The Janssen Pharmaceutical Companies of Johnson & Johnson issued the following announcement on Sept. 26.
- Approval represents first and only FDA-approved biologic indicated for newly diagnosed patients who are eligible for a stem cell transplant
- Marks the seventh approved indication for DARZALEX®
The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) approval of DARZALEX® (daratumumab) in combination with bortezomib, thalidomide and dexamethasone (VTd) for newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant (ASCT). The approval is based on results from the Phase 3 CASSIOPEIA (MMY3006) study that showed the addition of DARZALEX® to VTd before and after ASCT resulted in deeper responses, as indicated by the higher stringent complete response (sCR) rate, and improved progression-free survival (PFS) compared to VTd alone.1 The approval comes after the FDA granted Priority Review for the supplemental Biologics License Application (sBLA).
"The pivotal Phase 3 CASSIOPEIA study is one of the largest transplant studies ever conducted in multiple myeloma, and the largest study conducted with daratumumab," said Philippe Moreau, M.D., principal investigator and Head of the Hematology Department at the University Hospital of Nantes, France. "It's important that patients get a deep response from their frontline therapy, and CASSIOPEIA demonstrates that the addition of daratumumab to VTd before and after transplant markedly increased depth of response compared to VTd alone for patients with newly diagnosed multiple myeloma."
Data from the Phase 3 CASSIOPEIA study were first presented at the 2019 American Society of Clinical Oncology Annual Meeting and simultaneously published in The Lancet. Additionally, updates from the study were recently presented at the 17th International Myeloma Workshop Meeting. CASSIOPEIA is a two-part, Intergroupe Francophone du Myelome (IFM) study in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen Research & Development, LLC. Results from this first part of the trial showed that the primary endpoint of sCR rate post consolidation was significantly higher in the DARZALEX®-VTd arm compared to VTd alone (29 percent vs. 20 percent) (Odds Ratio [OR] = 1.60; 95 percent confidence interval [CI], 1.21–2.12; P=0.0010).1 The addition of DARZALEX® to VTd at a median follow-up of 18.8 months resulted in a 53 percent reduction in the risk of disease progression or death compared to VTd alone (Hazard Ratio [HR] = 0.47; 95 percent CI, 0.33–0.67; P<0.0001).1
"We are thrilled that newly diagnosed patients with multiple myeloma and their doctors have a new option with this combination," said Paul Giusti, President and CEO of the Multiple Myeloma Research Foundation (MMRF). "The Multiple Myeloma Research Foundation and Janssen share a mutual focus on accelerating development of new effective treatment options for patients. We are grateful for Janssen's continued commitment to myeloma patients and their families."
After consolidation, DARZALEX®-VTd also increased the rate of complete response or better (39 percent vs. 26 percent) (OR = 1.82; 95 percent CI, 1.40-2.36) and very good partial response or better (83 percent vs. 78 percent) (OR = 1.41; 95 percent CI, 1.04-1.92) compared to VTd alone, respectively.1
"The DARZALEX® clinical development program has led to many important firsts, but more importantly, it has generated key insights and understanding into the biology and treatment of multiple myeloma," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "Today's milestone marks the seventh FDA approval in less than four years for DARZALEX®, and the third for newly diagnosed patients. Yet our work is far from over, as we are committed to discovering and developing innovative treatments like DARZALEX® for the benefit of patients facing a multiple myeloma diagnosis."
The most frequent adverse reactions (>20 percent with at least 5 percent greater frequency in the DARZALEX®-VTd group) were infusion reactions, nausea, pyrexia, upper respiratory tract infection and bronchitis.1 Serious adverse reactions with a 2 percent greater incidence in the DARZALEX®-VTd arm compared to the VTd arm were bronchitis (2 percent vs. <1 percent) and pneumonia (6 percent vs. 4 percent), respectively.1 In the DARZALEX®-VTd combination arm, infusion-related reactions occurred in 35 percent of patients.1
This news comes on the heels of the second approval of DARZALEX® for the treatment of newly diagnosed patients with multiple myeloma who are transplant-ineligible, based on the Phase 3 MAIA study.
About the CASSIOPEIA Study1
This randomized, open-label, multicenter, Phase 3 study is sponsored by the French Intergroupe Francophone du Myelome (IFM) in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen Research & Development, LLC. The study included 1,085 newly diagnosed patients with previously untreated, symptomatic multiple myeloma who were eligible for high-dose chemotherapy and stem cell transplant (median age is 58). In the first part of the study, patients were randomized to receive induction treatment with VTd alone or in combination with DARZALEX®, high-dose therapy and ASCT, and consolidation therapy with VTd alone or in combination with DARZALEX®. The primary endpoint in this part of the study is the proportion of patients who achieve a sCR at the end of consolidation therapy. In the second part of the study, which is ongoing, patients who achieved a partial response or better in part one underwent a second randomization to receive maintenance treatment with DARZALEX® 16 mg/kg every eight weeks for up to two years or be observed with no further treatment. The primary endpoint in this part of the study is PFS.
About DARZALEX® (daratumumab)
DARZALEX® (daratumumab), the first CD38-directed antibody approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma.1 CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.2 DARZALEX® binds to CD38 and inhibits tumor cell growth causing myeloma cell death.1 DARZALEX® may also have an effect on normal cells.1 DARZALEX® is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.3,4,5,6,7,8,9,10 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such as smoldering myeloma.11,12
In the U.S., DARZALEX® received initial FDA approval in November 2015 as a monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.13 DARZALEX® received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.14 In June 2017, DARZALEX® received approval in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI.15 In May 2018, DARZALEX® received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with this disease.16 In June 2019, DARZALEX® received approval in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible.17
In August 2012, Janssen Biotech, Inc. entered into a global license and development agreement with Genmab A/S, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX®.18 For the full U.S. Prescribing Information, please visit www.DARZALEX.com.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.19,20 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.20,21 In 2019, it is estimated that 32,110 people will be diagnosed and 12,960 will die from the disease in the U.S. 21 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood counts, tiredness, high calcium levels, kidney problems or infections. 22
IMPORTANT SAFETY INFORMATION1
CONTRAINDICATIONS
DARZALEX® (daratumumab) 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 Reactions – DARZALEX® can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. 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.
Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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 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 are 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/or thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to the manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX® dose delay may be required to allow recovery of neutrophils and/or platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors for neutropenia or transfusions for thrombocytopenia.
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.
Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions, neutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia and upper respiratory tract infection.
DARZALEX® in combination with lenalidomide and dexamethasone (DRd): The most frequent (≥20%) adverse reactions for newly diagnosed or relapsed/refractory patients were, respectively, infusion reactions (41%, 48%), diarrhea (57%, 43%), nausea (32%, 24%), fatigue (40%, 35%), pyrexia (23%, 20%), upper respiratory tract infection (52%, 65%), muscle spasms (29%, 26%), dyspnea (32%, 21%), and cough (30%, 30%). In newly diagnosed patients, constipation (41%), peripheral edema (41%), back pain (34%), asthenia (32%), bronchitis (29%), pneumonia (26%), decreased appetite (22%), and peripheral sensory neuropathy (24%) were also reported. In newly diagnosed patients, serious adverse reactions (≥2% compared to Rd) were dehydration (2%), bronchitis (4%), and pneumonia (15%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were leukopenia (35%), neutropenia (56%), and lymphopenia (52%). In relapsed/refractory patients, serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (53%) and lymphopenia (52%).
DARZALEX® in combination with bortezomib, melphalan, and prednisone (DVMP): The most frequently reported adverse reactions (≥20%) were upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).
DARZALEX® in combination with bortezomib and dexamethasone (DVd): The most frequently reported adverse reactions (≥20%) were peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%), and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (48%) and thrombocytopenia (47%).
DARZALEX® in combination with bortezomib, thalidomide and dexamethasone (DVTd): The most frequent adverse reactions (≥20%) were infusion reactions (35%), nausea (30%), upper respiratory tract infection (27%), pyrexia (26%), and bronchitis (20%). Serious adverse reactions (≥2% compared to the VTd arm) were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (59%), neutropenia (33%), and leukopenia (24%).
DARZALEX® in combination with pomalidomide and dexamethasone (DPd): The most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% of patients included pneumonia (7%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were anemia (30%), neutropenia (82%), and lymphopenia (71%).
DARZALEX® as monotherapy: The most frequently reported adverse reactions (≥20%) were infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (40%) and neutropenia (20%).
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.
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