COPENHAGEN, Denmark ― Monotherapy with the novel antibody blinatumomab (Blincyto, Amgen Inc) beat standard chemotherapy, significantly improving overall survival in adult patients with relapsed/refractory adult lymphoblastic leukemia (R/R ALL), in the phase 3 TOWER trial.
"The drug shows an almost a twofold increase in overall survival compared with standard of care," said coauthor Max S. Topp, MD, associate professor of internal medicine, hematology, and oncology at the University Hospital of Wuerzburg, Germany.
Blinatumomab is the first immunotherapy to demonstrate an overall survival benefit in comparison with chemotherapy in this patient population, he added. "The drug shows an almost a twofold increase in overall survival compared with standard of care."
Blinatumomab is the first in the new class of bispecific T-cell engager (BiTE) drugs. BiTE drugs are designed to direct T-cells toward CD19, which is expressed on the surface of B-cell-derived ALLs and non-Hodgkin's lymphomas.
The drug received accelerated approval for R/R ALL from the US Food and Drug Administration in December 2014. The approval was based on the results of a single-arm phase 2 study.
The new results from the phase 3 TOWER trial were reported by Dr Topp here at the European Hematology Association (EHA) 2016 Congress.
The trial was conducted in 405 patients with relapsed or recurrent Philadelphia chromosome–negative precursor B-cell acute lymphoblastic leukemia. Patients were randomly assigned in a 2:1 ratio to receive either blinatumomab (n = 271) or standard-of-care chemotherapy (n = 134), consisting of the investigator's choice of one of four regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) ± anthracycline, or regimens based either on high-dose cytarabine arabinoside (HiDAC) (multiple brands), high-dose methotrexate (multiple brands), or clofarabine (Clolar, Genzyme Corporation).
Patients received blinatumomab in 6-week cycles of 4 weeks on therapy, with continuous infusion of 9 µg per day in week 1 of cycle 1, then 28 µg/day, and 2 weeks off therapy. Before initiating blinatumomab therapy, dexamethasone was administered for the prevention of cytokine release syndrome.
Patients who reached remission after two induction cycles were eligible to continue the therapy until relapse.
In the prespecified intent-to-treat analysis, which was conducted after the occurrence of 248 (75%) deaths, the primary endpoint of median overall survival was 7.7 months in the blinatumomab group compared with 4.0 months for the standard-of-care group (P = .011; hazard ratio = 0.71).
There were no significant differences in the overall survival between subgroups with respect to age, prior salvage therapy, or prior allogenic stem cell transplant.
In terms of secondary endpoints, patients in the blinatumomab group showed higher response rates compared with patients in the standard-of-care group, including complete remission (39% vs 19%; P < .001) and complete remission with partial or incomplete hematologic recovery (46% vs 28%, P = .001).
Adverse events, including neurologic events, were comparable for patients receiving blinatumomab and for those receiving the standard of care. Occurrences of neutropenia were less common in the blinatumomab group compared with the standard-of-care group (38% vs 58%), and infection rates were lower (34% vs 52%).
"Previous studies have shown much higher rates of neurologic events with blinatumomab, but the rate was decreased to only 9% in this study, which is nearly the same as the standard of care, and we believe that is due to better management strategies," Dr Topp said.
Cytokine release syndrome, which is "a hallmark of T-cell therapy," Dr Topp said, was reported in 5% of blinatumomab patients. No cases were reported in the standard-of-care group.
These new results support those reported in an earlier phase 2 study, published in 2015 in the journal Blood, and so were not unexpected, but they are still encouraging, commented Shai Izraeli, MD, professor and head of the Section of Functional Genomics and Childhood Leukemia at the Sheba Medical Center, Ramat Gan, Israel.
"The results are not all terribly surprising, as there were very strong indications from the phase 2 study that R/R ALL patients achieving minimal residual, disease-negative complete remission survive pretty long. However, this is indeed quite exciting," Dr Izraeli told Medscape Medical News.
Dr Izraeli added that in mobilizing autologous T cells against CD19-expressing B cells, blinatumomab is similar to chimeric antigen receptor (CAR) T cells, which are engineered to express anti-CD19 antibody. Results of the use of this approach were also reported at the meeting. The CAR T cells are probably more efficient than blinatumomab, Dr Izraeli said.
"Blinatumomab effectivity depends on the number of residual autologous T cells, while CAR-T cells are engineered ex vivo and then infused in high amount," he explained.
"It would be interesting to see a head-to-head comparison of blinatumomab and CAR-T in the same population of patients, but I doubt if such a clinical trial will be performed, for a variety of reasons," he said.
Dr Izraeli added that blinatumomab has three distinct disadvantages: It needs to be administered in a continuous infusion; it depends on the presence of autologous functional T cells; and it seems incapable of entering the central nervous system (CNS).
"The antibody probably does not enter the CNS, so probably it is not useful for treating CNS leukemia," Dr Izraeli said."CAR-T cells, however, do enter the CNS and are useful for treatment of CNS leukemia."
A separate but vital ongoing concern with all of the new therapies being developed for ALL is cost. As reported by Medscape Medical News in 2014, blinatumomab was set to be introduced at a cost of about $178,000, making it one of the most expensive oncology drugs on the market.
A decision to provide some relief in the United States in the form of reimbursement for the drug through the Centers for Medicare & Medicaid Services New Technology Add-On Payment program drew criticism, however, as reflected in a commentary in JAMA Oncology. Costs remain a worrisome issue.
"The cost of targeted therapies remains a huge issue, especially in ALL, which is a more curable disease," Dr Izraeli said.
"This is especially true for pediatrics. We currently cure close to 90% of patients with ALL with relatively cheap but toxic chemotherapy.
"If we have in the future a more targeted, less toxic therapy, such as immunotherapy, that will be dramatically more expensive, this could have huge ramification on the choice of therapy," he said.
The study was funded by Amgen. Dr Topp is a consultant for Amgen and received research funding from the company. Dr Izraeli has disclosed no relevant financial relationships.
European Hematology Association (EHA) 2016 Congress: Presented June 11, 2016.
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Cite this: Blinatumomab Beats Chemo for R/R ALL: Survival Doubled - Medscape - Jun 16, 2016.