On April 16, 2018 Cellectar Biosciences (Nasdaq: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported the presentation of a late breaker poster entitled "Phospholipid drug conjugates (PDC) show specificity for a broad range of tumor cells and provides a novel approach for targeted or precision therapy" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting underway in Chicago (Press release, Cellectar Biosciences, APR 16, 2018, View Source [SID1234525339]). Jarrod Longcor, chief business officer at Cellectar Biosciences will present this poster today, from 8:00 am – 12:00 pm (CT), poster section 43.

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The poster articulates how phospholipid ether platform provides tumor targeting for PDC molecules, irrespective of payload/warhead and their behavior once inside cells. These data provide valuable insight for the successful design of molecules for targeted delivery of cytotoxic payloads. In one of the studies presented, the result shows that Cellectar’s PDCs can effectively deliver cytotoxic payloads to the tumor cells without killing normal cells and that there is a 20-fold difference in the delivery of PDCs to the tumor versus normal cells.

"Many cancer treatments have clinical limitations that could be improved by the targeting our novel phospholipid ether technology and PDCs provide. Our research continues to suggest that our PDCs may offer an attractive method of targeting therapeutics to tumors. Our platform may provide distinct advantages over other technologies, not least of which is the diversity of payloads and linkers we can utilize," said James Caruso, chief executive officer of Cellectar Biosciences. "It is our goal to demonstrate that this level of diversity and specificity can translate into outcomes that will benefit cancer patients."

About Phospholipid Drug Conjugates
Cellectar’s product candidates are built upon a patented delivery and retention platform that utilizes optimized PDCs to target cancer cells. The PDC platform selectively delivers diverse oncologic payloads to cancerous cells and cancer stem cells, including hematologic cancers and solid tumors. This selective delivery allows the payloads’ therapeutic window to be modified, which may maintain or enhance drug potency while reducing the number and severity of adverse events. This platform takes advantage of a metabolic pathway utilized by all tumor cell types in all cell cycle stages. Compared with other targeted delivery platforms, the PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens. In addition, PDCs can be conjugated to molecules in numerous ways, thereby increasing the types of molecules selectively delivered. Cellectar believes the PDC platform holds potential for the discovery and development of the next generation of cancer-targeting agents.

On April 16, 2018 Cellectar Biosciences (Nasdaq: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported the presentation of CLR 131 preclinical data in a poster discussion entitled "Therapeutic Combination of Radiolabeled CLR1404 with External Beam Radiation in Head and Neck Cancer Murine Xenograft Models" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting underway in Chicago (Press release, Cellectar Biosciences, APR 16, 2018, View Source [SID1234525338]). The discussion, hosted on Sunday, April 15, 2018 was led by Chunrong Li, assistant scientist, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health.

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The purpose of the study was to evaluate the anti-tumor effect of CLR 131 in combination with external beam radiation (XRT). The results demonstrated uptake of CLR 131 across multiple head and neck cancer (HNC) cell lines and xenograft models, and synergistic anti-tumor effects when CLR 131 was combined with XRT. The combination of CLR 131 and fractionated XRT showed enhanced tumor growth inhibition compared with single modality treatment in the 6 HNC xenograft models. Importantly, the findings suggest potential efficacy using CLR 131 combined with reduced-dose XRT in HNC patients. High-dose XRT while effective for localized disease, produces significant co-morbidities for patients, especially those suffering from diffuse disease. The potential to reduce the XRT dose may also result in decreased toxicity to normal tissue, a common side effect of high-dose XRT.

As a key milestone of their Head and Neck SPORE Grant (NIH P50 DE026787), the University of Wisconsin-Madison is initiating the first human clinical trial combining CLR 131 and external beam radiation in patients with recurrent HNC in the second half of 2018. The costs associated with the Phase 1 study will be covered in their entirety through the grant and the study represents a fourth clinical trial using the company’s lead PDC, CLR 131.

"As we continue both preclinical and clinical evaluation of our lead cancer targeting compound CLR 131, our potential to meaningfully impact a broad range of cancers continues to grow," said James Caruso, chief executive officer of Cellectar Biosciences. "We are encouraged by the data highlighted at AACR (Free AACR Whitepaper) showing enhanced receptivity to treatment and inhibition of tumor growth, while potentially reducing toxicities associated with current standard of care treatment."

About CLR 131
CLR 131 is Cellectar’s investigational radioiodinated PDC therapy that exploits the tumor-targeting properties of the company’s proprietary phospholipid ether (PLE) and PLE analogs to selectively deliver radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. CLR 131, is in a Phase 2 clinical study in relapsed or refractory (R/R) MM and a range of B-cell malignancies and a Phase 1 clinical study in patients with (R/R) MM exploring fractionated dosing . In 2018 the company plans to initiate a Phase 1 study with CLR 131 in pediatric solid tumors and lymphoma, and a second Phase 1 study in combination with external beam radiation for head and neck cancer.

On April 16, 2018 Cancer Genetics, Inc. (Nasdaq:CGIX), a leader in enabling precision medicine for oncology through molecular markers and diagnostics, reported that it has received special 510(k) clearance from the U. S. Food and Drug Administration (FDA) for its Tissue of Origin test (TOO) following modifications made to test reagents and software (Press release, Cancer Genetics, APR 16, 2018, View Source [SID1234525337]).

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TOO is a microarray-based gene expression test that analyzes a tumor’s genomic information to help identify its origin, which is valuable in classifying metastatic, poorly differentiated, or undifferentiated cancers. TOO assesses 2,000 individual genes, covering 15 of the most common tumor types (representing 58 morphologies) and 90% of all solid tumors [1]. These tumors include thyroid, breast, non-small cell lung, pancreas, gastric, colorectal, liver, bladder, kidney, non-Hodgkin’s lymphoma, melanoma, ovarian, sarcoma, testicular germ cell, and prostate.
TOO is the only FDA-cleared test of its type and is Medicare-reimbursed. It is also the only test that provides a pathologist’s review and interpretation of a patient’s test results and diagnosis. TOO provides extensive analytical and clinical validation for statistically significant improvement in accuracy over other methods, including IHC [2]. TOO results lead to a change in patient treatment 65% of the time. In challenging cancers that require a second round of IHC, TOO increases diagnostic accuracy and confidence in site-specific treatment decisions [1].
"Our TOO Test represents a unique offering with the ability to add significant value to the continuum of care for cancer patients and greatly enhance our biopharma partners’ development efforts. This 510(k) clearance represents an important milestone toward our goal of gaining broad adoption of the test," said John A. (Jay) Roberts, Interim Chief Executive Officer and COO of Cancer Genetics. "An important element of our recently implemented transformation strategy is the identification of new methods through which to monetize our world-class test portfolio. We are currently evaluating several partnering opportunities that would expand the reach of the TOO Test and have the potential to generate high-margin revenue streams. We look forward to continuing this process as we leverage the capabilities of TOO to drive future growth."

Compared to the early version, the current TOO assay uses new labeling reagents and has a higher accuracy rate and a shorter workflow with similar precision and reproducibility. The low RNA input requirement of the early version is maintained. The combined result of these new features offers a further optimized clinical assay to help clinicians make diagnostic decisions and subsequent treatment selections.

Rita Shaknovich, Chief Medical Officer of CGI added, "Despite increasing excellence in the diagnostic workup for malignancies, there are approximately 150,000 newly diagnosed cases of metastatic cancer with unclear diagnosis in the U.S. and Europe each year [3]. This includes the subset of patients with cancers of unknown primary (CUP) and of uncertain origin. Increasingly complex algorithms and testing associated with a diagnostic workup also means that many challenging cases have insufficient amount of sample material for analysis. CGI’s TOO aids in identifying the source of such challenging tumors while using less material, and could be used as a diagnostic or confirmatory tool both for routine clinical testing and for clinical trial enrollment of patients with such tumors, enabling them to be considered for novel drug therapies."
The Company announced on April 2, 2018 that it has engaged Raymond James & Associates, Inc. as a financial advisor to assist with evaluating options for the Company’s strategic direction. These options may include raising additional capital, the acquisition of another company and / or complementary assets, the sale of the Company, or another type of strategic partnership. The Company’s Board of Directors is committed to evaluating all potential strategic opportunities and to pursuing the path most likely to create both near- and longer-term value for Cancer Genetics’ shareholders.
1. R Pillai, et al. Validation and Reproducibility of a Microarray-based Gene Expression Test for Identifying the Primary Site of Tumors in Formalin-Fixed Paraffin-Embedded Specimens. J Molec Diag 13 2011;13:48-56.
2. JP Grenert, et al. Gene Expression Profiling from Formalin-Fixed, Paraffin-Embedded Tissue for Tumor Diagnosis. Clin Chim Acta. 2011 Jul 15;412(15-16):1462-4.
3. Tomuleasa, Ciprian, et al. How to Diagnose and Treat a Cancer of Unknown Primary Site. Journal of Gastrointestinal & Liver Diseases 26.1 (2017).

On April 16, 2018 Bristol-Myers Squibb Company (NYSE: BMY) reported initial results from the pivotal Phase 3 study, CheckMate -227, evaluating the Opdivo (nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab, 1 mg/kg) combination in first-line advanced non-small cell lung cancer (NSCLC) patients with high tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb) (Press release, Bristol-Myers Squibb, APR 16, 2018, View Source [SID1234525336]). In the study, the combination demonstrated a superior benefit for the co-primary endpoint of progression-free survival (PFS) versus chemotherapy (HR 0.58; 97.5% CI: 0.41 to 0.81; p=0.0002). The PFS benefit was observed regardless of PD-L1 expression levels and in both squamous and non-squamous tumor histology. Additionally, based on an early descriptive analysis, encouraging overall survival was observed with the combination versus chemotherapy in patients with high TMB ≥10 mut/Mb (HR 0.79; 95% CI: 0.56 to 1.10).

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"CheckMate -227 is the first Phase 3 study to demonstrate the important clinical benefit of combining two immunotherapy agents to treat first-line NSCLC patients with high TMB," said Matthew D. Hellmann, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "Results demonstrated that first-line nivolumab plus ipilimumab can provide frequent, deep and durable responses compared with chemotherapy in patients with NSCLC who have TMB ≥10 mut/Mb. The trial also supports the rationale for molecular testing to determine potential biomarkers in patients with lung cancer."

These data were featured today during the official press program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago (Abstract #CT077). Findings will be presented at 11:35-11:55 AM CDT during the Clinical Trials Plenary Session, Immunotherapy Combinations: The New Frontier in Lung Cancer, and simultaneously published in The New England Journal of Medicine.

"Lung cancer is a highly complex disease, defined by multiple subtypes, making it increasingly important to define a more precise treatment approach for this disease," said Sabine Maier, development lead, thoracic cancers, Bristol-Myers Squibb. "We are excited to have advanced the science by establishing in this study that TMB was an important biomarker that predicted which first-line lung patients experienced a clinically meaningful progression-free survival benefit with a chemotherapy-sparing option, Opdivo plus low-dose Yervoy combination. These results are an example of our goal to understand each patient type through our leading translational research capabilities."
Grade 3-4 treatment-related adverse events (AEs) with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%) and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.
Additional Data from CheckMate -227 Presented at AACR (Free AACR Whitepaper) 2018
Additional data from CheckMate -227 presented at AACR (Free AACR Whitepaper) 2018 include subgroup analyses by tumor PD-L1 expression in patients with TMB ≥10 mut/Mb. In these analyses, PFS was significantly improved with the combination versus chemotherapy in patients with PD-L1 ≥1% (HR 0.62; 95% CI: 0.44 to 0.88) and PD-L1 <1% (HR 0.48; 95% CI: 0.27 to 0.85). Increased benefit with Opdivo plus low-dose Yervoy versus chemotherapy was also observed in patients with squamous histology (HR 0.63; 95% CI: 0.39 to 1.04) and non-squamous histology (HR 0.55; 95% CI: 0.38 to 0.80).

In the study, PFS also was evaluated with Opdivo versus chemotherapy among patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression as a secondary endpoint. An improvement in PFS with Opdivo monotherapy was not observed (HR 0.95; 97.5% CI: 0.61 to 1.48; p=0.7776).

About CheckMate -227
CheckMate -227 is an open-label Phase 3 trial evaluating Opdivo-based regimens versus platinum-doublet chemotherapy in patients with first-line advanced non-small cell lung cancer (NSCLC) across non-squamous and squamous tumor histologies. This program is comprised of three parts:
Part 1a: Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1
Part 1b: Opdivo plus low-dose Yervoy or Opdivo plus chemotherapy versus chemotherapy in patients whose tumors do not express PD-L1
Part 2: Opdivo plus chemotherapy versus chemotherapy in a broad population, regardless of PD-L1 or TMB status
There are two co-primary endpoints in Part 1 for the Opdivo plus Yervoy combination (versus chemotherapy): overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and progression-free survival (PFS) in patients with high tumor mutational burden (TMB) ≥10 mut/Mb across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). The primary endpoint in Part 2 is OS.
Secondary endpoints in TMB-selected patient populations were analyzed hierarchically: PFS with Opdivo monotherapy versus chemotherapy in patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression, and OS with Opdivo plus Yervoy versus chemotherapy in patients with TMB ≥10 mut/Mb. Based on this statistical hierarchy, OS in patients with TMB ≥10 mut/Mb with Opdivo plus Yervoy versus chemotherapy was a descriptive analysis.

In Part 1 of this study, patients were randomized 1:1:1 to Opdivo 3 mg/kg every two weeks plus low-dose Yervoy 1 mg/kg every six weeks; histology-based platinum-doublet chemotherapy every three weeks for up to four cycles; and Opdivo 240 mg every two weeks (Part 1a) or Opdivo 360 mg plus histology-based platinum-doublet chemotherapy every three weeks for up to four cycles, followed by Opdivo monotherapy (Part 1b).
Of all randomized patients in Part 1 (N=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB ≥10 mut/Mb, including 139 patients randomized to Opdivo plus Yervoy and 160 patients randomized to chemotherapy. In the trial, TMB was assessed using the validated assay, FoundationOne CDx.
About Tumor Mutational Burden (TMB)

Over time, cancer cells accumulate mutations that are not seen in normal cells of the body. Tumor mutational burden, or TMB, is a quantitative biomarker that reflects the total number of mutations carried by tumor cells. Tumor cells with high TMB have higher levels of neoantigens, which is thought to help the immune system recognize tumors and incite an increase in cancer-fighting T cells and an anti-tumor response. TMB is one type of biomarker that may help predict the likelihood a patient responds to immunotherapies.

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 advancing 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 24 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. Through our leading translational capabilities, we are pioneering immune biology research and identifying a number of potentially predictive biomarkers, including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of precision medicine for more patients with cancer.
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.
OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
OPDIVO (10 mg/mL) is an injection for intravenous (IV) use.
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 (e.g., 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.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

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 as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO as a 60-minute infusion prior to the infusion of 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 (n=236). 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. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

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 (n=236) 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%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). 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, headache, and abdominal pain.

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

Checkmate 067–advanced melanoma alone or in combination with YERVOY (ipilimumab); 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; Checkmate 238–adjuvant treatment of melanoma.
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.
About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd. (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On April 16, 2018 Bristol-Myers Squibb Company (NYSE: BMY) reported that Opdivo (nivolumab) 3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) as the first Immuno-Oncology combination therapy for previously untreated patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).1,2 In the Phase 3 CheckMate -214 clinical trial, the Opdivo + Yervoy combination demonstrated a significant and unprecedented increase in overall survival (OS) in this patient population compared to a current standard of care, sunitinib (Press release, Bristol-Myers Squibb, APR 16, 2018, View Source [SID1234525335]). An OS benefit was observed regardless of PD-L1 expression level.1,2,3 Opdivo + Yervoy also delivered durable responses, with a higher objective response rate (ORR) compared to sunitinib.1,2 Patients in the CheckMate -214 trial received four cycles of the Opdivo + low-dose Yervoy combination, followed by Opdivo maintenance therapy.1,2 In the combination arm of the trial, 79% of patients received all four doses of Opdivo + Yervoy and went on to the Opdivo monotherapy phase.4 Flexible dosing options are available during the Opdivo maintenance phase (480 mg infused every four weeks or 240 mg infused every two weeks).

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"Our goal is to provide cancer patients with medicines that have the potential to extend their lives. As the first treatment option to increase overall survival for subgroups of patients with advanced RCC compared to sunitinib, the Opdivo plus low-dose Yervoy combination helps deliver on that promise," said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. "This approval demonstrates our commitment to bringing Immuno-Oncology treatments that may improve outcomes to a broader range of RCC patients."
Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.1,2

Results from the CheckMate -214 trial in patients with previously untreated intermediate- and poor-risk advanced RCC include:
Overall Survival: Opdivo + Yervoy reduced the risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI]: 0.44 to 0.89; p<0.0001).1,2 The median OS was not yet reached for Opdivo + Yervoy (95% CI: 28.2 to not estimable [NE]) and was 25.9 months for sunitinib (95% CI: 22.1 to NE).1,2,3
Objective Response Rate: Opdivo + Yervoy was associated with a 41.6% ORR (95% CI: 36.9 to 46.5; p<0.0001; n=177/425) versus 26.5% for sunitinib (95% CI: 22.4 to 31.0; n=112/422).1,2
Complete and Partial Response Rates: The complete response (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425) and 1.2% for sunitinib (n=5/422), and the partial response (PR) rate was 32.2% for Opdivo + Yervoy (n=137/425) and 25.4% for sunitinib (n=107/422).1,2

Duration of Response: Among patients who responded, median duration of response (durability) for Opdivo + Yervoy was not yet reached (95% CI: 21.8 to NE), compared to 18.2 months for sunitinib (95% CI: 14.8 to NE).1,2
Progression-Free Survival: Progression-free survival (PFS) was 11.6 months for the Opdivo + Yervoy combination, compared to 8.4 months for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; p=not significant), which did not reach statistical significance.1,2
Among those with advanced RCC, 75% to 80% have one or more risk factors and are considered intermediate- and poor-risk patients according to International Metastatic Renal Cell Carcinoma Database Consortium criteria.5,6 These patients historically had a poor prognosis, and although there have been a number of treatment advances over the past decade, additional options to improve overall survival are still needed.7,8 Currently, only 36% of patients with advanced RCC survive beyond one year, and only 8% will live past five years.7,9
"Physicians treating advanced RCC have had few options to help achieve the goal of improved survival," said Robert J. Motzer, M.D., medical oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial Sloan Kettering Cancer Center. "Data from the CheckMate -214 trial demonstrated superior overall survival with Opdivo + Yervoy, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC. What’s more, the combination resulted in fewer overall Grade 3 and 4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels."
In CheckMate -214, the combination was associated with fewer overall Grade 3 or 4 adverse events than sunitinib (65% versus 76%).1,2 Treatment discontinuation due to adverse events occurred in 31% of patients in the Opdivo + Yervoy arm, compared to 21% in the sunitinib arm. Fifty-four percent (54%) of patients receiving Opdivo + Yervoy and 43% of patients receiving sunitinib had a dose delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction, which was not permitted for patients treated with the Opdivo + Yervoy combination. Serious adverse reactions occurred in 59% of patients receiving Opdivo + Yervoy and in 43% of patients receiving sunitinib.1,2
"Kidney cancer is the deadliest of all urological cancers, and too many patients are faced with this grim diagnosis," said Dena Battle, president, KCCure. "Today’s approval of Opdivo + Yervoy for advanced RCC has the potential to transform the first-line treatment landscape for kidney cancer. But for patients, it is more than just a new therapy option – it represents hope for a longer life."
Approval Based on CheckMate -214 Trial: Demonstrating Superior Overall Survival and Objective Response Rate vs. Sunitinib
CheckMate -214 is a Phase 3, randomized, open-label study evaluating the combination of Opdivo + Yervoy versus sunitinib in patients with previously untreated advanced RCC. In the intermediate- and poor-risk study population, 425 patients received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 3 mg/kg every two weeks, and 422 patients received sunitinib 50 mg once daily for four weeks, followed by two weeks off every cycle.1,2 The recommended dosing for the Opdivo + Yervoy combination is Opdivo 3 mg/kg followed by Yervoy 1 mg/kg each infused intravenously over 30 minutes on the same day every three weeks for four doses. After completing four doses of the combination, Opdivo should be administered intravenously 240 mg every two weeks or 480 mg every four weeks over 30 minutes until disease progression or unacceptable toxicity.1,2
The primary efficacy outcome measures of the trial were OS, ORR (CR+PR) and PFS as determined by an independent radiographic review committee (IRRC) in intermediate- and poor-risk patients. Patients were included regardless of their PD-L1 status.1,2 Data from CheckMate -214 were presented at the European Society for Medical Oncology Congress in September 2017 and the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in November 2017 and were published in the New England Journal of Medicine in March 2018.3,10,11
Select Safety Profile for the CheckMate -214 Trial
The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo + Yervoy were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency and colitis. The most common adverse reactions (≥20%) reported in patients receiving Opdivo + Yervoy were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%) and vomiting (20%).1,2
About Renal Cell Carcinoma
Renal cell carcinoma is the most common type of kidney cancer in adults, accounting for nearly 15,000 deaths in the United States each year.12,13 Clear-cell RCC is the most prevalent type of RCC and constitutes 70% to 80% of all patients.14 Renal cell carcinoma is approximately twice as common in men as in women.15 In the United States, the five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 8%.7
INDICATION
OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma (RCC).
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous use.
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 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients.
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 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.
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 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.
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 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) 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 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.
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. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 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, aplastic anemia, pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
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 a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients.
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 breastfeeding during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea.
Common Adverse Reactions
In Checkmate 214, the most common adverse reactions reported in at least 20% of patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and decreased appetite (21% vs 29%).
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.
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 advancing 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 24 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. Through our leading translational capabilities, we are pioneering immune biology research and identifying a number of potentially predictive biomarkers, including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of precision medicine for more patients with cancer.
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 Bristol-Myers Squibb’s Patient Access Support
Bristol-Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.
BMS Access Support, the Bristol-Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance and co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Support at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.
About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan