Targeted Therapy Combinations Feasible Before Chemoimmunotherapy for Newly Diagnosed DLBCL: Smart Start Trial

In the phase 2 Smart Start study, combination therapy with rituximab plus lenalidomide and ibrutinib produced a high overall response rate and durable responses in the first-line treatment of diffuse large B-cell lymphoma (DLBCL). These results, published in The Journal of Clinical Oncology, highlight the potential for further developing these alternative frontline therapies in this setting.

“Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades,” wrote Jason Westin, MD, University of Texas MD Anderson Cancer Center, Texas, and colleagues. “Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non–germinal center B-cell-like subset.”

The Smart Start trial enrolled a total of 60 patients. Patients received rituximab 375 mg/m² intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle. After 2 cycles, standard chemotherapy was added for 6 additional cycles.

The primary end points of the trial were overall response rate (ORR) after 2 cycles of rituximab plus lenalidomide and ibrutinib alone and complete response rate after completion of rituximab plus lenalidomide and ibrutinib with chemotherapy.

The median age of the enrolled patients was 63.5 years, with patients ranging in age from 29  83 years old, and with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after 2 cycles of rituximab plus lenalidomide and ibrutinib was 86.2%, and the complete response rate at the end of rituximab plus lenalidomide and ibrutinib with chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively.

In conclusion, “Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses, the study authors concluded. “This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.”

Source:

Westin J, Davis RE, Feng L, et al. Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma. J Clin Oncol. Published online August 11, 2022. doi:10.1200/jco.22.00597