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ENDEAVOR : Carfilzomib Increases Overall Survival Over Bortezomib in Patients With Relapsed / Refractory Multiple Myeloma
Previous results from the phase III ENDEAVOR study showed that treatment with the proteasome inhibitor carfilzomib plus dexamethasone extended progression-free survival ( PFS ) in patients with relapsed / refractory multiple myeloma ( MM ), compared with bortezomib plus dexamethasone ( 18.7 months vs . 9.4 months ; hazard ratio [ HR ] = 0.53 ; 95 % CI 0.44-0.65 ; p < 0.0001 ). According to the results of a second interim analysis published in Lancet Oncology , treatment with the carfilzomib combination also improved overall survival ( OS ), compared with the bortezomib combination in this patient population .
“ On the basis of these results , carfilzomib combined with dexamethasone should be considered a standard of care for patients with relapsed or refractory MM ,” reported the authors , led by Meletios A . Dimopoulos , MD , from the National and Kapodistrian University of Athens School of Medicine in Greece .
The open-label , randomized , controlled , head-to-head comparison of carfilzomib and bortezomib included 929 adult patients enrolled between June 2012 and June 2014 from 198 hospital or outpatient oncology centers in 27 countries . Eligible patients had received one to three prior lines of therapy and had achieved at least partial response to at least one line of therapy .
Patients were randomized 1:1 based on International Staging System ( I vs . II-III ) score , previous lines of therapy ( 1 vs . 2-3 ), previous proteasome inhibitor therapy ( yes vs . no ), and planned route of bortezomib administration for that cohort ( intravenous vs . subcutaneous ) to receive either :
• carfilzomib ( 20 mg / m 2 administered via a 30-minute intravenous infusion on days 1-2 ; escalated to 56 mg / m 2 thereafter , if tolerated , on days 1 , 2 , 8 , 9 , 15 , and 16 ) and dexamethasone ( 20 mg administered orally or via intravenous infusion on days 1 , 2 , 8 , 9 , 15 , 16 , 22 , and 23 ) in 28-day cycles ( n = 464 ; median age = 65 years ; interquartile range [ IQR ] = 58-72 years )
• bortezomib ( 1.3 mg / m 2 administered as an intravenous bolus or subcutaneous injection on days 1 , 4 , 8 , and 11 ) and dexamethasone ( 20 mg administered orally or via intravenous infusion on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , and 12 ) in 21-day cycles ( n = 465 ; median age = 65 years ; IQR = 60- 71 years )
At data cutoff ( January 3 , 2017 ), 398 patients had died : 189 in the carfilzomib cohort and 209 in the bortezomib group . The most common cause of death was progressive disease ( n = 118 [ 25 %] and n = 130 [ 28 %], respectively ), followed by adverse events ( AEs ; n = 30 [ 7 %] and n = 19 [ 5 %]) and unknown causes ( n = 41
“ On the basis of these results , carfilzomib combined with dexamethasone should be considered a standard of care .”
— MELETIOS A . DIMOPOULOS , MD
[ 9 %] and n = 60 [ 13 %]).
Treatment-related deaths were reported in five patients receiving carfilzomib ( related to pneumonia
[ n = 2 ], interstitial lung disease [ n = 1 ], septic shock [ n = 1 ], and unknown cause [ n = 1 ]) and two patients receiving bortezomib ( related to cardiac arrest [ n = 1 ] and pneumonia [ n = 1 ]).
After a median follow-up of 37.5 months ( range = 34.4-41.9 months ), OS was longer in patients receiving carfilzomib ( 47.6 months ; 95 % CI 42.5 to not reached ), compared with those receiving bortezomib ( 40.0 months ; 95 % CI 32.6-42.3 ; HR = 0.791 ; 95 % CI 0.648-0.964 ; p = 0.01 ). “ OS was similar between treatment groups for about the first 15 months , after which the curves started to separate ,” the authors reported .
However , in a post-hoc landmark analysis that measured OS from time of disease progression , the median OS did not differ between groups : 21.5 months ( 95 % CI 16.3-25.1 ) in the carfilzomib group and 21.5 months ( 95 % CI 18.3-26.2 ) in the bortezomib group ( HR = 1.032 ; 95 % CI 0.822-1.297 ; p = 0.61 ).
The median treatment exposure was 48.0 weeks ( IQR = 24.1-88.7 weeks ) in the carfilzomib group , which was “ nearly twice as long ” as in the bortezomib group ( 27.0 weeks ; IQR = 15-50 weeks ), the authors noted .
Incidences of grade ≥3 AEs , serious AEs , and fatal AEs were slightly higher in the carfilzomib cohort . Grade ≥3 AEs occurred in 81 percent ( n = 377 ) of carfilzomib-treated patients and 71 percent ( n = 324 ) of bortezomib-treated patients ( p value not reported ), the most common of which were anemia ( 16 % vs . 10 %, respectively ), hypertension ( 15 % vs . 3 %), pneumonia ( 9 % vs . 9 %), and thrombocytopenia ( 9 % vs . 9 %). Serious AEs occurred in 59 percent ( n = 273 ) of carfilzomib-treated patients and 40 percent ( n = 182 ) of bortezomib-treated patients , the most common of which were pneumonia ( 8 % vs . 9 %, respectively ), pyrexia ( 4 % vs . 1 %), dyspnea ( 4 % vs . 1 %), and acute renal failure ( 2 % vs . 2 %).
Dose reductions were required in 32 percent ( n = 146 ) of the carfilzomibtreated patients and 50 percent ( n = 230 ) of the bortezomib-treated patients . In the carfilzomib group , 415 patients ( 89.6 %) discontinued treatment , mostly related to disease progression ( n = 183 ) and AEs ( n = 96 ); in the bortezomib group , 429 ( 94.1 %) discontinued treatment , also mostly related to disease progression ( n = 208 ) and AEs ( n = 94 ).
The median time to next treatment ( starting from randomization ) was 26.3 months ( 95 % CI 24.2- 30.6 ) in the carfilzomib group and 14.4 months ( 95 % CI 12.6-16.6 ) in the bortezomib group ( p value not reported ). A potential limitation of the study is that subsequent therapies received during follow-up could have confounded interpretation of the OS analysis , the researchers noted .
“ Given the relapsing nature of MM , it would be of interest to know if the administration of one proteasome inhibitor in an early line of therapy affects the efficacy of another proteasome inhibitor given in a later line of therapy ,” the researchers wrote . However , this study could not provide a “ robust analysis ” on the topic because of heterogeneity in the subpopulations of patients , which is a limitation of the study .
Onyx Pharmaceuticals , Inc . – a subsidiary of Amgen Inc ., the manufacturer of carfilzomib – supported the study .
The authors report financial support from Amgen , Celgene , Janssen , Novartis , Takeda , Bristol-Myers Squibb , and Chugai .
REFERENCE
Dimopoulos MA , Goldschmidt H , Niesvizky R , et al . Carfilzomib or bortezomib in relapsed or refractory multiple myeloma ( ENDEAVOR ): an interim overall survival analysis of an openlabel , randomised , phase 3 trial . Lancet Oncol . 2017 August 23 . [ Epub ahead of print ]
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