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CLINICAL NEWS
Literature Scan
TABLE 2 . Treatment Response to Brentuximab Vedotin Plus Bendamustine
Overall response
Complete response
Partial response *
Stable disease
Not assessable
Disease progression
Phase I ( n = 28 ) Phase II ( n = 37 ) Total ( n = 65 )
17 ( 61 %) ( 95 % CI 41-79 )
29 ( 78 %) ( 95 % CI 62-91 )
46 ( 71 %) ( 95 % CI 58-81 )
5 ( 18 %) 16 ( 43 %) 21 ( 32 %)
12 ( 43 %) 13 ( 35 %) 25 ( 38 %)
4 ( 14 %) 5 ( 14 %) 9 ( 14 %)
1 ( 4 %) 0 1 ( 2 %)
6 ( 21 %) 3 ( 8 %) 9 ( 14 %)
* The patient with anaplastic large T-cell lymphoma had a partial response in phase I .
The second phase included 37 patients ( median age = 34 years ; range = 18-72 years ); 29 ( 78 %) achieved a response ( primary endpoint ). See TABLE 2 for all phase II efficacy outcomes .
The median duration of response was 4.3 months ( range = 0-7.1 months ) in phase I and 3.95 months ( range = 7.5 months to not reached ) in phase II . “ Responses were durable , with several patients being in remission for more than two years after receiving the combination treatment ,” the authors noted .
Median overall survival and progression-free survival were 43.3 months ( range = 11.3 months to not reached ) and 7.5 months ( range = 4.8-12.1 months ), respectively , in phase I , and were not reached in phase II . “ These results compare favorably with those obtained for various other conventional salvage regimens used before HCT in this setting ,” they added .
AEs occurring in phase II were decreased neutrophil count ( n = 10 ; 27 %) and lung infection ( n = 5 ; 14 %). Three ( 8 %) grade 4 events ( decreased neutrophil counts ) were observed .
Four patients discontinued treatment because of toxicity ( 2 in each phase ). Twenty-three patients ( 35 %) died , most commonly because of disease progression ( 14 in phase I ; 6 in phase II ). No deaths were related to treatment or AEs . “ With only 14 percent of patients reporting a grade 3 AE in phase I and 18 percent of patients reporting grade 3 or 4 toxicities in phase II , [ it appears ] the combination of brentuximab vedotin plus bendamustine is not more toxic than the single agents alone ,” the authors reported .
An exploratory analysis of changes in biomarker concentrations demonstrated that the mean baseline CD30 concentration in complete responders , compared with non-responders , was significantly different . However , the percentage change in CD30 concentration from baseline to end of treatment was not significantly different , suggesting that “ traditional biomarkers that might predict clinical outcomes in treatment-naïve patients , or [ in ] patients who received one previous therapy , might not be predictive in heavily pretreated patients .”
The study is limited by its small patient population and lack of a comparator arm . Randomized trials that allow formal cross-regimen efficacy comparisons are warranted , the researchers added . Teva and Seattle Genetics supported the study . The authors report financial relationships with Seattle Genetics .
REFERENCE
O ’ Connor OA , Lue JK , Sawas A , et al . Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin ’ s lymphoma : an international , multicentre , single-arm , phase 1 – 2 trial . Lancet Oncol . 2017 December 21 . [ Epub ahead of print ]

Mixed Results From SIMPLIFY-1 Complicate Myelofibrosis Treatment Decisions

The Janus kinase ( JAK ) inhibitor ruxolitinib is the only U . S . Food and Drug Administration – approved therapy for myelofibrosis ( MF ), but the resultant hematologic adverse events ( AEs ) can lead to dose reductions or interruptions .
In the SIMPLIFY-1 trial , Ruben A . Mesa , MD , director of the UT Health San Antonio Cancer Center in Texas , and co-authors evaluated momelotinib , an oral , small-molecule JAK1 / 2 inhibitor , as an alternative to ruxolitinib . Their results , published in the Journal of Clinical Oncology , were mixed : The investigational agent was noninferior to ruxolitinib for spleen volume reduction , but ruxolitinib was superior in reducing symptom burden .
The 24-week , multicenter , randomized , double-blind , double-dummy , phase III trial enrolled 432 JAK inhibitor – naïve adult patients with primary MF ( according to World Health Organization criteria ), post-polycythemia vera , or post-essential thrombocythemia MF ( according to International Working Group for Myelofibrosis Research and Treatment criteria ). Participants also had palpable splenomegaly ≥5 cm , adequate renal and hepatic function , and an Eastern Cooperative Oncology Group performance status score of ≤2 .
Patients were excluded if they had spleen irradiation within three months prior to study treatment , certain cancers , or uncontrolled concurrent illness .
Participants were stratified based on transfusion dependence ( yes or no ; defined as ≥4 units of red blood cells [ RBCs ] or hemoglobin < 8 g / dL in the prior 8 weeks ) and platelet count (< 100 × 10 9 / L , ≥100 × 10 9 / L and ≤200 × 10 9 / L , and > 200 × 10 9 / L ), then randomized 1:1 to receive :
• momelotinib 200 mg once-daily ( n = 215 ; mean age = 65.0 years ; standard deviation [ SD ] = 10.67 years )
• ruxolitinib 20 mg twice-daily ( n = 217 ; mean age = 64.4 years ; SD = 10.59 years )
Treatment discontinuation appeared to be more common in the momelotinib group ( 18.6 %) than the ruxolitinib group ( 7.4 %; p value not reported ), and a total of 376 patients completed the 24-week phase : 175 in the momelotinib group and 201 patients in the ruxolitinib group .
The primary endpoint ( spleen volume reduction ≥35 % from baseline at week 24 ) was evaluable in 184 momelotinib-treated patients and 204 ruxolitinibtreated patients . A similar number of patients in each treatment group achieved the primary endpoint ( n = 57 [ 26.5 %] vs . 63 [ 29.0 %]), for a non-inferiority proportion difference of 0.09 , making momelotinib non-inferior to ruxolitinib ( p = 0.01 ).
TABLE 3 . Any-Grade Adverse Events Reported in the SIMPLIFY-1 Treatment Groups
Momelotinib ( n = 215 )
Ruxolitinib ( n = 217 )
Thrombocytopenia
40 ( 18.7 %)
63 ( 29.2 %)
Diarrhea
38 ( 17.8 %)
43 ( 19.9 %)
Headache
37 ( 17.3 %)
43 ( 19.9 %)
Dizziness
34 ( 15.9 %)
25 ( 11.6 %)
Nausea
34 ( 15.9 %)
8 ( 3.7 %)
Peripheral neuropathy
22 ( 10.3 %)
10 ( 4.6 %)
Ruxolitinib was better than momelotinib in reducing symptoms ( secondary endpoint ; defined as total symptom score [ TSS ] reduction > 50 % reduction from baseline ). Of the 190 and 175 patients , respectively , available for TSS assessment , more ruxolitinib-treated patients met this endpoint ( n = 89 [ 42.2 %] vs . 60 [ 28.4 %]; n = 60 ), and non-inferiority for momelotinib was not met ( p = 0.98 ).
However , transfusion rate , transfusion independence , and transfusion dependence were improved with momelotinib :
• median rate of RBC transfusions : 0 units / month vs . 0.4 units / month ( ranges not reported ; p < 0.001 )
• transfusion-independent at week 24 ( 66.5 % vs . 49.3 %; p < 0.001 )
• transfusion-dependent at week 24 ( 30.2 % vs . 40.1 %; p = 0.019 )
The best overall response rate at 24 weeks in each cohort was low , but with a numeric advantage for the investigational agent ( 5.1 % for momelotinib and 3.2 % for ruxolitinib ; p value not reported ).
The mean duration of treatment exposure was 21.3 weeks ( range = 0.3-26.1 weeks ) with momelotinib and 23.3 weeks ( range = 1.3-26.9 weeks ) with ruxolitinib . Dose reductions or interruptions occurred in 26.2 percent and 56.0 percent of patients ( p value not reported ), respectively , most commonly because of adverse events ( AEs ; 17.3 % vs . 35.6 %, respectively ).
The most common , any-grade treatment-related AEs in the momelotinib and ruxolitinib cohorts are reported in TABLE 3 . Grade ≥3 AEs were reported by 35.5 percent of momelotinib-treated patients and 43.5 percent of ruxolitinibtreated patients . The most common grade ≥3 AEs in the momelotinib group were thrombocytopenia ( 7.0 %), anemia ( 5.6 %), diarrhea ( 2.8 %), hypertension ( 2.8 %), and neutropenia ( 2.8 %), while the most common in the ruxolitinib group were anemia ( 23.1 %), neutropenia ( 4.6 %), thrombocytopenia ( 4.6 %), and hypertension ( 4.2 %). Serious AEs occurred in 22.9 percent and 18.1 percent of patients , respectively .
Treatment discontinuation occurred more frequently in the momelotinib group ( 13.1 % vs . 5.6 %; p value not reported ), and seven deaths were reported in each cohort .
“ Results were mixed and indicate that although momelotinib may offer less symptom control than ruxolitinib , there is a comparable spleen response and a potential benefit in terms of anemia ,” the authors concluded .
The study is limited by its 24-week follow-up period . Long-term efficacy and safety evaluations are warranted , according to the authors . Gilead supported the study . ● The corresponding authors report financial support from Gilead , the manufacturer of momelotinib , and Incyte , the manufacturer of ruxolitinib . Impact Communications provided editorial support .
REFERENCE
Mesa RA , Kiladjian JJ , Catalano JV , et al . SIMPLIFY-1 : a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor – naïve patients with myelofibrosis . J Clin Oncol . 2017 ; 35:3844-50 .
44 ASH Clinical News March 2018