tumor disappearance. At the two-year mark, 36% of all patients were alive, and 34% were disease-free. These benefits were most notable in patients with specific subtypes of DLBCL.

“Many of these patients who stopped responding to standard treatments would have otherwise died within a year, and now we have a good proportion who are still alive past two years, and some past four years,” said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. “It’s gratifying to see these long-term remissions and potential cures in patients.”

BACKGROUND
Previous research identified various genetic pathways involved in the development and survival of DLBCL subtypes, such as activated B cell-like (ABC) DLBCL and germinal center B cell-like (GCB) DLBCL. Targeted drugs have shown effectiveness in blocking some pathways, but individual drugs rarely produced lasting responses due to tumors’ resistance through alternative survival pathways. Dr. Melani and his colleagues hypothesized that combining targeted drugs to block multiple survival pathways would lead to more durable responses.

Based on laboratory studies that analyzed which drugs could best be combined to kill DLBCL cells synergistically, the researchers designed the five-drug regimen for human trials. The drugs were administered simultaneously in two-week cycles, with a weeklong break between each cycle to limit side effects.

“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,” Dr. Melani said. “By putting five drugs together, we believe there will be some drug combination—either two, three, or more drugs—that will be particularly effective against that patient’s tumor.”

TRIAL RESULTS
In the phase 1b/2 trial, 50 patients with relapsed or treatment-resistant DLBCL received six cycles of the ViPOR regimen. Responses varied by DLBCL subtype, with complete responses seen in 8 of 13 (62%) patients with non-GCB DLBCL and 8 of 15 (53%) patients with a high-grade B-cell lymphoma form of GCB DLBCL known as “double hit.” At two years, patients with non-GCB DLBCL and double-hit GCB DLBCL had higher rates of both progression-free and overall survival than other study participants. ViPOR also helped 6 of 20 (30%) patients achieve lasting remissions after their lymphomas did not respond to or recurred following CAR T-cell therapy, the current standard of care for relapsed DLBCL.

Side effects of the five-drug regimen were generally mild to moderate compared with standard treatments and improved during treatment breaks. Only five patients had to stop treatment early due to various reasons, including side effects. The researchers believe that additional drugs could potentially be added to ViPOR to enhance its efficacy.

FUTURE STUDIES
A larger phase 2 study will be conducted at multiple centers to confirm the activity of ViPOR in patients with non-GCB DLBCL and double-hit GCB DLBCL. Further work is needed to develop therapies for GCB DLBCL subtypes that do not respond as well to ViPOR.

NCI’s Center for Cancer Research investigators Wyndham H. Wilson, M.D., Ph.D., Mark Roschewski, M.D., and Louis M. Staudt, M.D., Ph.D., co-led the study with Dr. Melani. Researchers from NIH’s National Center for Advancing Translational Sciences and other institutions also contributed to the study.