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FDA Accepts Application for Frontline Daratumumab for Myeloma
The U . S . Food and Drug Administration ( FDA ) received a supplemental biologics license application ( sBLA ) for daratumumab in combination with bortezomib , melphalan , and prednisone ( D-VMP ) for patients with newly diagnosed multiple myeloma ( MM ) who are ineligible for autologous hematopoietic cell transplantation ( AHCT ). The application was supported by results from the randomized , open-label , multicenter , phase III ALCYONE trial , which compared frontline D-VMP versus VMP alone in 706 patients ( median age = 71 years ; range = 40-93 years ) with MM who were ineligible for AHCT .
Participants were randomized 1:1 to receive a maximum of nine , six-week cycles of VMP or D-VMP in the following dosing regimens :
• VMP : bortezomib 1.3 mg / m 2 subcutaneously on days 1 , 4 , 8 , 11 , 22 , 25 , 29 , and 32 of cycle 1 , and days 1 , 8 , 22 , and 29 thereafter ; melphalan 9 mg / m 2 twice-daily ; and prednisone 60 mg / m 2 twice-daily on days 1-4
• D-VMP : VMP regimen plus daratumumab 16 mg / kg intravenously once-weekly during cycle 1 , every 3 weeks for cycles 2-9 , and oncemonthly thereafter
By June 12 , 2017 ( prespecified date of analysis ), patients had received a median of 12 treatment cycles ( range = 1-24 cycles ) in the D-VMP group and nine cycles ( range = 1-9 cycles ) in the VMP group . At a median follow-up of 16.5 months ( range not provided ), patients who received the daratumumab combination had a 50 percent reduction in the risk of progression or death , compared with VMP ( hazard ratio [ HR ] for progression-free survival [ PFS ] = 0.50 ; 95 % CI 0.38-0.65 ; p < 0.0001 ). The median PFS was not reached in the D-VMP group and was 18.1 months in the VMP group ( ranges not provided ).
More patients in the D-VMP group attained minimal residual disease-negative status , compared with patients in the control group ( 22.3 % vs . 6.2 %; HR = 4.36 ; 95 % CI 2.64-7.21 ; p < 0.0001 ).
Toxicity profiles were similar between study cohorts , except for the high incidence of any-grade upper respiratory tract infection ( 26.3 % vs . 13.8 %) and grade 3 / 4 pneumonia ( 11.3 % vs . 4.0 %) in the D-VMP group . Other common any-grade treatment-related adverse events ( AEs ) occurring in the D-VMP and VMP groups included neutropenia ( 49.7 % vs . 52.5 %), thrombocytopenia ( 48.8 % vs . 53.7 %), anemia ( 28.0 % vs . 37.6 %), and peripheral sensory neuropathy ( 28.3 % vs . 34.2 %). Common grade 3 / 4 AEs included neutropenia ( 39.9 % vs . 38.7 %), thrombocytopenia ( 34.4 % vs . 37.6 %), and anemia ( 15.9 % vs . 19.8 %).
Sources : Janssen press release , November 21 , 2017 ; Mateos MV , Dimopoulos MA , Cavo M , et al . Phase 3 randomized study of daratumumab plus bortezomib , melphalan , and prednisone ( D-VMP ) versus bortezomib , melphalan , and prednisone ( VMP ) in newly diagnosed multiple myeloma ( NDMM ) patients ( Pts ) ineligible for transplant ( ALCYONE ). Abstract LBA-4 . Presented at the 2017 American Society of Hematology Annual Meeting , December 12 , 2017 ; Atlanta , GA .
WHO Report : Fake Drug Trade Is Deadly
A report from the World Health Organization ( WHO ) found that counterfeit or substandard drugs are a growing threat to patients , particularly in low- and middleincome countries . WHO researchers pooled findings from 100 studies between 2007 and 2016 , covering more than 48,000 samples , and discovered that one in 10 drugs sold in developing countries is fake or substandard , leading to tens of thousands of deaths .
One in 10 drugs sold in developing countries is fake or substandard , leading to tens of thousands of deaths , according to a WHO analysis .
In addition , many authorized medicines do not meet quality standards for reasons such as improper storage .
The most common fake and lowquality drugs are antimalarials and antibiotics , but the problem extends to anti-cancer drugs as well . These drugs could contain incorrect doses or ingredients , or lack active ingredients .
A research team at the University of Edinburgh , which was commissioned by WHO to study this impact , noted that up to 72,000 deaths from childhood pneumonia could be attributed to the use of antibiotics with reduced activity , increasing to 169,000 deaths if drugs had no activity . Poor-quality drugs can also contribute to antibiotic resistance .
Another team from the London School of Hygiene and Tropical Medicine estimated that 116,000 additional deaths from malaria could be caused each year by bad antimalarials in sub-Saharan Africa .
Pharmaceutical sales in low- and middle-income countries reach nearly $ 300 billion per year , which implies that trade in fake medicines is a $ 30 billion business , according to a report from Reuters .
Since 2013 , the WHO has received 1,500 reports of fake and low-quality products , and sub-Saharan Africa accounts for 42 percent of these reports . No global data existed on this topic prior to 2013 .
Source : Reuters , November 28 , 2017 .
Mogamulizumab Receives Priority Review for CTCL
The FDA granted priority review to a biologics license application ( BLA ) for the anti-CCR4 monoclonal antibody mogamulizumab for patients with cutaneous T-cell lymphoma ( CTCL ) who have received at least one prior systemic therapy .
The BLA is based on findings from the phase III MAVORIC study , which demonstrated that mogamulizumab reduced the risk of disease progression or death by 47 percent , compared with vorinostat in patients with previously treated CTCL . The study included 372 people with histologically confirmed mycosis fungoides or Sézary syndrome ( two subtypes of CTCL ) that had not responded to at least one systemic therapy . Patients were randomized 1:1 to receive mogamulizumab 1.0 mg / kg weekly for the first month , then every two weeks ( n = 186 ; median age = 63.5 years ; range = 25-101 years ), or vorinostat 400 mg daily ( n = 186 ; median age = 65.0 years ; range = 25-89 years ). Patients receiving vorinostat whose disease progressed or had intolerable toxicity were permitted to crossover to the mogamulizumab cohort .
Median PFS was 7.7 months in the mogamulizumab arm ( range = 5.7-10.3 months ), compared with 3.1 months in the vorinostat arm ( range = 2.9-4.1 months ; HR = 0.53 ; 95 % CI 0.41-0.69 ; p < 0.0001 ). The PFS benefit with mogamulizumab was observed across predefined subgroups .
The overall response rate ( ORR ) was 28 percent with mogamulizumab versus 4.8 percent with vorinostat ( p < 0.0001 ). Grade 1 / 2 treatment-related AEs were reported by 54.9 percent of patients receiving mogamulizumab , and 42.4 percent experienced grade 3-5 AEs . The most common AEs ( occurring in > 20 % of patients ) associated with mogamulizumab and vorinostat included infusion-related reactions ( 33.2 % vs . 0.5 %) and skin eruptions ( 23.9 % vs . 0.5 %).
Sources : Kyowa Hakko Kirin press release , November 28 , 2017 ; Kim YH , Bagot M , Pinter-Brown L , et al . Anti-CCR4 monoclonal antibody , mogamulizumab , demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma ( CTCL ): results from the phase III MAVORIC study . Abstract # 817 . Presented at the 2017 American Society of Hematology Annual Meeting , December 11 , 2017 ; Atlanta , GA .
FDA Grants Priority Review to Pembrolizumab for PMBCL
The FDA granted priority review to an sBLA for the anti – PD-1 agent pembrolizumab for adult and pediatric patients with relapsed / refractory primary mediastinal large B-cell lymphoma ( PMBCL ).
The decision was based on results from a cohort of the ongoing , non-randomized , international , two-cohort , multicenter , phase II KEYNOTE-170 trial . The study included 29 patients with PMBCL who were transplant-ineligible or whose disease had relapsed after or was refractory to two or more prior lines of therapy .
By April 14 , 2017 ( data cutoff ), 49 patients with relapsed / refractory PMBCL ( median age = 33 years ; range = 20-61 years ) were followed for a median of 10.5 months ( range = 0.1-17.7 months ). The ORR was 41 percent ( 95 % CI 0.24-0.61 ) by blinded independent central review and 38 percent by investigator review . This included a 24 percent ( n = 7 ) complete response rate and 17 percent ( n = 5 ) partial response rate .
The median time to response was 2.8 months ( range = 2.4-5.5 months ), while the median duration of response was not reached ( range = 1.1-13.6 months ). Twelve-month overall survival ( OS ) was 62 percent , and median OS was not reached .
Thirty patients ( 57 %) experienced treatment-related AEs , and 11 ( 21 %) experienced grade 3 or 4 AEs . The most common AEs were neutropenia ( n = 11 ), hypothyroidism ( n = 4 ), asthenia ( n = 3 ), and pyrexia ( n = 3 ). Twenty-nine patients discontinued treatment , mostly because of clinical or radiological progression ( n = 24 ) or AEs ( n = 3 ). ●
Sources : Merck press release , December 11 , 2017 ; Zinzani PL , Thieblemont C , Melnichenko V , et al . Efficacy and safety of pembrolizumab in relapsed / refractory primary mediastinal large B-cell lymphoma ( rrPMBCL ): updated analysis of the Keynote-170 phase 2 trial . Abstract # 2833 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
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