Among the many exciting clinical trials results presented at the Annual Meeting of the American Society of Hematology (ASH) in December 2014, were three significant studies for Hodgkin Lymphoma (HL) patients. The studies, which included early stage studies of two new and promising therapies, nivolumab and pembrolizumab, as well as results from a large scale study examining brentuximab vedotin in post-transplant HL patients, may open new treatment options for HL patients who fail to respond to the currently available standard therapies.
AETHERA Trial Shows Brentuximab Vedotin Can Extend Progression-Free Survival in Post-transplant Patients
For the past twenty years, Hodgkin lymphoma patients who develop chemosensitive relapsed/refractory disease have been treated with high-dose chemotherapy plus autologous stem cell transplant (ASCT). For about 50 percent of patients, this strategy results in a cure, however, researchers have been unable to improve progression-free survival much beyond that 45 to 55 percent. The AETHERA trial tested brentuximab vedotin (Adcetris) as a maintenance therapy following ASCT in a randomized, multi-center study. Half of the 327 patients receiving treatment received a dose of brentuximab vedotin every 3 weeks, with the other half receiving a placebo for approximately 12 months. At a median follow-up of two years, patients in the brentuximab vedotin arm had a 65 percent progression-free survival rate, with the placebo arm at the average 45 percent. It is the first time a study has demonstrated that adding a maintenance therapy to post ASCT regimens can improve outcomes for Hodgkin lymphoma patients. Because HL patients who reach the stage where ASCT is an option have generally already had at least two other therapies fail, the significant improvement offered by the AETHERA trial’s therapy may save patients who have no other treatment options.
The study was presented at ASH as one of the keynote presentations (CONFIRM) by lead author Craig Moskowitz, MD of Memorial Sloan-Kettering Cancer Center. Dr. Moskowitz is a long time member of the Lymphoma Research Foundation’s (LRF) Scientific Advisory Board. The ASH presentation marked the first time the unblinded efficacy and safety data was presented publicly.
The abstract of this presentation is available here.
Nivolumab and Pembrolizumab Show Promise as Immunotherapies for Hodgkin Lymphoma
Early clinical results for the first two PD-1 blocking antibodies for Hodgkin lymphoma also made their debut at ASH. Programmed cell death-1 (PD-1) is an immune checkpoint receptor that can become overexpressed in many subtypes of lymphoma, allowing the tumor cells to shut down the activity of the normal T-cells in the immune system and avoid destruction. Both drugs have already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma (nivolumab received approval in December 2014, shortly after the ASH meeting concluded), and are now being tested in a variety of other cancers, including lymphoma.
In the nivolumab (Opdivo) study, twenty-three patients with relapsed or refractory Hodgkin lymphoma received biweekly doses as part of a study to check for safety and dose escalation. More than a third of the patients in the study had failed at least six prior treatments, and four-fifths of the patients had undergone a stem cell transplant with no success. Following treatment with nivolumab, four of the patients had no detectable tumor remaining and sixteen additional patients had their tumors shrink to less than half their original size. Though median overall survival has not yet been reached, the progression free survival rate at six months was 86 percent, with a majority still doing well more than a year after treatment. The study also included a cohort of non-Hodgkin lymphoma and multiple myeloma patients, which were reported separately; though results were not as dramatic in those subtypes, further studies of nivolumab in DLBCL and FL are in process.
The study, which was published online by the New England Journal of Medicine simultaneous with the ASH presentation, included contributions from LRF Scientific Advisory Board members Stephen Ansell, MD, PhD of Mayo Clinic (first author on the NEJM paper), and Margaret Shipp, MD of Dana-Farber Cancer Institute. The abstract of the NEJM paper may be accessed here.
The pembrolizumab (Keytruda) study (KEYNOTE-013) also enrolled Hodgkin lymphoma patients for whom other standard therapies had failed, in this case 29 patients who did not respond to brentuximab vedotin (Adcetris), 20 of whom had also relapsed following ASCT. As this trial is still ongoing, only preliminary results were available. After 12 weeks of treatment, 15 patients had reached a point in their treatment where their response could be evaluated. 3 of those patients (20 percent) had a complete response, with 5 additional patients reaching partial remission, for an overall response rate of 53 percent. Four patients who had their disease progress also saw a reduction in their overall tumor burden.
The trial was presented at ASH by first author Craig Moskowitz, MD of Memorial-Sloan Cancer Center and also included contributions from fellow SAB member Margaret Shipp, MD, of Dana-Farber Cancer Institute. These studies together suggest anti-PD-1 immunotherapy may be of significant help to Hodgkin lymphoma patients who have exhausted all other treatment options.