On November 3, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported a corporate update and reported financial results for the third quarter ended September 30, 2016 (Press release, Five Prime Therapeutics, NOV 3, 2016, View Source [SID1234516271]).

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"We have continued to make progress on all of our clinical and preclinical programs during the quarter," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "We achieved an important milestone by advancing into the Phase 1b portion of our clinical trial evaluating the immunotherapy combination of cabiralizumab (FPA008) with nivolumab in multiple tumor types. We believe targeting both the CSF1R and PD-1 pathways has the potential to produce a synergistic therapeutic effect. Our Phase 1 trial evaluating FPA144 in patients with gastric cancer is also progressing well. We have added cohorts to enroll gastric cancer patients with tumors at varying levels of FGFR2b expression as well as a cohort to evaluate bladder tumors that overexpress FGFR2b. Additionally, we continue to advance our pre-clinical programs and have begun IND-enabling activities for three of our immuno-oncology therapeutic candidates."

Business Highlights and Recent Developments

Clinical Pipeline:

Cabiralizumab (FPA008): an investigational antibody that inhibits CSF1R and has been shown to block the activation and survival of monocytes and macrophages. In the setting of advanced cancer, tumor-associated macrophages can inhibit the immune system’s ability to eradicate the disease. In pigmented villonodular synovitis (PVNS), a CSF-1-driven tumor, the bulk of the tumor mass in joints is formed by the macrophages themselves. Five Prime and Bristol-Myers Squibb (BMS) have an exclusive worldwide collaboration agreement for the development and commercialization of cabiralizumab for these and potentially additional indications.

Initiated Phase 1b portion of cabiralizumab/OPDIVO trial.
In October 2016, Five Prime initiated the Phase 1b portion of the clinical trial evaluating the immunotherapy combination of cabiralizumab with the PD-1 immune checkpoint inhibitor OPDIVO (nivolumab) in multiple tumor types. Five Prime and BMS are evaluating the safety, tolerability and preliminary efficacy of the combination in advanced solid tumors, including non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, glioblastoma, renal cell carcinoma and ovarian cancer. The Phase 1a/1b trial is expected to enroll approximately 280 patients.

Advanced the Phase 2 trial of cabiralizumab in patients with PVNS.
Five Prime continued enrollment and dosing in the Phase 2 trial of cabiralizumab in PVNS. During Phase 2, Five Prime is evaluating clinical measures, including response rate, pain and range of motion, in approximately 30 PVNS patients.

FPA144: an isoform-selective antibody in development as a targeted immuno-therapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family. FPA144 has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to increase direct tumor cell killing by recruiting natural killer (NK) cells. Five Prime retains global development and commercialization rights to FPA144.

Opened new gastric cancer cohorts and added a bladder cancer cohort in Phase 1 monotherapy trial of FPA144. Enrollment continues in the expansion portion of the trial evaluating the safety, PK and efficacy of biweekly 15 mg/kg infusions of FPA144 in patients with gastric cancer whose tumors highly overexpress FGFR2b. During the quarter, Five Prime added cohorts to evaluate FPA144 in patients with bladder cancer whose tumors overexpress FGFR2b and in patients with gastric cancer whose tumors express moderate or low levels of FGFR2b. Five Prime reported encouraging initial single-agent efficacy and safety data at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Announced FDA Orphan Drug Designation for FPA144 in July for the treatment of gastric cancer and cancer of the gastroesophageal junction in patients whose tumors overexpress FGFR2b.

FP-1039: a protein drug designed to intervene in FGF signaling. As a ligand trap, FP-1039 binds to and neutralizes FGF ligands (such as FGF2), preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells.

Although Five Prime regained full rights to FP-1039 from GlaxoSmithKline (GSK) in September, GSK will complete the ongoing Phase 1b trial combining FP-1039 with first-line pemetrexed and cisplatin in untreated, unresectable mesothelioma. GSK concluded trial recruitment with 25 patients enrolled at the 15 mg/kg dose, and continues to dose and follow patients. Five Prime plans to make decisions on potential future development of FP-1039 in mesothelioma once objective response rate, disease control rate and progression-free survival data are sufficiently mature.
Preclinical Research and Development:

IND-enabling studies initiated for preclinical development candidates. Five Prime advanced multiple preclinical immuno-oncology programs and initiated IND-enabling activities for three therapeutic candidates. In vivo data from preclinical studies of Five Prime’s tetravalent GITR agonist antibody (FPA154) have been accepted for presentation in a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting on November 11, 2016. Five Prime intends to share further details on all three programs during its R&D Day in New York City on December 8. The company’s goal is to file at least one IND application for a new molecule each year for the foreseeable future, beginning in 2017.

Completed multiple immuno-oncology research screens to identify new targets and drug candidates. Five Prime’s research team completed functional screens on CD8 T cells and regulatory T cells, as well as a comprehensive screen of all extracellular binding interactions in the "immunome," a defined subset of extracellular proteins selectively expressed on immune cells. The screens were conducted in order to identify new immuno-oncology targets, which the company is prioritizing for further development as new drug candidates, either as monotherapies or as part of combination regimens.
Summary of Financial Results and Guidance:

Cash Position. Cash, cash equivalents and marketable securities totaled $440.7 million on September 30, 2016, compared to $517.5 million on December 31, 2015. The decrease in cash was primarily attributable to cash used in operations to advance the FPA144 clinical trial, preclinical programs and tax payments.
Revenue. Collaboration revenue for the third quarter of 2016 increased by $0.8 million to $6.7 million from $5.9 million in the third quarter of 2015. This increase was primarily due to revenue recognized under the 2015 cabiralizumab collaboration agreement with BMS, under which Five Prime is reimbursed for the expenses from the cabiralizumab immuno-oncology trial.
R&D Expenses. Research and development expenses for the third quarter of 2016 decreased by $0.8 million to $23.9 million from $24.7 million in the third quarter of 2015. In the third quarter of 2015, the company recorded an $8.0 million expense related to in-licensing. Adjusted for this expense, research and development expenses increased $7.2 million over the prior year’s quarter, primarily related to advancing the FPA144 clinical trial, preclinical development and immuno-oncology research programs.
G&A Expenses. General and administrative expenses for the third quarter of 2016 increased by $3.9 million to $9.1 million from $5.2 million in the third quarter of 2015. This increase was primarily due to increases in payroll and stock-based compensation expenses.
Net Loss. Net loss for the third quarter of 2016 was $19.4 million, or $0.72 per basic and diluted share, compared to a net loss of $24.0 million, or $0.93 per basic and diluted share, for the third quarter of 2015.
Shares Outstanding. Total shares outstanding were 28.4 million as of September 30, 2016.
Cash Guidance. Five Prime continues to expect full-year 2016 net cash used in operating activities to be less than $120 million, comprising less than $90 million used in operations and less than $30 million used for tax payments. The company estimates ending 2016 with more than $400 million in cash, cash equivalents and marketable securities.

On November 3, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported financial results for the third quarter and nine months ended September 30, 2016 and provided a business update (Press release, Corvus Pharmaceuticals, NOV 3, 2016, View Source;p=RssLanding&cat=news&id=2219512 [SID1234516268]).

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"We continue to make good progress on the development of our lead product candidate, CPI-444," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "Enrollment in the dose-selection stage of our Phase 1/1b trial with CPI-444 is complete and we are now enrolling patients in the expansion cohort stage of the trial, which is open in 35 sites in the U.S., Canada and Australia. In addition, we reported data on CPI-444 at two recent scientific meetings."

RECENT BUSINESS PROGRESS
CPI-444 Program

Completed enrollment of 48 patients in four cohorts in the dose-selection part of the Phase 1/1b trial for the Company’s lead oral checkpoint inhibitor, CPI-444, as a single agent and in combination with Genentech’s TECENTRIQ (atezolizumab), an anti-PD-L1 antibody.
Selected an oral dose of 100 mg twice daily for 28 days for both the single agent and combination arms of the disease-specific expansion cohort stage of the trial, which is now enrolling.
Presented preclinical and preliminary biomarker data at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper) in September, which showed that CPI-444 is well tolerated and that single agent treatment is associated with activation of T-cells detected in the blood. Corvus believes this is the first demonstration of immune modulation in cancer patients receiving an adenosine antagonist.
Presented additional biomarker data from the Phase 1/1b study showing continued evidence of treatment-related immune activation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in October. CPI-444 continued to be generally well tolerated, with one patient experiencing a possibly drug related serious adverse event.
Other Product Candidates

Demonstrated in preclinical studies that Corvus’ anti-CD73 antibody directly inhibited catalytic activity of CD73 and was differentiated from other competitive CD73 antibodies. Large scale manufacturing of anti-CD73 is in progress and IND enabling studies have been initiated.
Selected a lead compound for Corvus’ interleukin-2 (IL-2)-inducible T-cell kinase (ITK) inhibitor program and initiated IND enabling studies.
UPCOMING MILESTONE

The Company expects to present preliminary efficacy data from the dose-selection part of the Phase 1/1b trial for CPI-444 in the fourth quarter of 2016.
THIRD QUARTER 2016 FINANCIAL RESULTS
At September 30, 2016, Corvus had cash, cash equivalents and marketable securities totaling $145.1 million. This compared to cash, cash equivalents and marketable securities of $94.4 million at December 31, 2015.

Research and development expenses for the three months ended September 30, 2016 totaled $7.7 million, an increase of $5.2 million from $2.5 million in the prior year period, primarily due to an increase of $1.2 million in personnel and related costs associated with higher headcount, an increase of $2.2 million in outside costs for the Phase 1/1b clinical trial for CPI-444, and an increase of $1.4 million in outside costs associated with other clinical development programs.

General and administrative expenses for the three months ended September 30, 2016 totaled $2.8 million, an increase of $2.2 million from $0.6 million in the prior year period, primarily due to an increase of $1.0 million in personnel and associated costs, an increase of $0.7 million in patent and related costs and $0.2 million in costs associated with operating as a public company.

The net loss for the three months ended September 30, 2016 was $10.3 million, compared with a net loss of $3.2 million, for same period in 2015. Total stock compensation expense for the three months ended September 30, 2016 was $1.3 million, compared to $0.1 million in the prior year period.

On November 3, 2016 Clovis Oncology, Inc. (NASDAQ:CLVS) reported financial results for the quarter ended September 30, 2016, and provided an update on the Company’s clinical development programs and regulatory outlook for the remainder of 2016 (Press release, Clovis Oncology, NOV 3, 2016, View Source;p=RssLanding&cat=news&id=2219461 [SID1234516267]).

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"We are actively preparing for a U.S. launch of rucaparib pending FDA’s decision on our NDA, and we have completed our Marketing Authorization Application submission seeking European approval for rucaparib," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "Importantly, we remain focused on exploring rucaparib more broadly, and expect several studies to initiate this quarter, including the TRITON2 study in prostate cancer, the ARIEL4 confirmatory study in ovarian cancer and investigator-sponsored studies exploring rucaparib as maintenance therapy in gastroesophageal cancer and also in combination with bevacizumab in ovarian cancer."

Third Quarter 2016 Financial Results

Clovis had $318.8 million in cash, cash equivalents and available-for-sale securities as of September 30, 2016. Cash used in operating activities was $60.3 million for the third quarter of 2016 and $212.0 million for the first nine months of 2016, compared with $71.7 million and $177.4 million for the comparable periods of 2015. Clovis had approximately 38.6 million outstanding shares of common stock as of September 30, 2016.

Clovis reported a net loss of $65.7 million, or ($1.70) per share, for the third quarter of 2016 and $278.4 million or ($7.24) per share for the first nine months of 2016. The net loss for the third quarter of 2015 was $98.6 million or ($2.62) per share and $233.3 million or ($6.62) per share for the first nine months of 2015. Net loss for the third quarter of 2016 included share-based compensation expense of $9.2 million and $29.7 million for the third quarter and the first nine months of 2016, respectively, compared to $12.4 million and $29.5 million for the comparable periods of 2015.

Notably, the net loss for the first nine months of 2016 includes a net expense non-cash impact of $49.9 million relating to the lucitanib product rights recorded in 2013 in connection with the Company’s acquisition of Ethical Oncology Science S.p.A. (EOS), comprised of a $104.5 million non-cash expense for the impairment of the intangible asset, a $25.5 million non-cash expense credit for the reduction in the fair value of the contingent purchase consideration liability and a $29.2 million related non-cash income tax benefit. The adjusted net loss excluding these items was $228.5 million or ($5.95) per share for the first nine months of 2016.

Research and development expenses totaled $54.3 million for the third quarter of 2016, and $196.7 million for the first nine months of 2016, compared to $76.1 million and $193.3 million, respectively, for the comparable periods in 2015. The decrease in expenses for the third quarter is primarily due to decreased development activities for rociletinib compared to the prior year partially offset by higher expenses associated with rucaparib development programs and launch preparation. The increase in expenses for the nine-month period is primarily due to increased development activities for the rucaparib program, launch preparation and increased personnel-related expenses, partially offset by lower expenses related to decreased clinical development activities for rociletinib.

General and administrative expenses totaled $9.2 million for the third quarter of 2016, and $28.5 million for the first nine months of 2016, compared to $8.3 million and $22.3 million for the comparable periods in 2015. The increase year over year is primarily due to higher legal expense and personnel costs for employees engaged in general and administrative activities.

Clovis expects cash used in operating activities for 2016 will total approximately $276 – $286 million, and to end the year with approximately $245 – $255 million in cash, cash equivalents and available-for-sale securities. This change to cash guidance is primarily related to the recent amendment to the worldwide license agreement with Pfizer for rucaparib which allows Clovis the option to defer payment of the milestone payments payable upon U.S. Food and Drug Administration (FDA) approval of a first NDA in the US and European Medicines Authority (EMA) approval of a first Marketing Authorization Application (MAA) in EU to a date that is 18 months after the date of achievement of such milestones, in exchange for certain higher payments related to the achievement of such milestones. The Company anticipates being able to continue to fund operations into 2018 from currently available cash, cash equivalents and available-for-sale securities.

2016 Key Milestones and Objectives for Rucaparib

During the third quarter of 2016, the rucaparib NDA regulatory filing was accepted by FDA for accelerated approval and granted priority review status with a PDUFA date of February 23, 2017. The application is for rucaparib as monotherapy treatment of patients with advanced ovarian cancer with deleterious BRCA-mutated tumors previously treated with two or more chemotherapies. Tumor BRCA mutations include germline and/or somatic mutations. Rucaparib was granted Breakthrough Therapy designation by the FDA in April 2015.

Foundation Medicine, Clovis’ companion diagnostic partner, has submitted a Premarket Approval (PMA) application for its tissue-based diagnostic assay designed to identify tumor BRCA mutations, including germline and somatic mutations, with the FDA. The timing of the submission is expected to allow for regulatory approval of the companion diagnostic at substantially the same time that rucaparib could be approved.

In addition, the Company submitted an MAA for rucaparib to the European Medicines Agency for a comparable ovarian cancer treatment indication earlier this week.

In October, in support of the potential U.S. commercial launch of rucaparib, we announced the signing of a long-term manufacturing agreement with Lonza, our current manufacturer. We expect that this new agreement for a dedicated manufacturing line will provide security of supply and reduce our cost of goods over time.

Clovis has completed enrollment in the ARIEL3 Phase 3 randomized maintenance study, with data expected to be available in 2H 2017. Pending positive data, the Company intends to follow up with a supplemental NDA (sNDA) for second-line maintenance therapy in women with ovarian cancer who have responded to platinum based therapy.

At the 2016 ESMO (Free ESMO Whitepaper) Congress in early October, the primary efficacy and safety data from the NDA dataset for rucaparib were presented in an oral session, including the following highlights:

The RECIST ORR (objective response rate as assessed by the investigator, which includes complete and partial responses) in the 106 patients evaluable for efficacy was 54% (95% CI: 43.8-63.5).
Duration of response by investigator assessment in the efficacy population was 9.2 months (95% CI: 6.6-11.7 months).
The most common treatment-emergent adverse events (AEs) (all grades) reported in ≥20 percent of patients in the safety population (n=377) included nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), increased ALT/AST (41%) and constipation (40%). The most common Grade 3/4 treatment-emergent AEs reported in ≥10 percent of patients were anemia (25%), asthenia/fatigue (11%) and ALT/AST elevations (11%).
Several clinical studies, including both Clovis-sponsored and investigator-initiated trials, recently initiated or are planned to begin enrolling patients during the fourth quarter. These include the Clovis-sponsored ARIEL4 confirmatory study in advanced BRCA mutant (inclusive of germline and somatic) ovarian cancer; an investigator-sponsored study evaluating rucaparib and bevacizumab in combination as a first-line maintenance therapy for advanced ovarian cancer; the investigator-initiated RUBY study in women with breast cancer whose tumors have a somatic BRCA mutation or homologous recombination deficient (HRD) signature other than a known germline BRCA mutation; the investigator-initiated PLATFORM study in gastroesophageal cancer in the first-line maintenance setting; and the Clovis-sponsored TRITON2 (Trial of Rucaparib in Prostate Indications) study in metastatic castrate-resistant prostate cancer (mCRPC), a Phase 2 single-arm study enrolling patients with BRCA mutations and ATM mutations (both inclusive of germline and somatic) or other deleterious mutations in other homologous recombination (HR) repair genes and all patients will have progressed after receiving one line of taxane-based chemotherapy and one or two lines of androgen-receptor (AR) targeted therapy.

The Clovis-sponsored TRITON3 study, a Phase 3 comparative study in mCRPC enrolling BRCA mutant and ATM mutant (both inclusive of germline and somatic) patients who have progressed on AR-targeted therapy and who have not yet received chemotherapy in the castrate-resistant setting is planned to initiate during the first quarter of 2017. TRITON3 will compare rucaparib to physician’s choice of AR-targeted therapy or chemotherapy in these patients. Also during the first quarter of 2017, the Phase 1b combination study of Genentech’s cancer immunotherapy Tecentriq (atezolizumab; anti-PDL1) and rucaparib for the treatment of gynecological cancers, with a focus on ovarian cancer, is expected to have the first patient initiated (FPI).

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for advanced ovarian cancer. Rucaparib was granted Breakthrough Therapy designation by the FDA in April 2015; and its NDA submission for the treatment of advanced ovarian cancer is currently under active review with the FDA. The MAA submission in Europe for a comparable ovarian cancer indication completed during the fourth quarter of 2016. Additionally, rucaparib is being developed as maintenance therapy in the ARIEL3 trial for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) commonly referred to as "BRCA-like." Data from ARIEL3 are expected in 2H 2017, which is expected to be followed by the submission of a sNDA for a second line or later maintenance indication. Clovis is also exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations, including prostate, breast and gastroesophageal cancers. Clovis holds worldwide rights for rucaparib.

On November 3, 2016 Cerus Corporation (NASDAQ: CERS) reported financial results for the third quarter ended September 30, 2016 (Press release, Cerus, NOV 3, 2016, View Source [SID1234516264]).

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Recent developments include:
The U.S. Food and Drug Administration’s (FDA) revised recommendations for protecting blood components from Zika virus was expanded to recommend use of pathogen reduction technology and/or an investigational blood screening test to all U.S. blood centers.

The first Cerus U.S. blood center customers have submitted biologics license applications to the FDA to request allowance for the interstate transport of INTERCEPT-treated platelet components.

Hemolife Fundacion Banco Nacional de Sangre became the first blood center to enter into routine use with the INTERCEPT Blood System in Colombia.

Cerus’ global commercial leadership was strengthened with the appointment of Vivek Jayaraman as chief commercial officer.
"U.S. momentum continues to build, with the number of customers initiating INTERCEPT production accelerating from just three at the beginning of the year to 17 customers to date. With another 22 contracted customers slated to begin production, we are in a healthy position for growth," said William ‘Obi’ Greenman, Cerus’ president and chief executive officer. "Beyond platelets and plasma, we are also moving forward with activities related to our red cell program, with plans to submit for European CE Mark approval and to initiate a U.S. Phase III trial."

Revenue
Product revenue for the third quarter of 2016 was $10.2 million, up 26% from the $8.0 million recognized during the same period in 2015. The increase in reported product revenue for the quarter was primarily driven by a year-over-year increase in INTERCEPT disposable kit demand of 30% in our EMEA and U.S. commercial regions. Product revenue for the first nine months of 2016 was $27.1 million, up 10% from the first nine months of 2015, driven primarily by increased kit sales in our EMEA region and sales to U.S. customers.

Revenue from our Biomedical Advanced Research and Development Authority (BARDA) agreement for the three and nine months ended September 30, 2016, was $0.3 million. We did not recognize any revenue from our BARDA agreement during the three and nine months ended September 30, 2015.

The Company continues to expect 2016 global product revenue in the range of $37 million to $40 million with anticipated growth supported by new business opportunities in both its European and U.S. markets.

Gross Margins
Gross margins on product revenue for the third quarter of 2016 were 46%, compared to 31% for the third quarter of 2015. Gross margins on product revenue for the first nine months of 2016 were 46%, compared to 30% for the first nine months of 2015. Gross margins on product revenue for the three and nine months ended September 30, 2016, increased primarily due to the Company’s disposable kit manufacturing agreement with Fresenius Kabi AG, entered into during the fourth quarter of 2015, and efficiencies realized in 2016 related to inventory management.

Operating Expenses
Total operating expenses for the third quarter of 2016 were $19.2 million, compared to $18.7 million for the third quarter of 2015. Total operating expenses for the first nine months of 2016 were $59.0 million, compared to $53.3 million for the first nine months of 2015. Selling, general and administrative expenses increased for the three and nine months ended September 30, 2016, primarily due to increased spending related to selling and marketing activities associated with the commercialization of INTERCEPT in the U.S. market. Research and development expenses drove the majority of the reported increase for the nine months ended September 30, 2016, primarily due to activities associated with clinical development of the red blood cell system, the pursuit of potential premarket applications supplement approvals for the platelet and plasma systems and the initial activities under the BARDA agreement.

Operating and Net Loss
Operating losses during the third quarter of 2016 were $14.3 million, compared to $16.2 million for the third quarter of 2015, and $46.3 million compared to $46.1 million for the nine months ended September 30, 2016 and September 30, 2015, respectively.
Net loss for the third quarter of 2016 was $14.4 million, or $0.14 per diluted share, compared to a net loss of $15.7 million, or $0.17 per diluted share, for the third quarter of 2015. Net loss for the first nine months of 2016 was $49.4 million, or $0.49 per diluted share, compared to a net loss of $41.1 million, or $0.48 per diluted share, for the same period of 2015.

Net loss for the third quarter of 2015 was positively impacted by the mark-to-market adjustments of the Company’s previously outstanding warrants, which resulted in non-cash gains of $1.1 million and $4.7 million during the third quarter of 2015 and first nine months of 2015, respectively. The Company has no remaining outstanding warrants and as such, does not expect mark-to-market adjustments going forward.

Cash, Cash Equivalents and Investments
At September 30, 2016, the Company had cash, cash equivalents and short-term investments of $81.2 million compared to $107.9 million at December 31, 2015.

At September 30, 2016, the Company had approximately $19 million in outstanding debt under its loan agreement with Oxford Finance.

On November 3, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported 17 presentations, including four oral presentations and 13 poster discussions, highlighting data from studies evaluating Opdivo (nivolumab), Sprycel (dasatinib) and Empliciti (elotuzumab), will be featured at the 58th Annual Meeting & Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, Calif. from December 3-6 (Press release, Bristol-Myers Squibb, NOV 3, 2016, View Source [SID1234516261]). The data presented at this meeting reinforce Bristol-Myers Squibb’s commitment to advancing hematology through the company’s Immuno-Oncology leadership and established heritage in blood cancer research.

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Fouad Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb, commented, "This research further demonstrates our longstanding heritage in hematology and innovative Immuno-Oncology science, underscoring our ongoing commitment to discover, develop and deliver potential critical new treatment options to people living with blood cancers. The new findings from our ongoing clinical trial program reveal a deeper understanding of the potential benefits our therapies may provide in hematologic malignancies with high unmet needs, including classical Hodgkin lymphoma, multiple myeloma and chronic myeloid leukemia."

Bristol-Myers Squibb’s agents will be featured in a total of 17 data presentations, including four oral presentations.

Classical Hodgkin Lymphoma

A Phase 1 Study of Nivolumab in Combination With Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate -039)
Author: Stephen M. Ansell
Abstract #183
Oral Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Novel Therapeutics and the Integration of PET Scans in Hodgkin Lymphoma and Peripheral T-Cell Lymphomas
Saturday, December 3 at 2:30 p.m. PT, Room 6AB

Patient Subgroup Analysis of Quality-of-Life Outcomes in CheckMate -205, a Phase 2 Study of Nivolumab in Patients With Classical Hodgkin Lymphoma
Author: Andreas Engert
Abstract #1831
Poster Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH

Chromosome 9p24.1/PD-L1/PD-L2 Alterations and PD-L1 Expression and Treatment Outcomes in Patients With Classical Hodgkin Lymphoma Treated With Nivolumab (PD-1 Blockade)
Author: Margaretha GM Roemer
Abstract #2923
Poster Session: 621. Lymphoma – Genetic/Epigenetic Biology: Poster II
Sunday, December 4 from 6:00 – 8:00 p.m. PT, Hall GH

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation After Treatment With Nivolumab for Relapsed/Refractory Hodgkin Lymphoma
Author: Phillippe Armand
Abstract #3502
Poster Session: 732. Clinical Allogeneic Transplantation: Results: Poster II
Sunday, December 4 from 6:00 – 8:00 p.m. PT, Hall GH

Preliminary Results From a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma
Author: Alex F. Herrera
Abstract #1105

Oral Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Emerging Immunotherapy Approaches in Hodgkin Lymphoma
Monday, December 5 at 4:30 p.m. PT, Room 6B

CheckMate -205 Update With Extended Minimum 12-Month Follow-up: A Phase 2 Study of Nivolumab in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma
Author: John Timmerman
Abstract #1110
Oral Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Emerging Immunotherapy Approaches in Hodgkin Lymphoma
Monday, December 5 at 5:45 p.m. PT, Room 6B

Multiple Myeloma

An Ongoing, Observational Cohort Study in Multiple Myeloma (PREAMBLE): Preliminary Efficacy Analyses in Patients With One Line of Prior Therapy
Author: Brian Durie
Abstract #2403
Poster Session: 904. Outcomes Research – Malignant Conditions: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH

Budget Impact Analysis of Introducing Elotuzumab in Combination With Lenalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: A U.S. Payer Perspective
Author: Ravi Potluri
Abstract #2363
Poster Session: 902. Health Services Research – Malignant Conditions: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH
Subgroup Analysis of U.S. Patients in PREAMBLE, an Ongoing, Multinational, Observational Study in Multiple Myeloma
Author: Ravi Vij
Abstract #2362
Poster Session: 902. Health Services Research – Malignant Conditions: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH

Safety and Efficacy of Elotuzumab With Lenalidomide/Dexamethasone for Multiple Myeloma in a Japanese Subpopulation Analysis of the Phase 3 ELOQUENT-2 Trial
Author: Kazuteru Ohashi
Abstract #3315
Poster Session: 653. Myeloma: Therapy, Excluding Transplantation: Poster II
Sunday, December 4 from 6:00 – 8:00 p.m. PT, Hall GH

Evaluation of Cardiovascular Comorbidities Among Patients With Multiple Myeloma in the United States
Author: Daniel J. Lenihan
Abstract #4794
Poster Session: 904. Outcomes Research – Malignant Conditions: Poster III
Monday, December 5 from 6:00 – 8:00 p.m. PT, Hall GH
Real-World Data Study for Epidemiology and Characteristics of Patients With Multiple Myeloma in Italy
Author: Giovanni Corrao
Abstract #5693
Publication Only

Chronic Myeloid Leukemia

Long-Term Safety of Dasatinib in Chinese Chronic Phase Chronic Myeloid Leukemia Patients With Imatinib Resistance or Intolerance: Results From a Six-Year Follow-up of a Multicenter Phase 2 Study
Author: Xiaojun Huang
Abstract #1928
Poster Session: 632. Chronic Myeloid Leukemia Therapy: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH
Treatment-Free Remission in Patients With Chronic Phase Chronic Myeloid Leukemia and in Stable Deep Molecular Response to Dasatinib – The DASFREE Study
Author: Neil P. Shah
Abstract #1895
Poster Session: 632. Chronic Myeloid Leukemia Therapy: Poster I
Saturday, December 3 from 5:30 – 7:30 p.m. PT, Hall GH

Adherence to Chronic Myeloid Leukemia Monitoring and Treatment Guidelines in Canadian Registries
Author: Christopher Hillis
Abstract #3079
Poster Session: 632. Chronic Myeloid Leukemia Therapy: Poster II
Sunday, December 4 from 6:00 – 8:00 p.m. PT, Hall GH
Evaluation of Healthcare Resource Utilization and Costs Among Patients With Chronic Myeloid Leukemia After Disease Progression
Author: Jabbour Elias
Abstract #3573
Poster Session: 902. Health Services Research – Malignant Conditions: Poster II
Sunday, December 4 from 6:00 – 8:00 p.m. PT, Hall GH

Early and Late Tyrosine Kinase Inhibitor Switching Patterns During the First 12 Months in SIMPLICITY, an Observational Study of Chronic Phase Chronic Myeloid Leukemia Patients in Routine Clinical Practice
Author: Stuart Goldberg
Abstract #937
Oral Session: 632. Chronic Myeloid Leukemia Therapy: TKI-Optimization and Switching
Monday, December 5 at 2:45 p.m. PT, Marriott Marquis San Diego Marina, Pacific Ballroom Salons 18-19
Incidence of Type II Diabetes Mellitus and Hyperlipidemia in Patients Prescribed Dasatinib or Nilotinib as First or Second Line Therapy for Chronic Myelogenous Leukemia
Author: Meg Franklin
Abstract #4766
Poster Session: 904. Outcomes Research – Malignant Conditions: Poster III
Monday, December 5 from 6:00 – 8:00 p.m. PT, Hall GH

Baseline Characteristics and Early Monitoring of Chinese Chronic Myeloid Leukemia Patients Treated With Dasatinib: Report From a Multicenter, Observational, Registry-Based Study
Author: Qian Jiang
Abstract #1928
Publication Only

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in CheckMate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In CheckMate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In CheckMate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In CheckMate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In CheckMate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In CheckMate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In CheckMate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In CheckMate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In CheckMate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In CheckMate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In CheckMate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In CheckMate 057, one patient (0.3%) developed immune-mediated hepatitis. In CheckMate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In CheckMate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In CheckMate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In CheckMate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In CheckMate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In CheckMate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In CheckMate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In CheckMate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In CheckMate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In CheckMate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In CheckMate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In CheckMate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In CheckMate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In CheckMate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In CheckMate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In CheckMate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In CheckMate 025, hyperglycemic adverse events occurred in 9% (37/406) patients.

Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In CheckMate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In CheckMate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In CheckMate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In CheckMate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In CheckMate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In CheckMate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In CheckMate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In CheckMate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In CheckMate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In CheckMate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In CheckMate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In CheckMate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In CheckMate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In CheckMate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In CheckMate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In CheckMate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In CheckMate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In CheckMate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In CheckMate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from CheckMate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In CheckMate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In CheckMate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In CheckMate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In CheckMate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In CheckMate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In CheckMate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In CheckMate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In CheckMate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In CheckMate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In CheckMate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In CheckMate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In CheckMate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

CheckMate Trials and Patient Populations

CheckMate 069 and 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 057 – non-squamous non-small cell lung cancer (NSCLC); CheckMate 025 – renal cell carcinoma; CheckMate 205/039 – classical Hodgkin lymphoma

Please see U.S. Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, for YERVOY.

Please see U.S. Full Prescribing Information for OPDIVO.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

On November 30, 2015, the U.S. Food and Drug Administration (FDA) approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received one to three prior therapies. On May 11, 2016, the European Commission approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received at least one prior therapy. The safety and efficacy of Empliciti is being evaluated by other health authorities.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

U.S. FDA-APPROVED INDICATION FOR EMPLICITI

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

EMPLICITI can cause infusion reactions. Common symptoms include fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.
Infections

In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI with lenalidomide/dexamethasone arm (ERd) and 74.4% in the lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28% (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22% (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Monitor patients for development of infections and treat promptly.
Second Primary Malignancies

In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hematologic malignancies were the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the development of SPMs.
Hepatotoxicity

Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepatotoxicity discontinued treatment; however, 6 out of 8 patients had resolution and continued treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.
Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.
Pregnancy/Females and Males of Reproductive Potential

There are no studies with EMPLICITI with pregnant women to inform any drug associated risks.
There is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and it is contraindicated for use in pregnancy. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.
Adverse Reactions

Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients.
Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).
Please see the full Prescribing Information for Empliciti .

About Sprycel

Sprycel was first approved by the FDA in 2006 for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, Sprycel was also approved for adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to prior therapy. It is the first and only BCR-ABL kinase inhibitor with survival data in its label for CP Ph+ CML patients who are resistant or intolerant to Gleevec (imatinib mesylate). Sprycel is approved and marketed worldwide for these indications in more than 60 countries.

Sprycel is also an FDA-approved treatment for adults with newly diagnosed CP Ph+ CML (since October 2010). Sprycel received accelerated FDA approval for this indication. Additional country approvals for this indication total more than 50.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL

SPRYCEL (dasatinib) is indicated for the treatment of adults with:

Newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
IMPORTANT SAFETY INFORMATION

Myelosuppression:

Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events:

SPRYCEL caused thrombocytopenia in human subjects. In addition, dasatinib caused platelet dysfunction in vitro. In all CML or Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of ≥grade 3 hemorrhage occurred in 2% of patients.

Most bleeding events in clinical studies were associated with severe thrombocytopenia
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
Fluid Retention:

SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients.

Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
Severe pleural effusion may require thoracentesis and oxygen therapy
Consider dose reduction or treatment interruption
Cardiovascular Events:

After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse events occurred:

Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH):

SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
QT Prolongation:

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval).

In clinical trials of patients treated with SPRYCEL at all doses (n=2440), 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 to 13.4 ms
SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy
Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions:

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
Tumor Lysis Syndrome (TLS):

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity:

Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose
Lactation:

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing infants from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions:

SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.

Drugs that may increase SPRYCEL plasma concentrations are:
CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction should be considered
Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease or temporary discontinuation should be considered
Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
Drugs that may decrease SPRYCEL plasma concentrations are:
CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered
Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
H 2 antagonists/proton pump inhibitors (eg, famotidine and omeprazole): Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
Drugs that may have their plasma concentration altered by SPRYCEL are:
CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL
Adverse Reactions:

The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies including 324 patients with newly diagnosed chronic phase CML and 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL.

The median duration of therapy in all 2712 SPRYCEL-treated patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:

1618 patients with chronic phase CML was 29 months (range 0–92.9 months)
Median duration for 324 patients in the newly diagnosed chronic phase CML trial was approximately 60 months
1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In the newly diagnosed chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.

In the overall population of 2712 SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

Among the 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse events leading to discontinuation were reported in 329 (20.3%) patients.

In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse events leading to discontinuation were reported in 191 (17.5%) patients.

Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

In newly diagnosed chronic phase CML patients:
Drug-related serious adverse events (SAEs) were reported for 16.7% of SPRYCEL-treated patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
The most common adverse reactions (≥15%) included myelosuppression, fluid retention, and diarrhea
Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
In patients resistant or intolerant to prior imatinib therapy:
Drug-related SAEs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
The most common adverse reactions (≥15%) included myelosuppression, fluid retention events, diarrhea, headache, fatigue, dyspnea, skin rash, nausea, hemorrhage and musculoskeletal pain
Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation