Approval broadens DARZALEX label to include fifth treatment option in the relapsed/refractory setting and represents the eighth approved indication for DARZALEX [20-August-2020] HORSHAM, Pa. , Aug. 20, 2020 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) approval of DARZALEX ® (
| HORSHAM, Pa., Aug. 20, 2020 /PRNewswire/ -- TheJanssen Pharmaceutical Inc. Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) approval of DARZALEX® (daratumumab) in combination with Kyprolis® (carfilzomib) and dexamethasone (DKd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received one to three previous lines of therapy. DARZALEX® has been approved in combination with two carfilzomib dosing regimens, 70 mg/m2 once weekly and 56 mg/m2 twice weekly, based on positive results from the Phase 3 CANDOR and Phase 1b EQUULEUS studies, representing the first-ever approval of an anti-CD38 with carfilzomib. “The significant increase in progression-free survival (PFS) seen among patients receiving the DKd regimen supports the use of this new combination for patients with relapsed and refractory multiple myeloma. We continue to advance effective regimens for the most critical patients who have already relapsed,” said Saad Z. Usmani, M.D., Division Chief of Plasma Cell Disorders, Atrium Health’s Levine Cancer Institute, and principal investigator of the CANDOR study. “The DKd regimen fills an important gap in the treatment landscape, as many patients may relapse following an immunomodulatory drug-based therapy, such as lenalidomide-containing regimens, and therefore new therapeutic options are needed.” Click to tweet: U.S. #FDA approved new combination regimen for patients with relapsed/refractory multiple #myeloma. See here for more details: bit.ly/2C8dc32 The CANDOR study is the first Phase 3 randomized trial to compare DKd versus carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory multiple myeloma. The study, which administered carfilzomib twice weekly, met its primary endpoint of PFS after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively.1 The median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm (Hazard Ratio=0.63; 95 percent confidence interval, 0.46- 0.85; P=0.0014), representing a 37 percent reduction in the risk of disease progression or death for patients treated with DKd versus Kd.1 The inclusion of once-weekly dosing of carfilzomib as an approved DKd regimen was supported by positive results from the open-label, multi-cohort Phase 1b EQUULEUS trial, which evaluated DARZALEX® in combination with various treatment regimens.2 “With this most recent approval of the DKd regimen, patients with multiple myeloma now have the option to receive treatment with DARZALEX and carfilzomib as early as their first relapse, which is a critical time in their treatment journey,” said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. “With our deep disease focus and commitment to develop regimens which can help improve patient outcomes for patients with relapsed multiple myeloma, the CANDOR study further establishes another DARZALEX-containing regimen (DKd) which may provide benefit for this patient population.” In CANDOR, the safety profile of DKd was generally consistent with the known safety profiles of DARZALEX® and Kd, and reflect a median treatment duration of 16.1 months for the DKd arm and 9.3 months for the Kd arm.1 Serious adverse events (AEs) occurred in 56 percent and 46 percent of patients who received DKd and Kd, respectively.1 The most frequent serious AE in the DKd arm, compared with the Kd arm, was pneumonia (14 percent vs 9 percent). Fatal AEs occurred in 10 percent of DKd patients and 5 percent of Kd patients, and the most frequent fatal AE was infection (5 percent vs 3 percent). About the CANDOR Study1 All patients received carfilzomib as a 30-minute intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter) and received 40 mg dexamethasone oral or IV weekly (20 mg/m2 for patients aged >75 years). In the treatment arm, DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and 16 mg/kg IV once weekly for the remaining doses of the first two cycles, then every two weeks for four cycles (cycles 3 to 6), and every four weeks thereafter. Of the patients randomized in the study, 92 percent had received a prior proteasome inhibitor, 42 percent had received prior lenalidomide, and 33 percent were lenalidomide-refractory.1 CANDOR is an Amgen-sponsored study and is co-funded by Janssen Research & Development, LLC. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT03158688. About the EQUULEUS Study2 About DARZALEX® In August 2012, Janssen entered into an exclusive global license and development agreement with Genmab A/S to develop, manufacture, and commercialize DARZALEX®.3 DARZALEX® has become a backbone therapy in the treatment of multiple myeloma, having been used in the treatment of more than 143,000 patients worldwide and more than 68,000 patients in the U.S. alone since its U.S. FDA approval in 2015. DARZALEX® is the first CD38-directed antibody approved globally to treat MM. CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.4 DARZALEX® binds to CD38 and inhibits tumor cell growth causing myeloma cell death.5 DARZALEX® may also have an effect on normal cells.5 Data across seven Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that DARZALEX®-based regimens resulted in significant improvement in progression-free survival and/or overall survival.5,6,7,8,9,10,11,12 Please see full Prescribing Information at www.DARZALEX.com. About Multiple Myeloma DARZALEX® IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation. WARNINGS AND PRECAUTIONS Infusion-Related Reactions DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. Interference With Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive Indirect Antiglobulin Test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®. Neutropenia and Thrombocytopenia DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets. Interference With Determination of Complete Response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose. The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy. ADVERSE REACTIONS The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia. Please click here to see the full Prescribing Information. About the Janssen Pharmaceutical Companies of Johnson & Johnson Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenGlobal and www.twitter.com/JanssenUS. Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Cautions Concerning Forward-Looking Statements # # # ___________________________ 1 Saad Z. Usmani, MD et al. Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-label, Phase 3 Study CANDOR (NCT03158688). 2019 American Society of Hematology Annual Meeting. December 2019.
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