In a head-to-head clinical trial, carfilzomib (Kyprolis) plus dexamethasone doubled the length of progression-free survival (PFS) when compared with bortezomib (Velcade) plus dexamethasone for individuals with relapsed or refractory multiple myeloma. Response rates were also significantly higher for those receiving carfilzomib, though neither medication could overcome high-risk cytogenetic factors.
The international multi-center phase 3 open-label ENDEAVOR study (clinicaltrials.gov ID: NCT01568866) compared outcomes for a total of 929 patients who were randomized 1:1 to receive one of the treatments. Randomization was stratified to account for prior treatments, including prior proteasome treatment, as well as disease severity by International Staging System stage.
Reporting for the ENDEAVOR investigators, Dr. Meletios Dimopoulos and his co-authors published their results in The Lancet simultaneously with a presentation at the annual meeting of the American Society of Hematology [Lancet Oncol, http://dx.doi.org/10.1016/S1470-2045(15)00464-7] . Dr. Dimopoulos is a professor in the department of clinical therapeutics at the school of medicine of the National and Kapodistrian University of Athens.
Courtesy Wikimedia Commons/KGH/Creative Commons License
Histopathological image of multiple myoloma. Smear preparation of bone marrow aspirate stained with May-Grünwald-Giemsa procedure.
The primary endpoint, PFS in the intention-to-treat population, differed significantly between the study arms when the data were analyzed at a pre-planned interim analysis. For those receiving carfilzomib, PFS was 18.7 months, compared with 9.4 months in the bortezomib group, for a hazard ratio of 0.53 (P less than 0.0001). Data were drawn from a pre-specified interim analysis, and study participation is ongoing, with 28-day dosing cycles repeated until disease progression occurrs or the patients experience unacceptable toxicity or withdraw consent.
Investigators had pre-specified subgroup analyses to examine what populations fared better and worse in each arm. Prior bortezomib exposure did not significantly affect PFS for those receiving carfilzomib. Not enough patients had received carfilzomib prior to the study to permit analysis of this effect. Though carfilzomib arm patients with high-risk factors on cytogenetic analysis fared slightly better than those on bortezomib, “neither proteasome inhibitor appears to significantly overcome the adverse prognostic effect of high-risk cytogenetics,” wrote Dr. Dimopoulos and his co-authors.
Secondary outcome measures included the numbers of patients in each arm achieving complete response or better (with this group broken into “stringent complete response” as well as complete response). Significantly more carfilzomib than bortezomib patients reached this mark (58 patients [13%] vs 29 patients [6%], P equal to 0.001). A larger group of patients in each arm met the secondary outcome measure of experiencing very good partial response or better, with those on the carfelzomib arm faring significantly better than those receiving bortezomib (252 [54%] vs 133 [29%], P less than 0.0001).
Dr. Dimopoulos and his co-authors remarked on the importance of these findings, noting that “The finding that the proportion of patients with a complete response or better and very good partial response or better was higher in the carfilzomib group than in the bortezomib group is encouraging because studies have shown an association between depth of response and improved survival in patients with multiple myeloma.”
ENDEAVOR’s safety analyses included all patients who received at least one dose of study drug. Overall, the carfilzomib patients had a 48% rate of serious adverse events (224 of 463 patients for this analysis), compared to 36% of the bortezomib group (162 of 456 patients).
On-study death rates were similar between the two groups, with 18 of 464 patients (4%) in the carfilzomib group and 16 of 465 patients (3%) in the bortezomib group dying during the study period. Four deaths in each arm were judged related to disease progression.
A pre-planned substudy examined cardiac function for patients in both study arms, and did not find increased risk of left or right ventricular dysfunction or cumulative cardiac injury for carfilzomib when compared with bortezomib.
The open label nature of the study, an acknowledged limitation, was necessitated by the different dosing regimens of the two drugs, but the treatment allocation was hidden from the independent review committee that assessed participant disease status. The funder was also masked to per-group treatment results.
Carfilzomib’s irreversable proteosome inhibition may lead to more sustained proteasomal inhibition, Dr. Dimopoulous and his co-authors posited. Also, carfilzomib can overcome bortezomib resistance and is more potent against cell lines naive to this class of drugs in preclinical studies, they said.
“Taken together, the results from the ENDEAVOR study suggest an important role for carfilzomib-based regimens for patients with relapsed or refractory jultiple myeloma,” wrote Dr. Dimopoulos and his collaborators.
The study was supported by Onyx Pharmaceuticals, Inc, a subsidiary of Amgen. Dr. Dimopoulos reported non-financial support from Onyx Pharmaceuticals, Celgene Corporation, and Ortho-Biotech. Several co-authors reported multiple financial associations with pharmaceutical companies.