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Results from ARROW Trial Point to Once-Weekly Carfilzomib Dosing
Carfilzomib is approved on a twice-weekly dosing schedule for the treatment of relapsed or refractory multiple myeloma ( MM ), but in the phase III ARROW trial , patients experienced better responses with a once-weekly dosing .
A more convenient schedule “ can improve access to this efficacious therapy for patients unable to make twice-weekly visits to the clinic ,” lead author María-Victoria Mateos , MD , PhD , from the University Hospital of Salamanca in Spain , noted during her presentation at the 2018 ASCO Annual Meeting , adding that treatment with the less-frequent , higher-dose carfilzomib was not associated with increased toxicity .
The phase III ARROW trial was designed to confirm earlier findings reported from the phase I CHAMPION-1 trial , which established 70 mg / m 2 as the maximum tolerated dose of carfilzomib . “ More than 100 patients received once-weekly 70 mg / m 2 on days 1 , 8 , and 15 – rather than the approved schedule of [ carfilzomib ] on two consecutive days on three consecutive weeks ,” study co-author James R . Berenson , MD , from the Institute for Myeloma and Bone Cancer Research in West Hollywood , California , told ASH Clinical News . “ We were encouraged enough by the results to give [ carfilzomib ] once a week in our clinic , even though it ’ s off-label .”
Between August 2015 and November 2016 , investigators enrolled 478 patients with relapsed and refractory MM who had received at least two prior lines of therapy ( including a proteasome inhibitor and an immunomodulatory drug ). Patients were randomized 1:1 to receive dexamethasone plus carfilzomib in one of two dosing schedules :
• once-weekly : carfilzomib 20 mg / m 2 on day 1 of cycle 1 , followed by carfilzomib 70 mg / m 2 on days 1 , 8 , and 15 for the subsequent treatment cycles ( n = 240 )
• twice-weekly carfilzomib : carfilzomib 20 mg / m 2 on day 1 of cycle 1 , followed by 27 mg / m 2 on days 8 , 9 , 15 , and 16 of subsequent cycles ( n = 238 )
Participants were treated for a median of 38 weeks in the once-weekly group and 29.1 weeks in the twice-weekly group ( ranges not reported ).
After a median follow up of 12 months ( range not reported ), 126 patients in the once-weekly group ( 53 %) and 148 in the twice-weekly group ( 62 %) experienced disease progression or death , for a median progression-free survival ( PFS ; primary endpoint ) of 11.2 months and 7.6 months , respectively . This translated to a hazard ratio for PFS of 0.69 for once- versus twice-weekly
carfilzomib ( 95 % CI 0.544-0.883 ; p = 0.003 ).
The superiority in PFS was seen across different patient subgroups , including those defined by age (< 65 or ≥65 years ), baseline Eastern Cooperative Oncology Group status , and International Staging System score , or refractoriness to bortezomib at baseline .
The overall response rate ( secondary endpoint ) also was higher in the once-weekly group : 63 percent versus
BESPONSA™ ( inotuzumab ozogamicin ) is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia ( ALL )
AIM FOR DEEP
REMISSION
Deep remission refers to MRD-negative remission , defined in the INO-VATE ALL study as leukemic cells comprising < 1 x 10 -4 of bone marrow nucleated cells per flow cytometry . 1
IMPORTANT SAFETY INFORMATION
WARNING : HEPATOTOXICITY , INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE ( VOD ) ( ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME ) and INCREASED RISK OF POST – HEMATOPOIETIC STEM CELL TRANSPLANT ( HSCT ) NON-RELAPSE MORTALITY ( NRM ):
• Hepatotoxicity , including fatal and life-threatening VOD , occurred in patients who received BESPONSA . The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment . The use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin ≥ upper limit of normal ( ULN ) before HSCT were significantly associated with an increased risk of VOD
• Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease , prior HSCT , increased age , later salvage lines , and a greater number of BESPONSA treatment cycles
• Elevation of liver tests may require dosing interruption , dose reduction , or permanent discontinuation of BESPONSA . Permanently discontinue treatment if VOD occurs . If severe VOD occurs , treat according to standard medical practice
• There was a higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA , resulting in a higher Day 100 post-HSCT mortality rate
Hepatotoxicity , Including Hepatic VOD : Hepatotoxicity , including fatal and life-threatening VOD , occurred in 23 / 164 patients ( 14 %) during or following treatment with BESPONSA or following subsequent HSCT . VOD was reported up to 56 days after the last dose during treatment or follow-up without an intervening HSCT . The median time from HSCT to onset of VOD was 15 days .
Patients with prior VOD or serious ongoing liver disease are at an increased risk of worsening liver disease , including development of VOD , following
40.8 percent ( odds ratio [ OR ] = 2.49 ; 95 % CI 1.72-3.60 ; p < 0.0001 ). This included a complete response rate of 5 percent and 2 percent , respectively .
Dr . Berenson called the results “ astonishing ,” because preclinical data suggested that carfilzomib two days in a row was better than once-weekly . The mechanisms behind the improved results with less-frequent dosing are still unclear , he added . “[ Perhaps ] getting the maximum concentration higher
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The efficacy of BESPONSA was established on the basis of CR ( 35.8 % [ 39 / 109 ; 95 % CI , 26.8-45.5 ] with BESPONSA vs 17.4 % [ 19 / 109 ; 95 % CI , 10.8-25.9 ] with SC ), the duration of CR ( 8.0 months [ 95 % CI , 4.9-10.4 ] with BESPONSA vs 4.9 months [ 95 % CI , 2.9-7.2 ] with SC ), and the proportion of MRD-negative CR ( 89.7 % [ 35 / 39 ; 95 % CI , 75.8-97.1 ] with BESPONSA vs 31.6 % [ 6 / 19 ; 95 % CI , 12.6-56.6 ] with SC ) in the first 218 randomized patients . 1
treatment with BESPONSA . Monitor closely for signs and symptoms of VOD ; these may include elevations in total bilirubin , hepatomegaly ( which may be painful ), rapid weight gain , and ascites . For patients proceeding to HSCT , the recommended duration of treatment with BESPONSA is 2 cycles . A third cycle may be considered for patients who do not achieve a CR or CRi and MRD-negativity after 2 cycles . Monitor liver tests closely during the first month post HSCT , then less frequently thereafter , according to standard medical practice .
Grade 3 / 4 increases in aspartate aminotransferase , alanine aminotransferase , and total bilirubin occurred in 7 / 160 ( 4 %), 7 / 161 ( 4 %), and 8 / 161 ( 5 %) patients , respectively .
Increased Risk of Post-HSCT Non-Relapse Mortality ( NRM ): There was a higher post-HSCT NRM rate in patients receiving BESPONSA , resulting in a higher Day 100 post-HSCT mortality rate . The rate of post-HSCT NRM was 31 / 79 ( 39 %) with BESPONSA and 8 / 35 ( 23 %) with investigator ’ s choice of chemotherapy . In the BESPONSA arm , the most common causes of post- HSCT NRM included VOD and infections . Monitor closely for toxicities post HSCT , including signs and symptoms of infection and VOD .
Myelosuppression : Myelosuppression , and severe , life-threatening , and fatal complications of myelosuppression , including hemorrhagic events and infections , have occurred with BESPONSA . Thrombocytopenia and neutropenia were reported in 83 / 164 patients ( 51 %) and 81 / 164 patients ( 49 %), respectively . Febrile neutropenia was reported in 43 / 164 patients ( 26 %).
Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection , bleeding / hemorrhage , or other effects of myelosuppression during treatment and provide appropriate management . As appropriate , administer prophylactic anti-infectives during and after treatment with BESPONSA . Dose interruption , dose reduction , or permanent discontinuation may be required .
42 ASH Clinical News