Drugs targeting the P13K-mTOR pathway add benefit when combined with standard R-CHOP therapy.
The drug everolimus can be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma, according to the results of a pilot study by Mayo Clinic researchers.
The researchers published their study findings in the July 2016 issue of The Lancet Haematology.
"There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma," said Patrick B. Johnston, M.D., Ph.D., a hematologist at Mayo Clinic in Rochester, Minnesota, and lead author of the published study. "This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial."
The combination of everolimus and R-CHOP was well-tolerated by patients, with no dose-limiting toxicity reached within the planned dose escalation. The vast majority of patients (96 percent) achieved an overall response, and all responders achieved a complete metabolic response to the treatment.
The findings indicate that drugs targeting the P13K-mTOR pathway — a cascade of molecules involved in cell growth and survival — add benefit when combined with standard R-CHOP therapy, the researchers said.
Lymphoma is the sixth most common cancer in the U.S., and diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma.
The standard accepted treatment for diffuse large B-cell lymphoma is R-CHOP delivered in a 21-day cycle for six cycles. However, this regimen typically cures only about 60 percent of patients.
Dr. Johnston and his colleagues scoured the scientific literature in search of ways to improve the cure rate. They found that two lines of evidence pointed toward targeting the P13K-mTOR pathway.
First, numerous studies have demonstrated the importance of this pathway in the pathogenesis of diffuse large B-cell lymphoma cells in the laboratory.
Second, clinical studies have documented the single-agent efficacy of everolimus (an mTOR inhibitor) in relapsed DLBCL.
Mayo Clinic researchers therefore decided to test a regimen that combined the standard R-CHOP with everolimus.
The researchers conducted a phase 1 feasibility study in 24 patients with new, previously untreated diffuse large B-cell lymphoma with the Alliance for Clinical Trials in Oncology, a National Cancer Institute cooperative group.
Patients received everolimus for 14 days in combination with R-CHOP-21. A large proportion of patients achieved an overall response (96 percent) and a complete metabolic response as assessed by positron emission tomography imaging (96 percent).
No relapses with diffuse large B-cell lymphoma occurred, and all patients achieved the predicted milestone of being event-free at 12 months from enrollment. The treatment was well-tolerated. The most common adverse events were hematologic in nature, such as grade 4 neutropenia (75 percent) and grade 3 febrile neutropenia (21 percent).
"This study is the first to integrate a P13K-mTOR agent with standard R-CHOP," Dr. Johnston said. "The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients."
This article was first published in Forefront, the online magazine from Mayo Clinic Cancer Center. This research project is from within the Hematologic Malignancies Program—one of 10 special-focused cancer research programs in the center.