On November 2, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported financial and operating results for its third quarter ended September 30, 2016 (Press release, Foundation Medicine, NOV 2, 2016, View Source [SID1234516193]). Highlights for the quarter included:

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Achieved third quarter revenue of $29.4 million, 16% year-over-year growth;
Reported 11,627 clinical tests in the third quarter, 45% year-over-year growth;
Grew FoundationCORE, the company’s molecular information knowledgebase, to nearly 100,000 patient cases;
Announced acceptance of FoundationOne for Parallel Review by FDA and CMS. If approved, FoundationOne could be the first FDA-approved comprehensive genomic profiling (CGP) assay to incorporate multiple companion diagnostics to support precision medicine in oncology and would be offered as a covered benefit to Medicare beneficiaries nationwide;
Added new immunotherapy clinical markers, Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI), to FoundationOne and FoundationOne Heme to help guide personalized immunotherapy-based treatment plans;
Published an additional 17 manuscripts in high-quality, peer-reviewed journals and delivered six podium and poster presentations at various medical and scientific meetings providing further evidence for the clinical impact of integrating CGP into routine cancer care;
Expanded patient access to CGP through Palmetto, the Medicare Administrative Contractor in North Carolina, who broadened a Local Coverage Determination, covering CGP for all stage IIIB and IV non-small cell lung cancer (NSCLC) patients at diagnosis by removing a patient’s smoking status as a coverage factor.
Foundation Medicine reported total revenue of $29.4 million in the third quarter of 2016, compared to $25.4 million in the third quarter of 2015. Revenue from biopharmaceutical partners grew 77% to $20.7 million in the third quarter of 2016, compared to $11.7 million in the third quarter of 2015. The increase in revenue demonstrates the company’s leading role in molecular information and the value of this information in informing and accelerating drug development for its oncology focused biopharmaceutical customers.

Revenue from clinical testing in the third quarter of 2016 was $8.7 million, compared to $13.7 million in the third quarter of 2015. The decrease was driven by various factors, the most significant of which was the transition in-network with a large national payer for stage IV NSCLC testing, which resulted in the termination of payments for testing in other indications.

The company reported 11,627 clinical tests in the third quarter of 2016, a 45% increase from the same quarter last year. This reported volume number includes 9,398 FoundationOne tests, 1,325 FoundationOne Heme tests and 904 FoundationACT tests.

"Foundation Medicine delivered another solid quarter highlighted by strong biopharma revenue and record clinical testing volume," said Michael Pellini, M.D., chief executive officer of Foundation Medicine. "We believe our progress on building distinct, yet synergistic clinical and biopharma businesses, developing applications that enable patient access to therapies and clinical trials, aggressively working towards reimbursement coverage and payment for our comprehensive genomic profiling assays and pursuing parallel review with FDA and CMS for FoundationOne will drive continued growth and value creation."

The company’s molecular information knowledgebase, FoundationCORE, grew to nearly 100,000 patient cases at the end of the third quarter. FoundationCORE is a unique asset and critical component of the value that Foundation Medicine delivers to its biopharmaceutical and physician customers. The increasing scale and breadth of this high quality, clinically relevant oncology data set derived from the company’s testing platform continues to enhance clinical practice and help enable improved outcomes for patients.

Total operating expenses for the third quarter of 2016 were approximately $44.9 million compared with $35.6 million for the third quarter of 2015. Net loss was approximately $31.3 million in the third quarter of 2016, or a $0.90 loss per share. At September 30, 2016, the company held approximately $167.9 million in cash, cash equivalents and marketable securities.

Recent Enterprise Highlights

Announced a collaboration with Sarah Cannon Research Institute (SCRI) in which SCRI will utilize Foundation Medicine’s full suite of assays to accelerate patient enrollment into clinical trials and facilitate data sharing across its network in the U.S.
Selected as the molecular information provider of choice by The Leukemia & Lymphoma Society for its landmark Beat AML Master Trial, a prospective study aimed at delivering a precision medicine approach to treat newly diagnosed Acute Myeloid Leukemia patients.
Announced the election of life sciences leader, Michael R. Dougherty, to its Board of Directors and the Board’s Audit Committee. Mr. Dougherty joins as an independent director and fills an existing vacancy on the Board.
2016 Outlook

Foundation Medicine’s business and financial outlook for 2016 is the following:

The company continues to expect 2016 revenue will be in the range of $110 to $120 million.
The company is increasing the bottom-end of its clinical volume guidance range and now expects to deliver between 40,000 and 41,000 FoundationOne and FoundationOne Heme clinical tests in 2016.
The company continues to expect operating expenses will be in the range of $175 and $185 million.

On November 2, 2016 Ocera Therapeutics, Inc. (NASDAQ:OCRX), a clinical stage biopharmaceutical company focused on acute and chronic orphan liver diseases, reported financial results for the quarter ended September 30, 2016, and provided updates on its clinical development programs of OCR-002 for the treatment of hepatic encephalopathy (HE), a debilitating liver disorder and significant burden on the healthcare system (Press release, Ocera Therapeutics, NOV 2, 2016, View Source [SID1234516192]).

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"We are pleased to report significant progress in our clinical programs. Enrollment in our STOP-HE Phase 2b study for acute hepatic encephalopathy has now surpassed 220 patients and, consistent with previous guidance, we expect to complete full enrollment of approximately 230 patients by year-end and publish top-line results of the study in the first quarter of 2017," said Linda Grais, M.D., Chief Executive Officer of Ocera. "In addition, dosing has commenced with our oral formulation of OCR-002 in a Phase 1 study in patients with cirrhosis as a chronic use option to maintain remission of HE. We remain on track to report results of part one of this study by year-end and initiate part two in the first half of 2017."

Select Third Quarter Financial Results

As of September 30, 2016, Ocera had cash, cash equivalents and investments of $32.5 million.
Net loss for the three and nine months ended September 30, 2016 was $7.1 million and $21.7 million, respectively. Net loss for the three and nine months ended September 30, 2015 was $6.6 million and $19.4 million, respectively. Basic and diluted net loss per share for the three and nine months ended September 30, 2016 was $0.32 and $1.01, respectively. Basic and diluted net loss per share for the three and nine months ended September 30, 2015 was $0.33 and $0.98, respectively.
Research and development (R&D) expense for the three months ended September 30, 2016 was $4.3 million, compared to $4.2 million for the same period in 2015. R&D expense for the nine months ended September 30, 2016 was $12.9 million, compared to $12.0 million for the same period in 2015. The increase in R&D expense for both the three and nine month periods was due primarily to an increase in headcount and related costs.
General and administrative (G&A) expense for the three months ended September 30, 2016 was $2.6 million, compared to $2.4 million for the same period in 2015. G&A expense for the nine months ended September 30, 2016 was $8.1 million, compared to $7.5 million for the same period in 2015. The increase in G&A expense for the three and nine month periods was due primarily to an increase in personnel-related costs, including stock-based compensation expense, as well as costs associated with professional service fees.
Net interest expense of $262,000 and $758,000 for the three and nine months ended September 30, 2016, respectively, was primarily attributable to interest and amortization associated with the debt facility which closed in July 2015.
Net cash proceeds generated from the Company’s "at the market" equity facility totaled approximately $6.0 million for the nine month period ended September 30, 2016.
Financial Guidance

Ocera reiterates its previous guidance and expects net use of cash for 2016 to be in the range of $22 million to $26 million, and updates its expectation that it will have sufficient cash to fund operations into the first quarter of 2018 based on its current operating plan. The Company previously estimated its cash runway into the fourth quarter of 2017. This improvement in projected cash runway is due primarily to the deferral of certain external development costs for OCR-002, lower than expected internal operating expenses, and cash proceeds generated from the "at the market" equity facility.

On November 2, 2016 CombiMatrix Corporation (NASDAQ:CBMX), a family health molecular diagnostics company specializing in DNA-based reproductive health and pediatric testing services, reported financial results for the three and nine months ended September 30, 2016, and provided a business update (Press release, CombiMatrix, NOV 2, 2016, View Source [SID1234516186]).

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"Excellent execution on our business initiatives keeps us squarely on the path to profitability," said Mark McDonough, CombiMatrix President and CEO. "Among quarterly financial highlights, we are reporting revenue growth of 29%, our third consecutive quarter of gross margin above 50% and record cash reimbursement of $3.1 million, or 95% of total revenues. Combined with our ability to manage expenses, we reduced both our operating loss and our cash burn by nearly half from one year ago.

"We are pleased with our recent performance and expect continued growth in revenue and test volume, along with consistent cash reimbursement and prudent expense management in the coming year with a focus on creating value for our shareholders," Mr. McDonough added. "Given our outlook, we are increasingly confident we will reach our goal of positive cash flow from operations by the fourth quarter of 2017."

Third Quarter Financial and Operating Highlights (all comparisons are with the third quarter of 2015)

Total revenues of $3.2 million, up 29%
Total test volume of 2,835, up 14%
Reproductive health revenues of $2.3 million, up 39%
Reproductive health test volume of 1,483, up 17%
Gross margin of 54.0%, up from 43.6%
Number of billable customers of 257, up 10%
Cash collections at new record of $3.1 million, or 95% of total revenue, up 29%

Volumes Revenues (in 000’s)
Q3 ’16 Q3 ’15 # Δ % Δ Q3 ’16 Q3 ’15 $ Δ % Δ
Prenatal 294 272 22 8 % $ 408 $ 368 $ 40 11 %
Miscarriage analysis 990 866 124 14 % 1,622 1,145 477 42 %
PGS 199 127 72 57 % 286 149 137 92 %
Subtotal – reproductive health 1,483 1,265 218 17 % 2,316 1,662 654 39 %
Pediatric 505 509 (4 ) (1 %) 589 558 31 6 %
Subtotal 1,988 1,774 214 12 % 2,905 2,220 685 31 %
FISH and karyotyping 847 721 126 17 % 306 261 45 17 %
Total – all tests 2,835 2,495 340 14 % 3,211 2,481 730 29 %
Royalties 37 45 (8 ) (18 %)
Total revenues $ 3,248 $ 2,526 $ 722 29 %


Volumes Revenues (in 000’s)
9 Mo’s. ’16 9 Mo’s. ’15 # Δ % Δ 9 Mo’s. ’16 9 Mo’s. ’15 $ Δ % Δ
Prenatal 860 936 (76 ) (8 %) $ 1,203 $ 1,214 $ (11 ) (1 %)
Miscarriage analysis 2,886 2,664 222 8 % 4,701 3,467 1,234 36 %
PGS 566 157 409 261 % 759 189 570 302 %
Subtotal – reproductive health 4,312 3,757 555 15 % 6,663 4,870 1,793 37 %
Pediatric 1,454 1,557 (103 ) (7 %) 1,646 1,687 (41 ) (2 %)
Subtotal 5,766 5,314 452 9 % 8,309 6,557 1,752 27 %
FISH and karyotyping 2,497 2,125 372 18 % 881 735 146 20 %
Total – all tests 8,263 7,439 824 11 % 9,190 7,292 1,898 26 %
Royalties 137 112 25 22 %
Total revenues $ 9,327 $ 7,404 $ 1,923 26 %

Financial Results

Three Months Ended September 30, 2016 and 2015

Total revenues for the third quarter of 2016 increased 29% to $3.2 million from $2.5 million for the third quarter of 2015. Reproductive health diagnostic test revenue, which includes prenatal microarrays, miscarriage analysis and preimplantation genetic screening (PGS), increased 39% to $2.3 million and testing volume increased 17% to 1,483. The third quarter 2016 revenue increase was driven primarily by higher test volume for reproductive health diagnostics, higher average revenue per test particularly for miscarriage analysis and PGS tests, and from an increase in the number of billable customers, which reached 257 during the third quarter of 2016 compared to 234 in the prior-year period.

Total operating expenses were $4.1 million for the third quarter of 2016 compared with $4.2 for the prior-year period. The decrease was due primarily to lower sales and marketing and research and development expenses, partially offset by higher general and administrative expenses due to higher personnel, investor relations and consulting costs and higher cost of services as a result of higher test volume. Gross margin for the third quarter of 2016 improved to 54.0% from 43.6% for third quarter of 2015.

The net loss attributable to common stockholders for the third quarter of 2016 was $856,000, or $0.38 per share, compared with a net loss attributable to common stockholders for the third quarter of 2015 of $1.7 million, or $2.00 per share, an improvement of $831,000.

Nine Months Ended September 30, 2016 and 2015

Total revenues for the first nine months of 2016 increased 26% to $9.3 million from $7.4 million for the first nine months of 2015. Revenues for the first nine months of 2016 included $9.2 million in diagnostic services revenue and $137,000 in royalty revenues.

Operating expenses for the first nine months of 2016 were $12.9 million compared with $12.4 million for the prior-year period, with the increase mainly due to higher general and administrative expenses and higher cost of services resulting from increased testing volumes, partially offset by lower sales and marketing expenses. Gross margin improved to 52.9% for the first nine months of 2016 from 44.8% for the first nine months of 2015.

The net loss attributable to common stockholders for the first nine months of 2016 was $5.2 million, or $3.48 per share, compared to $6.0 million, or $7.21 per share in 2015. The net loss attributable to common stockholders in 2016 reflected one-time, non-cash charges of $1.9 million related to deemed dividends from the issuance of Series F convertible preferred stock and warrants in the $8.0 million public offering that closed on March 24, 2016. This increase was partially offset by the reversal of the $890,000 Series E deemed dividend recognized in 2015 from the repurchase of those securities upon closing of our Series F public offering, partially reduced by the $656,000 deemed dividend paid to the Series E investors in February of 2016.

The Company reported $4.3 million in cash, cash equivalents and short-term investments as of September 30, 2016, compared with $3.9 million as of December 31, 2015. The Company used $813,000 and $3.4 million in cash to fund operating activities during the quarter and nine months ended September 30, 2016, respectively, compared with $1.5 million and $4.2 million used to fund operating activities during the comparable 2015 periods, respectively. The significant decreases in net cash used to fund operating activities for the 2016 periods resulted primarily from improved cash reimbursement of $3.1 million and $8.5 million for the three and nine months ended September 30, 2016, respectively, compared with $2.4 million and $7.0 million for the three and nine months ended September 30, 2015, respectively.

On November 2, 2016 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported business highlights and financial results for the third quarter ended September 30, 2016 (Press release, bluebird bio, NOV 2, 2016, View Source;p=RssLanding&cat=news&id=2218784 [SID1234516184]).

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"In recent months, we have made important advances in our gene therapy transduction and manufacturing processes, translational research and clinical development that will be critical for us to successfully bring LentiGlobin drug product to patients with transfusion-dependent β-thalassemia (TDT) and severe sickle cell disease (SCD). This includes implementing a new LentiGlobin manufacturing process that has been shown in vitro to consistently improve the percentage of cells transduced and vector copy number, and making a number of changes to the protocol for our ongoing severe SCD study that we believe have the potential to improve patient outcomes. We look forward to sharing initial clinical data from these improvements in 2017," said Nick Leschly, chief bluebird. "In September we announced a strategic alliance with Medigene around TCRs against four targets, a significant step forward in our efforts to build a broad, fully integrated immuno-oncology franchise. We anticipate sharing further progress in oncology in the first half of 2017, with presentation of initial data from our Phase 1 study of bb2121, our anti-BCMA CAR T program in multiple myeloma."

Recent Highlights

PHASE 3 HGB-207 STUDY OF LENTIGLOBIN OPENED – In September, bluebird bio opened the company’s first Phase 3 study of LentiGlobin drug product. HGB-207 is a global, multi-center study in patients with TDT with non-β0/β0 genotypes. This study will incorporate the addition of bluebird bio’s transduction enhancers to the drug product manufacturing process, and will be conducted under the same Investigational New Drug application (IND) as previous studies of LentiGlobin drug product in TDT. This study, which will include adult and adolescent patients (cohort #1) and pediatric patients (cohort #2), is intended to be pivotal in the U.S. and confirmatory in the E.U. bluebird bio plans to initiate the HGB-212 pivotal study of LentiGlobin drug product in patients with TDT with β0/β0 genotypes in 2017.

GENE THERAPY DAY – In October, bluebird bio held a Gene Therapy Day to provide updates on its LentiGlobin product candidate and its research, development and commercialization strategies. Highlights included:
A head-to-head in vitro comparison of manufacturing Process 1 and Process 2 consistently improved the percentage of cells transduced and vector copy number (VCN) in cells from TDT patients of all genotypes and severe SCD patients.

bluebird bio has implemented several amendments to the protocol of the ongoing HGB-206 study in severe SCD, with the goal of improving patient outcomes by increasing successful engraftment of transduced cells.

bluebird bio has reached general agreement with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on the regulatory paths forward for LentiGlobin in TDT in the U.S. and E.U.

STRATEGIC TCR ALLIANCE WITH MEDIGENE – In September, bluebird bio and Medigene announced that they have established a strategic alliance in cancer immunotherapy focused on four TCR targets. Under the terms of the agreement, Medigene will be responsible for the generation and delivery of TCRs using its TCR isolation and characterization platform. Following collaborative preclinical development, bluebird bio will assume sole responsibility for the clinical development and commercialization of the TCR product candidates and will receive an exclusive license for intellectual property covering the resulting TCRs.
LENTIGLOBIN ACCEPTED INTO EUROPEAN MEDICINES AGENCY (EMA) PRIME PROGRAM – In September, the EMA granted access to its Priority Medicines (PRIME) scheme for LentiGlobin drug product in the treatment of patients with TDT. The PRIME initiative provides enhanced support and increased interaction to companies, with the goal of optimizing development plans and speeding regulatory evaluations to potentially bring innovative medicines to patients more quickly. To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical data or nonclinical data.
Upcoming Anticipated Milestones

Presentation of updated TDT and SCD clinical data from the Northstar (HGB-204), HGB-205 and HGB-206 clinical studies at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in December
Presentation of early data from CRB-401, the Phase 1 trial of bb2121 in relapsed/refractory multiple myeloma in the first half of 2017
Third Quarter 2016 Financial Results and Financial Guidance

Cash Position: Cash, cash equivalents and marketable securities as of September 30, 2016 were $727.6 million, compared to $865.8 million as of December 31, 2015, a decrease of $138.2 million.
Revenues: Collaboration revenue was $1.6 million for the third quarter of 2016 compared to $1.3 million for third quarter of 2015.
R&D Expenses: Research and development expenses were $64.0 million for the third quarter of 2016 compared to $30.4 million for the third quarter of 2015. The increase in research and development expenses was primarily attributable to increased in-licensing milestones and fees, increased manufacturing costs and increased information technology and facilities costs to support the advancement of our clinical and pre-clinical programs, and increased employee payroll costs to support our overall growth.
G&A Expenses: General and administrative expenses were $14.6 million for the third quarter of 2016 compared to $13.7 million for the third quarter of 2015. The increase in general and administrative expenses was primarily attributable to increased employee compensation expense due to increased headcount, partially offset by decreased stock-based compensation expense.
Net Loss: Net loss was $77.0 million for the third quarter of 2016 compared to $42.9 million for the third quarter of 2015.
Financial guidance: bluebird bio expects that its cash, cash equivalents and marketable securities of $727.6 million as of September 30, 2016 will be sufficient to fund its current operations through 2018.

On November 2, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported new data evaluating the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) and Opdivo plus new investigational Immuno-Oncology assets, including lirilumab, will be presented at the 2016 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 31st Annual Meeting from November 9 – 11 in National Harbor, Maryland (Press release, Bristol-Myers Squibb, NOV 2, 2016, View Source [SID1234516183]). These presentations underscore Bristol-Myers Squibb’s dedication to investigating complementary Immuno-Oncology compounds that target different immune system pathways, including the ongoing study of Opdivo and Yervoy, with the goal of discovering transformational combinations that may offer the most significant improvements in overall survival and address areas of high unmet patient need.

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"We look forward to presenting new data at SITC (Free SITC Whitepaper) from our innovative Immuno-Oncology pipeline," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "Research has shown that targeting multiple immune system pathways may enhance anti-tumor responses, and there are a vast number of combinations to explore. We are committed to discovering novel pathways and complementary mechanisms that have the potential to significantly improve the standard of care in a broad range of tumor types."

Bristol-Myers Squibb is focused on developing transformational Immuno-Oncology combination therapies and expects to have 13 Immuno-Oncology compounds and seven targeted oncology compounds in the clinic by early 2017.

A listing of late-breaking and oral presentations is included below:

Late-Breaking Oral Presentations

Preliminary efficacy from a Phase 1/2 study of the natural killer cell–targeted antibody, lirilumab in combination with nivolumab in squamous cell carcinoma of the head and neck
Author: R. Leidner
Poster #456
Oral Late Breaking Abstract Session II
Saturday, November 12 at 11:15 – 11:30 am/EST
Efficacy and safety of nivolumab plus ipilimumab in metastatic urothelial carcinoma: First results from the Phase I/II CheckMate 32 Study
Author: P. Sharma
Poster #449
Oral Late Breaking Abstract Session II
Saturday, November 12 at 11:30 – 11:45 am/EST
Oral Presentations

Clinical safety and efficacy assessment of the CD137 agonist urelumab alone and in combination with nivolumab in patients with hematologic and solid tumor malignancies
Author: E. Massarelli
Poster #239
Oral Presentation: Beyond Single Agents: The Future of Combination Immunotherapies
Saturday, November 12 at 10:40 – 10:55 am/EST
The full set of data to be presented at SITC (Free SITC Whitepaper) by Bristol-Myers Squibb also includes:

Initial experience administering BMS-986016, a monoclonal antibody that targets lymphocyte activation gene (LAG)-3, alone and in combination with nivolumab to patients with hematologic and solid malignancies
Author: E. Lipson
Poster #238
Saturday, November 12 at 12 – 1 pm/EST
Enhanced vaccine-induced T-cell responses observed with ipilimumab (anti-CTLA-4) treatment in a nonhuman primate pharmacodynamic model
Author: J. Loffredo
Poster #102
Saturday, November 12 at 12 – 1 pm/EST
Assessing the potential for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by combining the CD137 antibody urelumab with rituximab or cetuximab in patients with refractory lymphoma or select advanced solid tumors
Author: N. Segal
Poster #267
Friday, November 11 at 12:15 – 1:30 pm/EST
Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

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 12 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 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 the confirmatory trials.

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

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

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

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

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. 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 patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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 patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

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 HSCT 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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313). 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 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). 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 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) 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 (≥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 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 017 – squamous non-small cell lung cancer (NSCLC); CheckMate 057 – non-squamous 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.