On November 7, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported operating results for third-quarter 2017 and provided an update on the Company’s commercial products and development programs (Press release, TESARO, NOV 7, 2017, View Source [SID1234521691]).

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"Exiting the third quarter, ZEJULA achieved 60% market share of the ovarian cancer patient population treated with a PARP inhibitor. This is a result of our team’s solid execution, and is supported by the feedback from physicians and patients, which continues to be excellent with regards to the benefit ZEJULA provides for women living with ovarian cancer," said Lonnie Moulder, CEO of TESARO. "Looking ahead, we are actively preparing for two additional product launches in 2017 — ZEJULA in Europe and VARUBI IV in the U.S. — and expanding our niraparib development programs to broaden its use with the PRIMA Phase 3 first line ovarian cancer study and the initiation of multiple combination studies in ovarian, lung, and breast cancer. We are rapidly advancing our pipeline of immuno-oncology candidates with three antibodies now in the clinic, and we are excited about the potential for the combination of TSR-022 and TSR-042 to meaningfully benefit patients with advanced solid tumors."

Recent Business Highlights

On October 25, 2017, the U.S. Food and Drug Administration (FDA) approved the intravenous (IV) formulation of VARUBI (rolapitant), and the U.S. commercial launch is planned for November. The unit demand for VARUBI oral capsules increased 74% for Q3 2017 vs. Q3 2016, as the brand continues to penetrate the U.S. oral NK-1 market.
ZEJULA (niraparib) is the most prescribed PARP inhibitor in the U.S., with approximately 2,500 patients treated during the month of September.
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for ZEJULA as a monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete response (CR) or partial response (PR) to platinum-based chemotherapy.
Pre-launch preparations continue in support of a European launch of ZEJULA by year-end 2017 beginning with Germany, pending European Commission approval.
The niraparib expanded access program (EAP) in Europe has enrolled more than 350 patients to date.
Clinical trials were initiated to support planned Phase 3 studies of niraparib combined with our anti-PD-1 antibody, TSR-042, in patients with lung and ovarian cancers and to evaluate niraparib plus TSR-042 in patients with advanced or metastatic cancers suitable for treatment with an anti-PD-1 antibody, including ovarian and lung.
Enrollment continues in the PRIMA trial of niraparib for patients with first-line ovarian cancer and the QUADRA trial of niraparib for the treatment of patients with ovarian cancer who have received three or more prior lines of chemotherapy.
The Phase 2 TOPACIO trial of niraparib plus pembrolizumab is ongoing with additional data expected in 1H 2018. Preliminary Phase 2 data presented at ESMO (Free ESMO Whitepaper) showed activity in patients with platinum-resistant ovarian cancer and patients with triple-negative breast cancer.
The Janssen GALAHAD Phase 2 efficacy and safety study of niraparib in men with metastatic castration-resistant prostate cancer and DNA-repair anomalies is ongoing to support a planned regulatory submission in 2019.
Phase 1 data for TSR-042 (anti-PD-1 antibody) presented at ESMO (Free ESMO Whitepaper) demonstrated a predictable safety profile and clinical activity in heavily pre-treated patients. The GARNET registration trial of TSR-042 continues to enroll patients with metastatic microsatellite instability-high (MSI-H) cancers.
To support initiation of planned Phase 3 studies, a clinical study was initiated to evaluate TSR-042 in combination with carboplatin-paclitaxel in patients with advanced or metastatic cancer.
Enrollment continues in the Phase 1 AMBER combination study of TSR-022 (anti-TIM-3 antibody) plus TSR-042, and the Phase 1 CITRINO dose-escalation trial of TSR-033 (anti-LAG-3 antibody). Data from the monotherapy, dose-escalation portion of the AMBER trial of TSR-022 will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting on November 10.
Third Quarter 2017 Financial Results

TESARO reported total revenue of $142.8 million for the third quarter of 2017, compared to $17.0 million for the third quarter of 2016.

Net product revenue totaled $41.8 million for the third quarter of 2017, which included ZEJULA revenues of $39.4 million and VARUBI/VARUBY revenues of $2.4 million. This compares to net product revenue of $1.3 million for the third quarter of 2016.

License, collaboration, and other revenue totaled $101.0 million for the third quarter of 2017 and included the $100.0 million up-front payment received as part of the license agreement with Takeda. This compares to license, collaboration, and other revenue of $15.7 million for the third quarter of 2016, which included the majority of the $15.0 million up-front payment received as part of the Zai Lab license agreement.

Cost of sales totaled $7.5 million for the third quarter of 2017 and included $6.2 million associated with product revenue and $1.3 million related to amortization of milestones recorded upon FDA approval of ZEJULA and first commercial sales of VARUBI/VARUBY in the U.S. and Europe. Cost of sales totaled $0.8 million for the third quarter of 2016.

Research and development expenses increased to $73.4 million for the third quarter of 2017, compared to $60.8 million for the third quarter of 2016, driven primarily by increased headcount, the advancement of our earlier-stage immuno-oncology portfolio, and expansion of the TSR-042 and TSR-022 programs.

Selling, general and administrative expenses increased to $84.0 million for the third quarter of 2017, compared to $37.7 million for the third quarter of 2016, primarily due to increased headcount, activities in support of the launches of ZEJULA and VARUBY in the U.S. and Europe, and higher professional service fees.

Operating expenses as described above include total non-cash, stock-based compensation expense of $25.0 million for the third quarter of 2017, compared to $12.9 million for the third quarter of 2016.

Net loss totaled $25.3 million, or ($0.47) per share, for the third quarter of 2017, compared to a net loss of $87.9 million, or ($1.72) per share, for the third quarter of 2016.

As of September 30, 2017, TESARO had approximately $521.3 million in cash and cash equivalents and approximately 54.4 million outstanding shares of common stock.

Corporate Objectives

TESARO intends to achieve the following key objectives:

Commercial Products:

Continue to execute on the ongoing U.S. launch of ZEJULA and solidify its position as the market-leading PARP inhibitor for patients with recurrent ovarian cancer;
Launch ZEJULA in Europe by year-end 2017, pending European Commission approval; and
Launch VARUBI IV in the U.S.
Pipeline Candidates:

Rapidly advance the GARNET registration trial of TSR-042 in MSI-H cancers, with the intent of supporting accelerated FDA approval;
Define the registration path in platinum-resistant ovarian cancer and triple negative breast cancer in Q1 2018, pending data from TOPACIO trial;
Report initial data for the AMBER trial of TSR-022 in combination with TSR-042 in 2018;
Complete the dose escalation phase of the TSR-033 CITRINO trial and in early 2018 initiate a combination trial of TSR-033 plus TSR-042;
Initiate OVARIO, a Phase 2 clinical trial of niraparib in combination with bevacizumab in patients with first-line ovarian cancer by year end;
Initiate a Phase 3 clinical trial of niraparib in combination with TSR-042 in first-line ovarian cancer in 1H 2018; and
Initiate a Phase 3 clinical trial of niraparib in combination with TSR-042 in NSCLC in 2H 2018.

On November 7, 2017 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported financial results for the third quarter ended September 30, 2017 (Press release, Tracon Pharmaceuticals, NOV 7, 2017, View Source;p=RssLanding&cat=news&id=2315121 [SID1234521692]).

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Third Quarter 2017 and Recent Corporate Highlights

We continue to enroll patients in the randomized Phase 3 TAPPAS trial of TRC105 combined with Votrient (pazopanib) for the treatment of advanced angiosarcoma. Currently, more than 20 sites are open for accrual in the U.S., and sites in EU countries are expected to be open by year-end. As a reminder, the initial TAPPAS sample size of 124 patients is designed to detect an improvement in progression-free survival (PFS) from four to seven months. The trial uses an adaptive design that allows for expansion of patient numbers and selective enrollment of a responsive subtype of angiosarcoma while preserving type-1 error. TRACON expects that the interim analysis will be conducted in the second half of 2018.

In October, two posters highlighting TRC105 were presented at the 18th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (IASLC) in Yokohama, Japan. Initial data from patients in the ongoing Phase 1b study of TRC105 in combination with Avastin (bevacizumab) and chemotherapy for the treatment of non-squamous cell lung cancer were presented. Three of eight (37%) evaluable patients had partial responses by RECIST 1.1, including one patient who achieved an 81% reduction in tumor volume. The complete enrollment of approximately 18 patients is expected by the end of 2018. In addition, investigators at the University of Alabama-Birmingham presented a "trials in progress" poster which detailed the study design of the Phase 1b dose-escalation trial of TRC105 and Opdivo (nivolumab) in patients with metastatic non-small cell lung cancer that is open for accrual.

In September, TRACON announced that enrollment was completed in the randomized Phase 2b TRAXAR study of TRC105 and Inlyta (axitinib) in patients with advanced or metastatic renal cell carcinoma (RCC). The Company expects to report top-line PFS data from this study in early 2018 based on the observed rate of events of disease progression or death that define the PFS endpoint. We expect the study to have at least 80 events confirmed by the independent central review committee at the time of data readout, which should provide at least 70% power to detect an improvement in PFS from 4.8 months with Inlyta to 7.2 months with the combination of TRC105 and Inlyta. PFS will also be assessed in patients with predefined levels of two soluble biomarkers, osteopontin and TGF-β receptor III, which correlated with response in the Phase 1 portion of the trial.

In July, following completion of the Phase 1/2 PAVE trial, TRACON and its partner, Santen Pharmaceutical Co. Ltd. (Santen), announced initiation of the randomized Phase 2a AVANTE study of DE-122, the ophthalmic formulation of TRC105, for the treatment of patients with wet age-related macular degeneration (AMD). The Phase 2a study is a randomized controlled trial designed to assess the safety and efficacy of repeated intravitreal injections of two different doses of DE-122 in combination with Lucentis (ranibizumab) compared to single agent Lucentis in patients with wet AMD. The Phase 2a study initiation resulted in a $7.0 million milestone payment to TRACON.
"The recently achieved progress across our pipeline positions us well for several important potentially value-creating milestones in the first half of 2018," said Charles Theuer, M.D., Ph.D., President and CEO of TRACON. "In addition, we are highly encouraged by our partner Santen’s decision to advance DE-122 into the randomized Phase 2 AVANTE study in wet AMD."

Expected Upcoming Milestones Through 1H ‘18

Presentation of updated safety, pharmacokinetics and efficacy data from the completed Phase 1b/2 trial of TRC105 and Votrient in patients with angiosarcoma at the annual meeting of the Connective Tissue Oncology Society (CTOS) in Maui on November 9, 2017.

Presentation of early response data from the multicenter Phase 1/2 trial of TRC105 and Nexavar (sorafenib) in patients with hepatocellular carcinoma.

Completion of dose escalation in the Phase 1/2 clinical trial of TRC253 in patients with prostate cancer.

Announcement of top-line data from the randomized Phase 2 TRAXAR trial of TRC105 in combination with Inlyta.

Presentation of data from Santen’s completed Phase 1/2 PAVE trial of DE-122.
Third Quarter 2017 Financial Results

Cash, cash equivalents and short-term investments were $35.9 million at September 30, 2017, compared to $44.4 million at December 31, 2016.

Collaboration revenue for the third quarter of 2017 was $7.5 million compared to $0.8 million for the third quarter of 2016.

Research and development expenses for the third quarter of 2017 were $4.3 million compared to $4.5 million for the third quarter of 2016.

General and administrative expenses for the third quarter of 2017 were $1.8 million compared to $1.9 million for the third quarter of 2016.

Net income for the third quarter of 2017 was $1.2 million compared to a net loss of $5.9 million for the third quarter of 2016.
Investor Conference Call

The Company will hold a conference call today at 4:30 p.m. EST / 1:30 p.m. PST to provide an update on corporate activities and to discuss the financial results of its third quarter of 2017. The dial-in numbers are (855) 779-9066 for domestic callers and (631) 485-4859 for international callers. Please use passcode 7458759. A live webcast of the conference call will be available online from the Investor/Events and Presentation page of the Company’s website at www.traconpharma.com.

After the live webcast, a replay will remain available on TRACON’s website for 60 days.

On November 7, 2017 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of autoimmune disease, asthma and allergic diseases, and cancer, reported financial results for the third quarter ended September 30, 2017 and provided a review of business and clinical highlights (Press release, Xencor, NOV 7, 2017, View Source [SID1234521693]).

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"Our third quarter results highlight the promise of our XmAb technology to create a broad pipeline of engineered antibodies with improved performance across a range of unmet needs," said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor. "We recently announced promising, final results from our Phase 2 trial of XmAb5871 in IgG4-RD, which suggest that XmAb5871 may offer patients the first approved therapy for this newly-defined autoimmune disease and support advancement of the program into a Phase 3 trial. Today, we are pleased to announce data from our Phase 1b trial of subcutaneously administered XmAb7195, which shows potent IgE reduction with improved tolerability compared to intravenous administration, and supports subcutaneous administration in future development. In addition, we continue to advance our bispecific oncology pipeline targeting the tumor microenvironment, have opened the IND for XmAb18087, our first solid tumor targeting bispecific, and expect to report the first clinical data from our oncology pipeline in 2018."

Recent Business Highlights and Upcoming Clinical Plans

XmAb5871: XmAb5871 is a first-in-class monoclonal antibody that targets CD19 with its variable domain, and uses Xencor’s XmAb immune inhibitor Fc domain to target FcyRIIb, a receptor that inhibits B-cell function. XmAb5871 is currently in a Phase 2 clinical study for the treatment of systemic lupus erythematosus (SLE).

· Initiation of Phase 3 trial in IgG4-RD expected in 2H18.
· Initial data from SLE Phase 2 trial expected in late 2018.

In November 2017, Xencor announced the final results from its Phase 2 trial of XmAb5871 in IgG4-RD. 12 of 15 patients (80%) dosed completed the study, and all 12 achieved the primary endpoint of at least a two-point reduction in the IgG4-RD Responder Index (IgG4-RD RI) on Day 169. None of the 12 required corticosteroids (CS) after month two, and eight patients (53%) achieved disease remission (IgG4-RD of 0 and no CS after two months) and the other four achieved IgG4-RD RI scores of <4 at Day 169. Fourteen of 15 patients (93%) achieved a decrease of > 5 in the IgG4-RD RI. XmAb5871 was well-tolerated, with all XmAb5871-related adverse events (AEs) graded as mild to moderate and no XmAb5871-related serious AEs reported. These results will be presented today at 8:15 pm ET during a late-breaking oral presentation at the American College of Rheumatology (ACR) 2017 Annual Meeting titled, "Final Results of an Open Label Phase 2 Study of a Reversible B Cell Inhibitor, Xmab5871 in IgG4-Related Disease."

Xencor met with the Division of Pulmonary, Allergy and Respiratory Products (DPARP) of the Food and Drug Administration (FDA) in a Type B End of Phase 2 meeting in July 2017 to discuss the optimal pathway to advance XmAb5871 into Phase 3 development in IgG4-RD. The meeting resulted in guidance on endpoint definition and a path forward for Phase 3 development in IgG4-RD, which the FDA recognizes as a new disease entity with no regulatory precedence for an approval pathway. Based on the Phase 2 results and these preliminary discussions with DPARP, a randomized, placebo-controlled, double-blinded Phase 3 trial of approximately 250-350 patients evaluating the addition of XmAb5871 to standard of care is planned to be initiated in the second half of 2018. Xencor also intends to seek scientific advice from the European Medicines Agency in early 2018.

XmAb7195: XmAb7195 is a first-in-class monoclonal antibody that targets IgE with its variable domain and uses Xencor’s XmAb immune inhibitor Fc domain to target FcyRIIb, resulting in three distinct mechanisms of action for reducing IgE levels.

Xencor recently completed its subcutaneous (SC) administration Phase 1b study of XmAb7195 evaluating four once-weekly doses of SC XmAb7195. The first part of this study was an open-label bioequivalence trial ranging from 0.1 to 1.0 mg/kg in cohorts of six healthy volunteers. The second part of the trial was a randomized, double-blinded, placebo-controlled multiple-ascending dose study in atopic patients at doses of 1.5 and 2.0 mg/kg. The half-life of SC XmAb7195 ranged from 3.6 – 4.9 days, comparable to the previously reported half-life of 3.9 days of intravenously administered XmAb7195. Bioavailability after the fourth dose exceeded 50%, which is typical for monoclonal antibodies, and drug concentration levels increased with successive doses.

Subcutaneous administration of XmAb7195 was well tolerated. No severe AEs or serious treatment-emergent AEs occurred during the study. The most frequently occurring treatment-emergent AEs were injection-site related and most were mild. No diffuse urticaria or other systemic hypersensitivity reactions were reported. No apparent effect of SC XmAb7195 on platelet count was seen when dosed at 0.1 – 1.0 mg/kg weekly for four weeks. At 1.5 – 2.0 mg/kg weekly for four weeks, mild platelet count reductions were observed. Four of 15 patients in the 2.0 mg/kg group had at least one platelet count of less than 150 x 103/mL at some time point. The lowest count observed was 126 x 103/mL, and recovery to within normal range occurred within a few days.

In 23 of 27 (85%) subjects with detectable baseline free IgE (> 9.59 ng/mL limit of quantitation); (median 76.2 ng/mL, range: 17.4-846 ng/mL), treated with four weekly SC XmAb7195 doses of 0.3 to 2.0 mg/kg, free IgE was suppressed to below the limit of quantitation (BLQ) at some time point during the treatment period. In 20 (74%) subjects, BLQ values were maintained for the remainder of the treatment period and for at least seven days following the last dose. Similarly, in the subgroup of atopic subjects, 14 of 14 (100%) subjects with detectable baseline free IgE (median 150.0 ng/mL, range: 46.4-846 ng/mL) treated with four weekly SC XmAb7195 doses of 1.5 to 2.0 mg/kg, free IgE was suppressed to BLQ at some time point during the treatment period. In 12 (86%) atopic subjects, BLQ values were maintained for the remainder of the treatment period and for at least seven days following the last dose. Similarly, total IgE was profoundly suppressed in nearly all subjects for at least seven days following the last dose.

These results support subcutaneous delivery for future development, and analysis of the data is proceeding to determine the optimal dosing schedule. Xencor is seeking a development partner for XmAb7195.

Bispecific Oncology Pipeline: Xencor’s initial bispecific antibody programs are tumor-targeted antibodies that contain both a tumor antigen binding domain and a cytotoxic T-cell binding domain (CD3). These bispecific antibodies activate T cells for highly potent and targeted killing of malignant cells. Their XmAb Fc domains confer long circulating half-lives, stability and ease of manufacture. XmAb14045 is currently in a Phase 1 study for the treatment of acute myeloid leukemia (AML) and other CD123-expressing hematologic malignancies, and XmAb13676 is currently in a Phase 1 study for the treatment of B-cell malignancies.

· Initial data from XmAb14045 Phase 1 trial expected in 2018, pending alignment on timing with Novartis.
· Initial data from XmAb13676 Phase 1 trial expected in 2018, pending alignment on timing with Novartis.
· The Investigational New Drug (IND) application for XmAb18087, a somatostatin receptor 2 (SSTR2) x CD3 bispecific antibody for the treatment of neuroendocrine tumors and gastrointestinal stromal tumors, was approved in October 2017; clinical trial start expected in the first quarter of 2018.

Xencor is expanding its bispecific pipeline to build a suite of tumor microenvironment activators that engage multiple targets, such as T-cell checkpoints or agonists, with three IND’s scheduled to be filed over the next 12 months:

· IND application filing for XmAb20717, a PD-1 x CTLA-4 dual checkpoint inhibitor for the treatment of multiple oncology indications, expected in 2018.
· IND application filing for XmAb22841, a CTLA-4 x LAG-3 dual checkpoint inhibitor for the treatment of multiple oncology indications, expected in 2018.
· IND application filing for XmAb23104, a PD-1 x ICOS bispecific antibody for the treatment of multiple oncology indications, expected in 2018.

At the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2017 Annual Meeting in November, Xencor will present preclinical data on XmAb20717 and XmAb23104.

Partnered XmAb Programs: Nine pharmaceutical companies and the National Institutes of Health are advancing novel drug candidates either discovered at Xencor or that rely on Xencor’s proprietary XmAb technology. Seven such programs are currently undergoing clinical testing, including two in Phase 3 studies.

Third Quarter Ended September 30, 2017 Financial Results:

Cash, cash equivalents and marketable securities totaled $373.0 million as of September 30, 2017, compared to $403.5 million on December 31, 2016. The decrease reflects net spending on operations in the nine months ended September 30, 2017.

Revenues for the third quarter ended September 30, 2017 were $7.1 million, compared to $7.8 million for the same period in 2016. Revenues for the nine months ended September 30, 2017 were $24.8 million, compared to $81.1 million for the same period in 2016. Revenues in the three and nine-month period ended September 30, 2017 were earned primarily from the Company’s Amgen and MorphoSys collaborations, compared to revenues from the same period in 2016, which were earned primarily from the Company’s Novartis and Amgen collaborations.

Research and development expenditures for the third quarter ended September 30, 2017 were $19.4 million, compared to $14.1 million for the same period in 2016. Total research and development expenses for the nine-month period ended September 30, 2017 were $51.4 million, compared to $38.5 million for the same period in 2016. The increased research and development spending for the three and nine months ended September 30, 2017 is primarily due to increased spending on the Company’s bispecific pipeline and development candidates.

General and administrative expenses for the third quarter ended September 30, 2017 were $4.2 million, compared to $3.0 million in the same period in 2016. Total general and administrative expenses for the nine-month period ended September 30, 2017 were $13.1 million, compared to $10.0 million for the same period in 2016. Increased spending on general and administrative expenses for the three and nine months ended September 30, 2017 reflects increased staffing and stock-based compensation charges.

Non-cash, share based compensation expense for the nine months ended September 30, 2017 was $10.2 million, compared to $5.9 million for the same period in 2016.

Net loss for the third quarter ended September 30, 2017 was $15.6 million, or $(0.33) on a fully diluted per share basis, compared to a net loss of $8.1 million, or $(0.20) on a fully diluted per share basis, for the same period in 2016. For the nine months ended September 30, 2017, net loss was $37.1 million, or $(0.79) on a fully diluted per share basis, compared to a net income of $32.7 million, or $0.78 on a fully diluted per share basis, for the same period in 2016. The higher loss for the three months ended September 30, 2017 over the loss reported for the same period in 2016 is primarily due to additional research and development expenses on the Company’s bispecific pipeline and development candidates, while the loss reported for the nine months ended September 30, 2017 compared to the income earned over the same period in 2016 is primarily due to revenue reported from the Company’s Novartis collaboration in 2016 and additional research and development expenses in 2017.

The total shares outstanding was 46,955,365 as of September 30, 2017, compared to 41,138,851 as of September 30, 2016. The increase in total shares at September 30, 2017 reflects the sale of shares in the December 2016 financing.

Financial Guidance:

Based on current operating plans, Xencor expects to have cash to fund research and development programs and operations beyond 2020. Xencor expects to end 2017 with approximately $340 million in cash, cash equivalents and marketable securities.

Conference Call and Webcast:

Xencor will host a conference call today at 4:30 p.m. ET (1:30 p.m. PT) to discuss these third quarter 2017 financial results and provide a corporate update.

The live call may be accessed by dialing (877) 359-9508 for domestic callers or (224) 357-2393 for international callers, and referencing conference ID number: 99272433. A live webcast of the conference call will be available online from the investor relations section of the company’s website at www.xencor.com. The webcast will be archived on the company’s website for 30 days.

On November 7, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported results from a new exploratory analysis of the phase 3 CheckMate -214 trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) versus the standard of care, sunitinib, in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma (RCC) (Press release, Bristol-Myers Squibb, NOV 7, 2017, View Source [SID1234521642]). In an exploratory analysis of PD-L1 expression subgroups, an overall survival (OS) advantage was seen with the Opdivo plus Yervoy combination over sunitinib in both the PD-L1 expression level <1% [HR= 0.73, (CI: 95% 0.56 to 0.96)] and ≥1% subgroups [HR= 0.45 (CI: 95% 0.29 to 0.71)]. The median overall survival (OS) was not reached for the Opdivo plus Yervoy combination or sunitinib for those with PD-L1 levels < 1%, and for patients with PD-L1 expression levels ≥1%, the median OS was not reached for the combination and was 19.6 months for sunitinib. The safety profile of Opdivo plus Yervoy was consistent with that of previous reports.

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These data will be presented on November 10 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 32nd Annual Meeting in National Harbor, MD, during the High Impact Clinical Trial Results Session from 3:50 to 4:05 PM EST (Abstract #O38). Previously, the Company announced the phase 3 trial stopped early, at the Data Monitoring Committee’s recommendation, for statistically significant superiority in OS with Opdivo plus Yervoy versus sunitinib. Results of CheckMate -214, including the primary endpoints of OS, objective response rate (ORR) and progression-free survival (PFS) in intermediate- and poor-risk patients, were presented earlier this year at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress on September 10 in Madrid, Spain.

"After seeing overall survival data from CheckMate -214 two months ago, the scientific community has been eager to understand the role of subgroups in these results," said Robert J. Motzer, M.D., Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. "We’re pleased to show that in CheckMate -214, patients with first-line advanced renal cell carcinoma saw an overall survival benefit across PD-L1 expression levels. The PD-L1 analysis results, quality of life data and safety profile advance our understanding of the combination’s potential to address a high unmet need for intermediate- and poor-risk patients with advanced disease."

Findings from an exploratory endpoint showed patients reported statistically significantly better kidney cancer symptom control with the Opdivo plus Yervoy combination compared to sunitinib, when assessed using a valid tumor-specific patient-reported kidney cancer scale in the FKSI-19. Through the first six months of data, when completion rates exceeded 80%, a 3-6 point difference was observed, which is considered clinically meaningful.

"As a leader in Immuno-Oncology, we are committed to improving overall survival and are encouraged by these results in patients with advanced renal cell carcinoma, whose treatment options remain limited," said Arvin Yang, M.D., Ph.D., development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb. "We continue to evaluate the potential of Opdivo plus Yervoy in this population and look forward to discussing these results with regulatory authorities."

About CheckMate -214

CheckMate -214 is a phase 3, randomized, open-label study evaluating the combination of Opdivo plus Yervoy versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma. Patients in the combination group received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks. Patients in the comparator group received sunitinib 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Patients were treated until progression or unacceptable toxic effects. The primary endpoints of the trial are overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) in an intermediate- to poor-risk patient population (approximately 75% of patients). Safety is a secondary endpoint.

Grade 3/4 adverse events (AEs) were reported in 46% of patients (252/547) in the combination group, compared with 63% of patients (337/535) in the sunitinib group. The most common grade 3/4 AEs in the combination group were fatigue (4%), diarrhea (4%), nausea (2%), decreased appetite (1%), and, in less than 1% each, pruritus, hypothyroidism and hypertension. In the sunitinib group, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), Palmar-plantar erythrodysaesthesia syndrome (9%), diarrhea (5%), stomatitis (3%), mucosal inflammation (3%), nausea (1%), decreased appetite (1%), and in less than 1% each, hypothyroidism and dysgeusia. Adverse events (AEs) leading to discontinuation were reported in 22% of patients (120/547) in the combination group, compared with 12% of patients in the sunitinib group (64/535). Seven treatment-related deaths occurred in the combination group and four in the sunitinib group.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all patients. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. Globally, the five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 12.1%.

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 for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies 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 how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

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 60 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 50 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 adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adults and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory 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 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. 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 Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, 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), 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, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia.

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, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia.

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%).

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

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; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma; Checkmate 040 – hepatocellular carcinoma.

On November 7, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that 23 abstracts spanning its expansive oncology research program will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 32nd Annual Meeting from November 8 – 12 in National Harbor, Maryland (Press release, Bristol-Myers Squibb, NOV 7, 2017, View Source [SID1234521643]). The research reinforces the breadth of the Company’s oncology pipeline, sourced through internal and external innovation to address areas of high unmet need, as well as the integration of translational research driving the Company’s approach to Immuno-Oncology (I-O) drug development and continued research of the Opdivo (nivolumab) plus Yervoy (ipilimumab) combination.

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"We continue to deepen our understanding of cancer biology and investigate novel mechanisms to address areas of high unmet need, with the goal of establishing new standards of care," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "Through our research initiatives and broad clinical program investigating Opdivo, Yervoy and combinations with novel I-O targets, we are able to advance the next wave of potentially transformative combinations and use translational research to identify the right treatments for the right patients who may benefit from these therapies."

Presentations that illustrate the Company’s approach include the following:

Ongoing Study of Opdivo:

Data from trials across multiple tumor types evaluating Opdivo-based combinations will be presented.

Late-Breaking Abstract: Nivolumab + ipilimumab v sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma: results from CheckMate 214, including overall survival by subgroups
Author: R. Motzer
Abstract #: O38
Oral Presentation: High Impact Clinical Trial Results
Friday, November 10, 3:50 – 4:05 p.m. ET, Maryland Ballroom
Pooled 3-year overall survival data from phase II and phase III trials of nivolumab combined with ipilimumab in advanced melanoma
Author: M. Postow (to be presented by S. Hodi)
Abstract #: O21
Oral Presentation: High Impact Clinical Trial Results
Friday, November 10, 3:35 – 3:50 p.m. ET, Maryland Ballroom
Long-term survival in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab
Author: S. Topalian
Abstract #: P216
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Resource use and cost implications associated with treatment-free interval experienced on immunotherapies
Author: M. Atkins
Abstract #: P258
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Innovative Pipeline:

Updates from the Company’s oncology pipeline designed to address unmet patient needs and drive the next wave of transformative combinations in I-O will be presented. Highlights include late-breaking data evaluating IDO1 inhibitor BMS-986205 in combination with Opdivo for advanced forms of bladder and cervical cancer, as well as first disclosures for early assets targeting CSF1R and OX40.

Late-Breaking Abstract: Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers
Author: J. Luke
Abstract #: O41
Oral Presentation: Late Breaking Abstract Session II
Saturday, November 11, 12:00 – 12:15 p.m. ET, Maryland Ballroom
Late-Breaking Abstract: First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors
Author: Z. Wainberg
Abstract #: O42
Oral Presentation: Clinical Trials: Novel Combinations
Saturday, November 11, 4:30 – 4:45 p.m. ET, Maryland Ballroom A
OX40 T cell costimulatory agonist BMS-986178 alone or in combination with nivolumab in patients with advanced solid tumors: initial phase 1 results
Author: A. Olszanski
Abstract #: O17
Oral Presentation: Clinical Trials: Novel Combinations
Saturday, November 11, 4:00 – 4:15 p.m. ET, Maryland Ballroom A
Selection of first-in-human starting dose of anti-OX40 agonist monoclonal antibody BMS-986178 using a pharmacokinetic/pharmacodynamic-based approach
Author: C. Huang
Abstract #: P420
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Optimizing anti-OX40 mediated immunotherapy: preclinical exploration of the relationship between antitumor activity and isotype choice, ligand blocking capacity, dose and schedule
Author: C. Gao
Abstract #: P373
Poster Presentation
Friday, November 10, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Preclinical and Translational Research Driving I-O Approach:

New preclinical and translational research to be presented, conveying the importance of better understanding disease biology and its intersection with the immune system to identify patients most likely to benefit from I-O therapy, including results from the first comprehensive multi-tumor profiling study evaluating LAG-3 expression, as well as data evaluating the gut microbiome of dMMR/MSI-H colorectal cancer patients treated with Opdivo.

Late-Breaking Abstract: Multitumor profiling of lymphocyte activation gene 3 (LAG-3) and association with immune cell phenotypes
Author: R. Edwards
Abstract #: P510
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Microbiome analyses in patients with previously treated, deficient DNA mismatch repair/microsatellite instability-high metastatic colorectal cancer treated with nivolumab with or without ipilimumab: CheckMate 142
Author: S. Kopetz
Abstract #: P392
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Critical role of hematopoietic progenitor kinase 1 in anti-tumor immune responses
Author: D. You
Abstract #: P339
Poster Presentation
Friday, November 10, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Circulating T cell subpopulations correlate with immune inflammatory signatures at the tumor site in melanoma and non-squamous non-small cell lung cancer
Author: N. Manjarrez-Orduño
Abstract #: P62
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Targeting CSK kinase activity to enhance anti-tumor immunity
Author: C. Wang
Abstract #: P155
Poster Presentation
Friday, November 10, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Non-fucosylated anti-CTLA-4 antibody enhances vaccine-induced T-cell responses in a non-human primate pharmacodynamic vaccine model
Author: J. Loffredo
Abstract #: P55
Poster Presentation
Friday, November 10, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Efficacy of interleukin 2 and interleukin 15 for in situ vaccination in a mouse melanoma model
Author: A. Rakhmilevich
Abstract #: P286
Poster Presentation
Saturday, November 11, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
Clinical and Translational Collaborations:

Data will also be presented from key clinical and translational collaborations that seek to evaluate combinations of Opdivo with novel targets and increase understanding of emerging issues in oncology.

Pivot-02: Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors
Author: A. Diab
Abstract #: O20
Oral Presentation: Clinical Trials: Novel Combinations
Saturday, November 11, 5:00 – 5:15 p.m. ET, Maryland Ballroom A
Phase 1/2 study of CB-839, a first-in-class oral glutaminase inhibitor, in combination with nivolumab in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer
Author: F. Meric-Bernstam
Abstract #: O16
Oral Presentation: Clinical Trials: Novel Combinations
Saturday, November 11, 3:30 – 3:45 p.m. ET, Maryland Ballroom A
Combining in situ vaccination with checkpoint blockade enhances an endogenous anti-tumor B-cell response resulting in tumor-specific humoral memory
Author: C. Heinze
Abstract #: P37
Poster Presentation
Friday, November 10, 12:30 – 2:00 p.m. ET, Prince George Exhibition Hall DE
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 for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with more than 15 clinical-stage programs designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies 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 how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

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 60 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 50 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 adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory 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 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. 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 Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, 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), 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, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia.

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, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).. In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.

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%).

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

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; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma; Checkmate 040 – hepatocellular carcinoma.