Darzalex®▼ (daratumumab) Regimen Shows Significant Increase in Progression-Free Survival in Treatment of Patients with Relapsed/Refractory Multiple Myeloma

• First Phase 3 study showed the benefit of adding CD38-directed antibody daratumumab to carfilzomib and dexamethasone vs carfilzomib and dexamethasone alone

• Data selected as a Late-Breaking Abstract at ASH 2019

BEERSE, Belgium–(BUSINESS WIRE)–The Janssen Pharmaceutical Companies of Johnson & Johnson announced today results from the Phase 3 CANDOR study showing that the addition of Darzalex^® (daratumumab) to carfilzomib (Kyprolis^®▼) and dexamethasone (DKd), compared to carfilzomib and dexamethasone (Kd) alone, significantly improved progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, resulting in a 37 percent reduction in the risk of disease progression or death (Hazard Ratio [HR]=0.63; 95 percent confidence interval [CI], 0.46-0.85; p=0.0014).¹ The study results were reported for the first time and presented as a Late-Breaking Abstract (#LBA-6) at the 2019 American Society of Hematology (ASH) Annual Meeting.

“These data from the Phase 3 CANDOR study reinforce the growing body of evidence supporting the use of daratumumab-containing regimens in the treatment of multiple myeloma,” said Saad Z. Usmani, M.D., Division Chief of Plasma Cell Disorders, Levine Cancer Institute, and principal investigator. “The results provide important evidence for this combination regimen in the relapsed and refractory setting, where there is still significant unmet need, especially for lenalidomide refractory patients.”

Results from the CANDOR study showed that, compared to Kd alone, DKd resulted in significantly longer PFS and response rates.¹ The primary endpoint of PFS was met after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively.¹ Median PFS was not reached in the DKd arm versus 15.8 months in the Kd arm.¹ At 12 months, patients in the DKd arm had a 10 times higher rate of minimal residual disease (MRD)-negativity compared to patients treated with Kd alone (12.5 percent vs. 1.3 percent; p<0.0001).¹ Overall response rate (ORR) was 84 percent in the DKd arm, compared to 75 percent in the Kd arm (p=0.0040).¹ The rate of complete response (CR) or better was 29 percent (DKd) and 10 percent (Kd).¹ Median treatment duration was longer in the DKd arm than in the Kd arm (17.5 vs. 10.1 months).¹

“The CANDOR data show that daratumumab in combination with carfilzomib and dexamethasone may be a promising treatment option for patients with multiple myeloma who have relapsed after 1-3 prior regimens, especially in patients with previous lenalidomide and bortezomib treatment,” said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. “This Phase 3 study adds to the body of evidence related to the use of daratumumab in combination with established regimens for the treatment of patients with relapsed multiple myeloma. We are committed to the continued study of daratumumab as a treatment in patients with multiple myeloma.”

“These positive data further confirm the versatility of daratumumab as a treatment option for patients with multiple myeloma across a range of settings,” said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. “We’re excited about the potential role that this combination could have as a new therapeutic approach for this patient population.”

CANDOR is an Amgen-sponsored study and is co-funded by Janssen Research & Development. The study included patients who had received 1–3 prior lines of therapy for multiple myeloma.1 Of the patients randomised in the study, 42 percent and 90 percent had previous exposure to lenalidomide and bortezomib, respectively; 33 percent were lenalidomide-refractory; and 29 percent were bortezomib-refractory.¹

Median overall survival (OS) was not reached in either arm at a median follow-up time of 17 months (HR=0.75; 95 percent CI, 0.49–1.13; p=0.0836).¹ In general, the safety profile of DKd was consistent with the known safety profiles of daratumumab and Kd, with the exception of treatment emergent fatal adverse events which were higher in the DKd arm compared to the Kd arm.¹ The incidence of grade 3 and above adverse events (AEs) was 82 percent and 74 percent of patients in DKd and Kd, respectively, while serious AEs (SAEs) occurred in 56 percent and 46 percent of patients, respectively.¹ The frequency of grade 3 and above cardiac failure was 4 percent (DKd) and 9 percent (Kd); leading to similar discontinuations of carfilzomib observed in both arms (DKd, 4 percent vs Kd, 5 percent).¹ The rate of treatment discontinuation due to AEs was similar in both arms (DKd, 22 percent vs. Kd 25 percent).¹ Five deaths were reported as being treatment-related in the DKd arm (pneumonia, sepsis, septic shock, Acinetobacter infection, and cardio-respiratory arrest, n=1 each).¹

#ENDS#

In Europe, daratumumab is indicated:²

• in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who are newly diagnosed with multiple myeloma
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy
• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy

About the CANDOR study

CANDOR is a randomised, open-label Phase 3 study of daratumumab, carfilzomib, and dexamethasone (DKd) compared to carfilzomib and dexamethasone (Kd) alone.¹ The study evaluated 466 relapsed or refractory patients with multiple myeloma from 120 global sites who had received 1-3 prior therapies.¹ The primary endpoint was progression-free survival, and the key secondary endpoints were overall response rate, minimal residual disease and overall survival.¹ PFS was defined as time from randomisation until disease progression or death from any cause.¹

Patients were randomised 2:1 to DKd or Kd¹ and all patients received carfilzomib twice weekly as a 30-minute intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.³ The administration could be within ± two days for each scheduled dose.³ The dose was 20 mg/m² on days 1 and 2 during cycle 1 and 56 mg/m² beginning on day 8 and thereafter.³ All patients received 40 mg dexamethasone oral or IV weekly on days 1 and 2 of cycle 1 (20 mg for patients >75 years).³ In the treatment arm, daratumumab was administered intravenously at 8 mg/kg on days 1 and 2 of cycle 1, and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3 to 6), and every 4 weeks for the remaining cycles or until disease progression.³

For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT03158688.

About daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.⁴ Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.² A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.⁷ Since launch, daratumumab has been used to treat more than 100,000 patients worldwide.⁵ Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.^{6,7,8,9,10,11,12,13} Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.^14,15 For more information, please see www.clinicaltrials.gov.

For further information on daratumumab, please see the Summary of Product Characteristics on the European Medicines Agency (EMA) website at: https://www.ema.europa.eu/documents/product-information/darzalex-epar-product-information_en.pdf.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.¹⁶

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.¹⁷ In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.¹⁸ Almost 60 percent of patients with MM do not survive more than five years after diagnosis.¹⁹

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.²⁰ Refractory multiple myeloma is when a patient’s disease progresses within 60 days of their last therapy.^21,22 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.²³ While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.²⁴ Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.²⁵

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. Learn more at www.janssen.com/emea. Follow us at www.twitter.com/janssenEMEA for our latest news.

Janssen Research & Development, LLC, Cilag GmbH International; Janssen Biotech, Inc. and Janssen-Cilag International NV are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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Cautions Concerning Forward-Looking Statements

This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding the benefits of daratumumab for the treatment of patients with multiple myeloma. 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 materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, Janssen-Cilag International NV, Janssen-Cilag Limited, Janssen Biotech, Inc., any of the Janssen Pharmaceutical Companies of Johnson & Johnson and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions 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 30, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q 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. Neither the Janssen Pharmaceutical Companies of Johnson & Johnson nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

 

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.

² European Medicines Agency. DARZALEX summary of product characteristics, August 2019. Available at: https://www.ema.europa.eu/documents/product-information/darzalex-epar-product-information_en.pdf Last accessed November 2019.

³ ClinicalTrials.gov. Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. (CANDOR). NCT03158688. Available at: https://clinicaltrials.gov/ct2/show/NCT03158688 Last accessed December 2019.

⁴ Fedele G, di Girolamo M, Recine U, et al. CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNgamma cytokines and proliferation. Mediat Inflamm. 2013;2013:564687.

⁵ Janssen. Data on file: RF-82203. Daratumumab: New patient starts launch to date. December 2019

⁶ ClinicalTrials.gov. A study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. NCT02076009. Available at: https://clinicaltrials.gov/ct2/show/NCT02076009 Last accessed December 2019.

⁷ ClinicalTrials.gov. Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. NCT02136134. Available at: https://clinicaltrials.gov/ct2/show/NCT02136134 Last accessed December 2019.

⁸ ClinicalTrials.gov. A study to evaluate daratumumab in transplant eligible participants with previously untreated multiple myeloma (Cassiopeia). NCT02541383. Available at: https://clinicaltrials.gov/ct2/show/NCT02541383 Last accessed December 2019.

⁹ ClinicalTrials.gov. A study of combination of daratumumab and Velcade (bortezomib) melphalan-prednisone (DVMP) compared to Velcade melphalan-prednisone (VMP) in participants with previously untreated multiple myeloma. NCT02195479. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479 Last accessed December 2019.

¹⁰ ClinicalTrials.gov. Study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in participants with previously untreated multiple myeloma. NCT02252172. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172 Last accessed December 2019.

¹¹ ClinicalTrials.gov. A study of Velcade (bortezomib) melphalan-prednisone (VMP) compared to daratumumab in combination with VMP (D-VMP), in participants with previously untreated multiple myeloma who are ineligible for high-dose therapy (Asia Pacific region). NCT03217812. Available at: https://clinicaltrials.gov/ct2/show/NCT03217812 Last accessed December 2019.

¹² ClinicalTrials.gov. Comparison of pomalidomide and dexamethasone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone (EMN14). NCT03180736. Available at: https://clinicaltrials.gov/ct2/show/NCT03180736 Last accessed December 2019.

¹³ ClinicalTrials.gov. Study of carfilzomib, daratumumab and dexamethasone for patients with relapsed and/or refractory multiple myeloma (CANDOR). NCT03158688. Available at: https://clinicaltrials.gov/ct2/show/NCT03158688 Last accessed December 2019.

¹⁴ ClinicalTrials.gov. A study to evaluate 3 dose schedules of daratumumab in participants with smoldering multiple myeloma. NCT02316106. Available at: https://clinicaltrials.gov/ct2/show/NCT02316106 Last accessed December 2019.

¹⁵ ClinicalTrials.gov. An efficacy and safety proof of concept study of daratumumab in relapsed/refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. NCT02413489. Available at: https://clinicaltrials.gov/ct2/show/NCT02413489 Last accessed December 2019.

¹⁶ Johnson & Johnson. Janssen Biotech announces global license and development agreement for investigational anti-cancer agent daratumumab. Press release August 20, 2012. Available at: https://www.jnj.com/media-center/press-releases/janssen-biotech-announces-global-license-and-development-agreement-for-investigational-anti-cancer-agent-daratumumab Last accessed December 2019.

¹⁷ American Society of Clinical Oncology. Multiple myeloma: introduction. Available at: https://www.cancer.net/cancer-types/multiple-myeloma/introduction Last accessed December 2019.

¹⁸ GLOBOCAN 2018. Cancer Today Population Factsheets: Europe Region. Available at: https://gco.iarc.fr/today/data/factsheets/populations/908-europe-fact-sheets.pdf Last accessed December 2019.

¹⁹ De Angelis R, Minicozzi P, Sant M, et al. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study. Eur J Cancer. 2015;51:2254-68.

²⁰ Abdi J, Chen G, Chang H, et al. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget. 2013;4:2186–207.

²¹ National Cancer Institute. NCI dictionary of cancer terms: refractory. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=350245 Last accessed December 2019.

²² Richardson P, Mitsiades C, Schlossman R, et al. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program. 2007:317-23.

²³ National Cancer Institute. NCI dictionary of cancer terms: relapsed. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=45866 Last accessed December 2019.

²⁴ American Cancer Society. Multiple myeloma: early detection, diagnosis and staging. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8740.00.pdf Last accessed December 2019.

²⁵ Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-57.

December 2019

CP-128940

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