Daratumumab (DARZALEX™) Combined with Standard Treatment for Multiple Myeloma Produced Deep and Durable Responses in Relapsed or Refractory Patients

ORLANDO, Fla. and RARITAN, N.J., Dec. 6, 2015 /PRNewswire/ -- Janssen Research & Development, LLC announced new data from the ongoing Phase 1/2 GEN503 investigational study showing the human CD38-directed monoclonal antibody daratumumab (DARZALEX™), in combination with lenalidomide and dexamethasone, yielded an overall response rate (ORR) of 81 percent in relapsed or refractory multiple myeloma patients who had received a median of two prior therapies. After 18 months of treatment, investigators observed an overall survival (OS) rate of 90 percent, with 72 percent of patients experiencing progression-free survival (PFS).¹ The data, from the part 2 cohort expansion phase of GEN503, were presented today during the official press program at the 57^th Annual American Society of Hematology (ASH) Meeting and Exposition in Orlando, FL and will be presented in full during an oral abstract session on Monday, December 7 at 7:30 a.m. Eastern Time (ET).

"Daratumumab has already shown pronounced activity as a single-agent immunotherapy in a heavily pre-treated patient population with relapsed or refractory multiple myeloma. These findings suggest that it has the potential to induce rapid, deep, and durable responses in combination with standard treatment in earlier lines of therapy," said lead study author, Torben Plesner, M.D., Vejle Hospital, Vejle, Denmark. "These data are particularly exciting, as 72 percent of patients treated with daratumumab combination therapy did not progress or relapse after 18 months of treatment."

The cohort expansion phase of the open-label, international, multicenter, dose escalating Phase 1/2 GEN503 study enrolled 32 patients who had received a median of two prior lines of therapy. Stringent complete response (sCR) was reported in 25 percent of patients (n=8), complete response (CR) was reported in 9 percent (n=3), very good partial response (VGPR) was reported in 28 percent (n=9), and partial response (PR) was reported in 19 percent (n=6). Among all patients, the median times to first and best response were one month (95 percent confidence interval [CI], 0.5-5.6) and 5.1 months (95 percent CI, 0.5-14.4), respectively. The median duration of response was not reached.¹

"With daratumumab we sought to introduce a new immunotherapy approach to treating multiple myeloma through several, immune-mediated mechanisms of action that could redefine the treatment paradigm for certain patients. These preliminary findings reaffirmed our strong belief in the potential for daratumumab and led us to further evaluate this combination in relapsed or refractory and newly diagnosed multiple myeloma patients in the now ongoing POLLUX and MAIA Phase 3 studies," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development. "We are looking forward to seeing the full results of these and other trials from our robust clinical program, which will help unlock the full potential of the first approved human CD38-directed monoclonal antibody as both a single agent and in combination with standard treatment."

The two-part GEN503 study is comprised of a dose escalation study (part 1) and a cohort expansion study (part 2). In part 1, patients received daratumumab in combination with lenalidomide (25 mg orally on days 1 through 21 of every 28-day cycle) and dexamethasone (40 mg intravenously and orally once weekly). Daratumumab 2-16 mg/kg body weight was administered as an intravenous infusion given weekly for the first eight weeks, then bi-weekly (every two weeks) for the next 16 weeks, and then monthly until disease progression or unmanageable toxicity for 24 months in total. In part 2, all patients were administered the recommended Phase 2 daratumumab dose (16 mg/kg), patients refractory to lenalidomide were excluded, and patients with at least one prior line of therapy were included.²

In this study, the most common adverse events (AEs) included neutropenia (84 percent), cough (47 percent), muscle spasms (44 percent) and diarrhea (44 percent). Fifty percent of patients experienced serious AEs, but only neutropenia (n=3), gastroenteritis (n=2) and pyrexia (n=2) occurred in more than one patient. Eighteen patients (56 percent) had infusion reactions; these were generally mild to moderate (Grade ≤2) and usually occurred during the first infusion. Infusion reactions were managed with pre-medication or by slowing infusion rate. No additional safety signals were observed.¹

Other Data Presentations at ASH  
In a separate presentation at ASH 2015, researchers will present updated data from an ongoing open-label, multicenter, Phase 1b study showing daratumumab in combination with pomalidomide and dexamethasone produced rapid, deep and durable responses in relapsed or refractory multiple myeloma patients who had received at least two (median of 3.5) prior lines of therapy, including two or more consecutive cycles of lenalidomide and bortezomib, and were refractory to their last line of treatment. The combination of daratumumab with pomalidomide and dexamethasone was well-tolerated and resulted in little additional toxicity with the exception of daratumumab-related infusion reactions. The data will be presented during an oral abstract session on Monday, December 7 at 7:45 a.m. ET.³

Researchers also presented data at ASH 2015 from a combined efficacy analysis of the open-label, multicenter Phase 1/2 GEN501 and Phase 2 MMY2002 (SIRIUS) trials, which found single-agent daratumumab (16 mg/kg) demonstrated a 31 percent ORR in heavily pre-treated relapsed or refractory multiple myeloma patients who have exhausted other approved treatment options. Additionally, after a median follow-up of 14.8 months, investigators estimated the median OS would be 19.9 months (95 percent CI, 15.1–not estimable) for the combined analysis if patients continued treatment. These data were presented during an oral abstract session on Saturday, December 5.⁴

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.^5,6 Multiple myeloma is the third most common blood cancer in the U.S., following only leukemia and lymphoma.⁷ Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.⁸ Globally, it is estimated that 124,225 people will be diagnosed, and 87,084 will die from the disease in 2015.^9,10 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.¹¹ Patients who relapse after treatment with standard therapies (including proteasome inhibitors [PI] or immunomodulatory agents) typically have poor prognoses and few remaining options.⁶

About DARZALEX™ (daratumumab) 
DARZALEX™ (daratumumab) injection for intravenous use is the first human CD38-directed monoclonal antibody (mAb) approved anywhere in the world.¹² CD38 is a surface protein that is overexpressed on multiple myeloma cells.¹³ Daratumumab is believed to induce tumor cell death through apoptosis, in which a series of molecular steps in a cell lead to its death^12,14 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).^12,15,16 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin's lymphoma.

DARZALEX was approved on November 16, 2015 in the U.S. for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DARZALEX is the first mAb to receive regulatory approval to treat relapsed or refractory multiple myeloma.¹²

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.¹⁷ Janssen is currently the global sponsor of all but one clinical study. DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc.

DARZALEX™ (daratumumab) Important Safety Information – Professional

CONTRAINDICATIONS - None

WARNINGS AND PRECAUTIONS

Infusion Reactions - DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. 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, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

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 for life-threatening (Grade 4) reactions. 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 the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing - Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (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.

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: fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection.

Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS - No drug interaction studies have been performed.

About Janssen Research & Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development, LLC; and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit www.janssen.com for more information.

Janssen in Oncology 
Our goal is to fundamentally alter the way cancer is understood, diagnosed and managed, reinforcing our commitment to the patients who inspire us. In looking to find innovative ways to address the cancer challenge, our primary efforts focus on several treatment and prevention solutions. These include a focus on hematologic malignancies, prostate cancer and lung cancer; cancer interception with the goal of developing products that interrupt the carcinogenic process; biomarkers that may help guide targeted, individualized use of our therapies; as well as safe and effective identification and treatment of early changes in the tumor microenvironment. Please visit http://www.janssen.com for more information.  

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in new product development, including the uncertainty of clinical success and of obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 28, 2014, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

^1.      Plesner, T. Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503). Presented at the 57^th Annual American Society of Hematology (ASH) Meeting and Exposition, December 6, 2015, Orlando, FL. Press Briefing.

^2.      ClinicalTrials.gov. Daratumumab in Combination with Lenalidomide and Dexamethasone in Relapsed and Relapsed-refractory Multiple Myeloma (NCT01615029). Available at https://www.clinicaltrials.gov/ct2/show/NCT01615029. Last Accessed December 2015.

^3.      Chari, A et al. Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with ≥2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma (MM) (Abstract #508). Presented at the 57^th Annual American Society of Hematology Meeting and Exposition, December 7, 2015, Orlando, FL.

^4.      Usmani, S et al. Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. (Abstract #29). Presented at the 57^th Annual American Society of Hematology Meeting and Exposition, December 5, 2015, Orlando, FL.

^5.      American Cancer Society. "Multiple Myeloma Overview." http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed December 2015.

^6.      Kumar, SK et al. Leukemia. 2012 Jan; 26(1):149-57.

^7.      National Cancer Institute. "A Snapshot of Myeloma." Available at www.cancer.gov/research/progress/snapshots/myeloma. Accessed December 2015.

^8.      American Cancer Society. "What are the key statistics about multiple myeloma?" Available at http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed December 2015.

^9.      GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide: Number of New Cancers in 2015. Available at http://globocan.iarc.fr/old/burden.asp?selection_pop=224900&Text-p=World&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=3&type=0&window=1&submit=%C2%A0Execute. Accessed December 2015.

^10.    GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide: Number of Cancer Deaths in 2015. Available at http://globocan.iarc.fr/old/burden.asp?selection_pop=224900&Text-p=World&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=3&type=1&window=1&submit=%C2%A0Execute. Accessed December 2015.

^11.    American Cancer Society. "How is Multiple Myeloma Diagnosed?" Available at http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed December 2015.

^12.    DARZALEX Prescribing Information, November 2015. Available at https://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf. Accessed December 2015.

^13.    Fedele, G et al. CD38 Ligation in Peripheral Blood Mononuclear Cells of Myeloma Patients Induces Release of Protumorigenic IL-6 and Impaired Secretion of IFNγ Cytokines and Proliferation. Mediators Inflamm. 2013;2013:564687.

^14.    Jansen, JH et al. Blood. 2012; 120.2974.

^15.    de Weers, M et al. Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors. The Journal of Immunology. February 1, 2011. Vol. 186, No. 3 1840-1848.

^16.    Overdijk, M et al. Phagocytosis Is A Mechanism of Action for Daratumumab. Available at https://ash.confex.com/ash/2012/webprogram/Paper51257.html. Accessed December 2015.

^17.    Janssen Biotech, Inc. "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab." Issued August 30, 2012.

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