On June 6, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) reported results from the first pivotal, international, multicenter, open-label, Phase II study of avelumab*, which showed a 31.8% objective response rate (ORR) (28 of 88 patients; 95.9% CI: 21.9–43.1%†), in the pre-planned primary analysis of the study, and a manageable safety profile in patients with metastatic Merkel cell carcinoma (MCC) who were treated with avelumab in second or subsequent lines of therapy (Press release, Pfizer, JUN 6, 2016, View Source [SID:1234513077]). Tumor responses were rapid, with 78.6% of patients (22 of 28) responding within 7 weeks of starting treatment, and durable, with 82.1% of patients (23 of 28) still responding at the time of analysis. No unexpected safety signals were reported. These data will be reported today during an oral presentation at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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"To see a tumor response in almost a third of patients in this trial, and for the majority to keep responding after six months, represents a potential breakthrough for this challenging disease," said lead investigator Howard L. Kaufman, M.D., FACS, Rutgers Cancer Institute of New Jersey, USA. "Currently, the only treatment option available for advanced stages of this aggressive type of skin cancer is chemotherapy, where the response rates are not adequate or durable."

Metastatic MCC has a poor prognosis with less than 20% of patients surviving longer than five years.1 Although chemotherapy is considered a second-line treatment option for metastatic MCC, it is not a standard of care. Current guidelines recommend that these patients participate in clinical trials.2

"This is an important milestone for us as this is the largest data set of any anti-PD-L1 or anti-PD-1 reported to date in this patient population," said Luciano Rossetti, Executive Vice President, Global Head of Research & Development in the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "The clinically meaningful tumor response rate for avelumab in metastatic Merkel cell carcinoma where chemotherapy has failed, reinforces our belief in the promise of this molecule, particularly considering the high unmet need in this disease."

In the trial, eight patients (9.1%) achieved complete responses and 20 patients (22.7%) achieved partial responses. The median duration of response has not been reached (95% CI: 8.3 months – not estimable; range, 2.8–17.5+ months). Tumor responses were seen in patients regardless of the status of certain biomarkers (PD-L1 and Merkel cell polyomavirus). The progression-free survival (PFS) rate at 6 months was 40% (95% CI: 29–50%, estimated by the Kaplan-Meier method). Early data also showed an overall survival (OS) rate at 6 months of 69% (95% CI: 58–78%) and a median OS of 11.3 months (7.5–14.0 months); however, these OS data are still maturing since minimum follow-up was 6 months for inclusion in this analysis. Treatment-related adverse events (AEs) occurred in 62 patients (70.5%); the most common were fatigue (23.9%) and infusion-related reactions (17.0%), all of which were Grade 1 or 2. Grade 3 treatment-related AEs were reported in four patients (4.5%). There were no Grade 4 treatment-related AEs or deaths.

"This has been an exciting ASCO (Free ASCO Whitepaper) for the strategic collaboration between the two companies, between the MCC data and the other encouraging responses observed across a broad range of tumors," said Chris Boshoff, M.D., PhD., Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "The clinical benefits for avelumab as a monotherapy in notably hard-to-treat cancers may be amplified even further when combined with other therapies."

Avelumab has received multiple regulatory designations in MCC from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), including Orphan Drug (FDA and EMA), Fast Track and Breakthrough status (FDA). There are plans to submit marketing applications for avelumab to regulatory authorities based on these data.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, Phase II study of avelumab conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33–88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received avelumab 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was 6 months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at 6 and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of avelumab.

*Avelumab is the proposed nonproprietary name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

†Multiplicity adjustment accounting for interim analysis to achieve overall 95% confidence level.

References

Lemos B, Storer B, Iyer J, et al. Pathologic Nodal Evaluation Improves Prognostic Accuracy in Merkel Cell Carcinoma: Analysis of 5,823 Cases as the Basis of the First Consensus Staging System for this Cancer. Journal of the American Academy of Dermatology. 2010;63:751-761.
NCCN Merkel Cell Carcinoma Guidelines Version I. 2016. Available from: www.nccn.org/professionals/physician_gls/PDF/mcc.pdf (link is external). Accessed April 2016.
About Avelumab

Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US

Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy, as well as in combination regimens, and is striving to find new ways to treat cancer.

About Merck KGaA, Darmstadt, Germany

All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe (link is external) to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

Merck KGaA, Darmstadt, Germany, is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life – from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2015, Merck KGaA, Darmstadt, Germany, generated sales of € 12.85 billion in 66 countries.

Founded in 1668, Merck KGaA, Darmstadt, Germany, is the world’s oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany operates as EMD Serono, MilliporeSigma and EMD Performance Materials in the United States and Canada.

On June 6, 2016 GlycoMimetics, Inc. (NASDAQ:GLYC) reported dosing of the first patient with relapsed/refractory acute myeloid leukemia in the Phase 2 portion of its ongoing Phase 1/2 clinical trial evaluating its novel E-selectin antagonist, GMI-1271, combined with induction chemotherapy (Press release, GlycoMimetics, JUN 6, 2016, View Source [SID:1234513101]).

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For the study’s Phase 2 portion, the optimal dose has been determined, and clinical investigators will expand the number of patients receiving GMI-1271 to obtain additional safety and efficacy data. Study enrollment is limited to patients at least 18 years old with relapsed or refractory AML and who would be treated with mitoxantrone, etoposide, and cytarabine (‘MEC’). All patients must be eligible to receive this chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive an additional cycle of treatment.

"The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "In the second half of this trial, we will further assess if patients with relapsed or refractory AML respond well to this combination approach while also including those who have been newly diagnosed with the disease in a separate arm of the study. If the second half confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what can be done with currently available therapies."

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study is expected to include approximately 25 participants.

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

On June 6 2017 BIOCAD reported that it has obtained a marketing authorization for its rituximab biosimilar in Bolivia and Honduras under the trade name USMAL (Press release, Biocad, JUN 6, 2017, View Source [SID1234527805]). First shipments will start in the beginning of the third quarter of 2017. BIOCAD will be able to supply as much rituximab as needed for Bolivian and Honduran patients. Considering competitive price of the Russian biosimilar, estimated drug availability will double.

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Rituximab has become the first BIOCAD product to enter Latin America, which is strategically important for further business development in the markets of the MERCOSUR and other countries in region. Now the drug is being registered in other countries of this region and by the end of 2017 BIOCAD is expecting to get two more marketing authorization certificates.

The launch of the Russian biosimilar in the Bolivian and Honduran markets, where only originators are present, will provide the patients with an access to affordable and highly effective treatment of cancer, thus improving their life quality and expectancy.

High quality of Russian rituximab has been demonstrated in large-scale international clinical trials involving patients from Russia, Ukraine, Belarus, India, South Africa and Columbia. Starting from 2011 pharmacological properties of the biosimilar, as well its efficacy and safety have been extensively studied in the clinical development program in patients with lymphoma and those with severe rheumatoid arthritis. The equivalence of the Russian drug to the originator has been supported by multiple physicochemical and biological studies conducted in line with EMA guidelines and ICH philosophy.

With its production capacity, BIOCAD is ready to realize the export potential and stably supply high-tech biosimilars. Growing internationally, BIOCAD successfully ships rituximab biosimilar to seven countries, including Kazakhstan, Vietnam and Sri Lanka. The next step for expanding Latin American markets will be the launch of trastuzumab and bevacizumab biosimilars that already have marketing authorizations and are being distributed in other countries.

On June 6, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported results from its Phase 3 trial of VYXEOS (cytarabine: daunorubicin) Liposome for Injection (also known as CPX-351) in patients with high-risk (secondary) acute myeloid leukemia (AML) were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting (Press release, Celator Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513035]). As previously reported, the trial met its primary endpoint demonstrating a statistically significant improvement in overall survival. The Phase 3 trial compared to the standard of care regimen of cytarabine and daunorubicin known as 7+3.

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The median overall survival for patients treated with VYXEOS in the study was 9.56 months compared to 5.95 months for patients receiving 7+3, representing a 3.61 month improvement in favor of VYXEOS. The hazard ratio (HR) was 0.69 (p=0.005) which represents a 31% reduction in the risk of death versus 7+3. The percentage of patients alive 12 months after randomization was 41.5% on the VYXEOS arm compared to 27.6% on the 7+3 arm. The percentage of patients alive 24 months after randomization was 31.1% on the VYXEOS arm compared to 12.3% on the 7+3 arm.

Event-free survival was also statistically significant in favor of VYXEOS. The HR was 0.74 (p-value=0.021). The median event-free survival was 2.53 months in the VYXEOS arm compared to 1.31 months in the 7+3 arm.

"We believe the promising primary efficacy results of CPX-351 in high risk AML, across multiple parameters, support its use as the new standard of care in a difficult-to-treat population," said Jeffrey E. Lancet, M.D., senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center and the principal investigator for the study. "This is an important step forward in the treatment of a terrible disease, and hopefully this platform for synergistic drug delivery will continue to advance the field."

VYXEOS also demonstrated a statistically significant improvement in induction response rate (CR+CRi of 47.7% versus 33.3%; p=0.016) and this significance was maintained for the analysis of CR alone (CR of 37.3% versus 25.6%, p=0.040).

Thirty-four percent of VYXEOS treated patients received a stem cell transplant (SCT) compared to 25% of 7+3 treated patients. In a landmark survival analysis of patients receiving a SCT, VYXEOS patients had significantly improved survival post-transplant (HR was 0.46 (p-value=0.0046)). The median overall survival had not been reached in the VYXEOS treated patients compared to 10.25 months in the 7+3 treated patients.

Thirty-day and sixty-day all-cause mortality favored VYXEOS. Thirty-day mortality was 5.9% compared to 10.6% and sixty-day mortality was 13.7% versus 21.2%.

Grade 3-5 non-hematologic and hematologic adverse events were similar between the VYXEOS and 7+3 arms.

The company expects to submit a New Drug Application (NDA) for VYXEOS with the U.S. Food and Drug Administration (FDA) by the end of the third quarter of 2016 and submit a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) in the first quarter of 2017.

"We are very pleased to have this opportunity to share the data from our Phase 3 trial with the oncology community. This successful outcome represents an important advance for AML patients, their families and clinicians," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals. "We thank the patients and investigators who participated in this study and we will work closely with regulatory authorities to make this new treatment available to the AML community as soon as possible."

The clinical trial was conducted in partnership with The Leukemia & Lymphoma Society (LLS) through its Therapy Acceleration Program (TAP), which has supported the clinical development of VYXEOS beginning in Phase 2.

Phase 3 Trial Design

The randomized, controlled, Phase 3 trial (Protocol NCT01696084), enrolled 309 patients at 39 sites in the United States and Canada, and compared VYXEOS to the conventional cytarabine and daunorubicin treatment regimen (commonly referred to as 7+3) as first-line therapy in older (60-75 years of age) patients with high-risk (secondary) AML. Patients were stratified for age (60 to 69 and 70 to 75 years of age) and AML type; treatment-related AML, AML with documented history of myelodysplastic syndrome (MDS) with prior treatment with hypomethylating agent therapy, AML with documented history of MDS without prior hypomethlyating agent therapy, AML with a documented history of chronic myelomonocytic leukemia (CMMoL), and de novo AML with a karyotype characteristic of MDS.

Patients were randomized 1:1 to receive either VYXEOS or 7+3. Patients could receive one or two inductions, and responding patients could receive one or two consolidations. First induction for VYXEOS was 100u/m2; days 1, 3, and 5 by 90-minute infusion and for the control arm was cytarabine 100mg/m2/day by continuous infusion for 7 days and daunorubicin 60mg/m2 on days 1, 2, and 3 (7+3). Second induction for VYXEOS-treated patients was 100u/m2 on days 1 and 3, and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

Only patients with documented CR or CRi were eligible to receive chemotherapy consolidation. Consolidation for VYXEOS-treated patients was 65u/m2 on days 1 and 3 and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

About VYXEOS

VYXEOS (cytarabine:daunorubicin) Liposome for Injection, also known as CPX-351, is a nano-scale co-formulation of cytarabine and daunorubicin at a synergistic 5:1 molar ration. VYXEOS represents a novel approach to developing combinations of drugs in which molar ratios of two drugs with synergistic anti-tumor activity are encapsulated in a nano-scale liposome in order to maintain the desired ratio following administration. The FDA granted Breakthrough Therapy designation to VYXEOS for the treatment of adults with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). VYXEOS was granted orphan drug status for the treatment of AML by the FDA and the European Commission. VYXEOS was also granted Fast Track designation for the treatment of elderly patients with secondary AML by the FDA.

About AML

Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood characterized by the uncontrolled proliferation of immature blast cells in the bone marrow. AML is generally a disease of older adults, and the median age of a patient diagnosed with AML is about 67 years. The American Cancer Society estimates that there will be 19,950 new cases of AML and 10,430 deaths from AML in the U.S. in 2016. In Europe the number of new cases is estimated to be 18,000 and in Japan the number is 5,500. The Company estimates that nearly 70 percent of AML patients are over the age of 60, and approximately 75% are intermediate or high risk. Furthermore, approximately half of those patients are considered suitable for intensive treatment.

Even with current treatment, overall survival for AML is poor. In patients over 60 years of age, the 5 year survival rate is less than 10%. In high-risk (secondary) AML, overall survival is lower, resulting in an acute need for new treatment options for these patients.

On June 6, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported longer-term follow-up results from Phase 3 studies of IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, JUN 6, 2016, View Source [SID:1234513058]). Findings include an analysis of outcomes from the RESONATETM (PCYC-1112) and RESONATETM-2 (PCYC-1115) trials, which showed IMBRUVICA was associated with favorable progression-free survival (PFS) and overall survival (OS) regardless of line of therapy (previously treated or treatment-naïve; abstract 7520). Other data include first-ever presentation of longer-term follow-up data from the HELIOS (CLL3001) trial showing IMBRUVICA in combination with bendamustine and rituximab (BR) continued to demonstrate superiority over time versus placebo plus BR in relapsed/refractory CLL/SLL patients (abstract 7525), along with improvements in quality of response.

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These data showcasing additional clinical evidence of IMBRUVICA in CLL/SLL will be presented today in a poster session at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago from 8:00 – 11:30 a.m. CDT. The RESONATE and RESONATE-2 analysis will also be featured as a poster discussion today from 1:15 – 2:45 p.m. CDT. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

"Our clinical data presented at this year’s ASCO (Free ASCO Whitepaper) from several randomized studies demonstrate solid durability of response with IMBRUVICA in patients with CLL/SLL with additional follow-up of up to three years," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "This evidence of deepening responses with continued therapy and long-term survival with IMBRUVICA over time, used either as a single agent or in combination, positions this therapy as a potentially beneficial treatment option for a variety of patients with CLL or SLL, regardless of when it is prescribed in the treatment journey."

An analysis of the RESONATE and RESONATE-2 trials showed IMBRUVICA was associated with favorable PFS and OS outcomes, as well as a high overall response rate (ORR) in previously treated and treatment-naïve patients with CLL/SLL, regardless of line of therapy. The median PFS and OS were not reached in treatment-naïve or previously-treated patients; 89-92% of patients treated with ibrutinib at first or second line of therapy remained progression-free at two years. Additionally, ORR was high in both previously treated and treatment-naïve patients (92% and 91%, respectively). The safety profile was similar for both patient groups1 and was consistent with previously-reported outcomes. Data from the RESONATE and RESONATE-2 studies served as the basis for the 2014 and 2016 FDA approvals of IMBRUVICA for patients with CLL/SLL.

The most commonly occurring adverse reactions (? 20%) in studies that supported the FDA approvals for patients with CLL/SLL were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10% of patients receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.

Additionally, after a median follow-up of 25.4 months, data from the HELIOS trial showed the combination of IMBRUVICA plus BR continued to demonstrate a significant improvement in investigator-assessed PFS (the primary endpoint) (74.8%) versus placebo plus BR (20.9%) in patients with relapsed/refractory CLL/SLL (median not reached versus 14.2 months, respectively; HR [95% CI]: 0.199 [0.15, 0.26], P<0.0001). The updated investigator-assessed ORR for IMBRUVICA plus BR was 87.2%, as compared with 66.1% for placebo plus BR (P<0.0001) and the rate of complete responses (CRs) and CRs with incomplete bone marrow recovery (CRi) improved in the IMBRUVICA plus BR arm (33.9% versus 7.2% in the placebo plus BR arm). OS was not reached in either arm (HR [95% CI]: 0.670 [0.44, 1.02], P=0.587). Safety was consistent with the first analysis.2 Notably, positive results from the initial analysis (median follow-up: 17 months) supported the May 2016 update to the IMBRUVICA U.S. Prescribing Information.

The prevalence of CLL is approximately 115,000 patients in the U.S.3 with approximately 15,000 newly diagnosed patients every year.4 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.5 CLL and SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.3

About the RESONATE Study
RESONATE is a Pharmacyclics-sponsored randomized, multi-center, open-label, international Phase 3 study that examined ibrutinib versus ofatumumab in relapsed/refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.

Results from RESONATE were featured in the official press program at ASCO (Free ASCO Whitepaper) in Chicago in June 2014 and simultaneously published in The New England Journal of Medicine.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study which enrolled 269 treatment-naïve patients with CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved PFS, as assessed by an independent review committee (IRC).

Results from RESONATE-2 were first presented in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Orlando, FL in December 2015 and simultaneously published in The New England Journal of Medicine. The results were also part of the official press program at ASH (Free ASH Whitepaper) 2015.

About the HELIOS Study
HELIOS is a Janssen-sponsored, randomized, multi-center, double-blind, placebo-controlled, Phase 3 study which enrolled 578 CLL/SLL patients who had received at least one prior systemic therapy. Patients were randomized to receive IMBRUVICA or placebo, once daily continuing until disease progression or unacceptable toxicity with six cycles of BR. The study met its primary endpoint, demonstrating improved IRC assessed PFS.

Data from an interim analysis of HELIOS were first presented during the official press program at ASCO (Free ASCO Whitepaper) in Chicago in May 2015. The results were also published in The Lancet Oncology in December 2015.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).6 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably. 7

IMBRUVICA is approved to treat patients with CLL/SLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.7

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

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