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Merck Presents Details on Immuno-Oncology Program Including First-in-Man Milestone with Investigational Bi-Functional Immunotherapy

On October 1, 2015 Merck, a leading company for innovative and top-quality high-tech products in healthcare, life science and performance materials, reported an update on key immuno-oncology and oncology research and development projects, illustrating visible progress across all pipeline stages (Press release, Merck KGaA, OCT 1, 2015, View Source [SID:1234507627]).

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Among others, the company announced that it started investigating a novel, potential first-in-class bi-functional immunotherapy in clinical trials with the potential to offer an alternative therapy to anti-PD-1/anti-PD-L1 and other immunotherapies. Merck also showed good progress in its avelumab development program, which it is driving together with Pfizer. If successful, the companies expect the first potential commercial launch for avelumab in 2017, and are working toward at least one additional potential launch per year through 2022.

"We have a focused and differentiated pipeline in immuno-oncology, oncology and immunology that has the potential to make a substantial difference in the lives of patients," said Luciano Rossetti, Head of Global R&D at the biopharmaceutical business, Merck Serono, in an investor call following presentations at this year’s European Cancer Congress (ECC) in Vienna, which took place Sept. 25 – 29. "Our priorities include accelerating high-priority programs and ensuring launch success to secure long-term growth."

Merck has been rebuilding its research and development organization over the past four years, with new leadership and improved R&D operating model. Rigorous project prioritization, increased efficiency and more agile decision making has allowed the company to progress its R&D productivity. Merck is on track to deliver a continuous flow of innovative specialty medicines in areas of high unmet medical need, including several promising earlier stage assets.

Merck expects more than 3,000 patients treated with Avelumab by 2016
Regarding the avelumab clinical development program, Merck said it is on track to meet its 2015 goals of collaborating on up to 20 clinical programs, including initiating up to six pivotal trials. By the end of 2016, Merck expects more than 3,000 patients to be treated across more than 15 tumor types and lines of therapy.

In September, the US Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) for avelumab in Merkel cell carcinoma (MCC). MCC is a very rare disease in which malignant (cancer) cells form in the skin. This orphan drug designation does not guarantee market approval, but could imply seven years of market exclusivity upon approval and other incentives.

Beyond avelumab, Merck today also disclosed details on other key immuno-oncology programs aimed at helping patients fight difficult-to-treat cancers. These projects include its CAR-T/Intrexon T-cell therapies, which could form the next cornerstone of cancer immunotherapy. The innovative chimeric antigen receptor t-cell treatments modulate the immune system’s natural ability to fight tumors.

In addition, Merck gave details on its investigational molecule, M7824, for which it has initiated and treated the first patient in a phase I, open-label, multiple-ascending clinical trial, targeting to enroll 106 patients. This potential first-in-class bi-functional immunotherapy is designed to simultaneously block two immuno-inhibitory pathways that are commonly used by cancer cells to evade the immune system, thereby controlling tumor growth by restoring and enhancing anti-tumor immune responses.

"The initiation of the M7824 clinical trial marks the next milestone in Merck’s strategy to build an innovative portfolio of cancer immunotherapies that may work synergistically to potentially maximize patient benefit," Rossetti said. "This is the first phase I trial industry-wide for this class of molecule and we expect to see key data during the second half of 2016."

In the broader field of oncology, Merck reiterated that it expects to have key data on its oncology treatment evofosfamide, a hypoxia-activated pro drug currently tested in clinical phase III trials in soft tissue sarcoma and pancreatic cancer, during the fourth quarter of 2015. In addition, the company disclosed details of its tepotinib program, an investigational small molecule inhibitor of the c-met receptor tyrosine kinase, as well as its DNA-PK inhibitor M3814, which has the potential for a first-in-class orally administered selective DNA-PK inhibitor.

The webcast can be followed live here (starting at 14:00 CEST), the presentation will be available at the Investor Relations section of our website.

XOMA Announces Development and Commercialization Agreement for First-in-Class Anti-TGF-beta Antibody Program in Immuno-Oncology

On October 1, 2015 XOMA Corporation (Nasdaq:XOMA), a leader in the discovery and development of therapeutic antibodies, reported it has exclusively licensed the global development and commercialization rights to its anti-transforming growth factor-beta (TGFb) antibody program to Novartis. Under the terms of the agreement, XOMA will receive $37.0 million in the form of an upfront payment and is eligible to receive up to $480.0 million if all development, regulatory, and commercial milestones are met (Press release, Xoma, OCT 1, 2015, View Source [SID:1234507625]).

In addition, XOMA is eligible to receive royalties on product sales that range from the mid-single digits to the low double digits. In connection with this license agreement, Novartis has agreed to extend the maturity date on the approximately $13.5 million of outstanding debt under the secured note agreement, which bears interest at the six-month LIBOR plus 2% (currently 2.53%), to September 30, 2020. XOMA has also agreed to reduce the royalty rate to XOMA associated with Novartis’ clinical stage anti-CD40 antibodies.

"XOMA and Novartis have worked closely together for several years to develop new product candidates. When they expressed interest in our anti-TGFb program, we knew Novartis was the best company to bring this exciting potential therapy to the patients whom it may help," stated John Varian, Chief Executive Officer of XOMA. "Novartis is recognized as a leader in oncology, where an anti-TGFb molecule has real potential either as monotherapy or in combination with other therapeutic options.

"We had said we did not plan to raise equity capital at our recent stock price in order to fund the development of our very exciting endocrine portfolio. With this non-dilutive liquidity of essentially $50.5 million, we currently project this capital, in combination with our planned cost savings measures, will fund operations into 2017. We remain on track to begin our XOMA 358 Phase 2 clinical program this fall and fully anticipate we will have the data from these studies during that timeframe," concluded Mr. Varian.

About TGF-beta

Transforming growth factor-beta (TGFb) is a potent immune suppressive cytokine that is involved in many cellular processes, including inhibition of cell growth and immune suppression. While TGFb is essential for normal tissue homeostasis, elevated levels of TGFb may drive the progression of numerous diseases, including advanced metastatic cancer and fibrosis.

Three isoforms of TGFb exist in humans: TGFb1, 2 and 3. TGFb1 is overexpressed in many cancers and is believed to increase the likelihood of metastasis. Inhibiting TGFb1 and 2 while sparing TGFb3 may reduce tumor-protecting regulatory T cells, while allowing for the development of cytotoxic immune responses enhanced by TGFb3, improving the therapeutic index of TGFb inhibitors. Given the role of the TGFb pathway in cancer, it has become an attractive target for cancer drug development.

About XOMA 089

Discovering the TGFb antibody program was made possible because of XOMA’s proprietary antibody discovery technology platform. XOMA 089 is a fully human, high-affinity, late preclinical monoclonal antibody that neutralizes TGFb1 and 2 while sparing TGFb3. Data have shown this compound to be both active against tumor growth in preclinical models of head and neck cancer as well as breast cancer and breast cancer metastasis. Preclinical data also suggest that it may be synergistic with PD1 inhibition and work highlighting these results was recently presented at the 2015 FASEB meeting on the TGFb Superfamily: Signaling in Development and Disease. XOMA has made significant progress regarding this lead compound on both the understanding of its activity, mechanism of action, as well as preclinical toxicology and manufacturing. Other antibodies included in this license agreement inhibit TGFb1, which may be a more appropriate approach to certain indications. These antibodies have potential in immuno-oncology either as a monotherapy and may be particularly amenable to combination therapies, especially with immune checkpoint inhibitors.

Merck and DNAtrix Announce Phase 2 Immuno-Oncology Collaboration in Patients with Aggressive Form of Brain Cancer

On October 1, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, and DNAtrix reported they have entered into an oncology clinical study collaboration to evaluate the efficacy and safety of DNX-2401, DNAtrix’s oncolytic immunotherapy, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in a Phase 2, multi-centered study of patients with recurrent glioblastoma, the most aggressive form of brain cancer for which there is no cure (Press release, Merck & Co, OCT 1, 2015, View Source [SID:1234507624]).

DNX-2401 is a conditionally replicative oncolytic adenovirus designed to specifically target cells defective in the Retinoblastoma (Rb) pathway, which is present in many cancers. Several DNX-2401 clinical studies have demonstrated a favorable safety profile and strong tumor-killing potential in patients with recurrent glioblastoma. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. KEYTRUDA is currently approved in the United States for certain types of advanced metastatic melanoma.

"We are excited to enter into this important collaboration with Merck as we investigate the potential anti-tumor effect that combining our two immunotherapies – DNX-2401 and KEYTRUDA – may offer patients with this aggressive disease," said Frank Tufaro, Ph.D., chief executive officer of DNAtrix.

"The collaboration with DNAtrix further strengthens our efforts to progress the field of immuno-oncology and identify potential combinations that will significantly advance the care of people with cancers for which there have been few advancements," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We look forward to studying the potential synergistic effects that combining DNX-2401 and KEYTRUDA could have in the treatment of patients with recurrent glioblastoma."

The agreement is between DNAtrix and Merck, through a subsidiary. Additional details of the collaboration were not disclosed.

About Glioblastoma

Glioblastoma is a type of glioma, which are tumors that arise from glial cells, or supportive brain cells that help to keep neurons in place and functioning well. Glioblastoma is highly malignant because the cells reproduce quickly and are supported by a large network of blood vessels. While glioblastoma rarely spreads elsewhere in the body, these tumors arise from normal brain cells, so it is easy for them to invade and live within normal brain tissue. Glioblastoma represents 17 percent of all primary brain tumors and 54 percent of all gliomas.

About DNX-2401

DNX-2401 is an investigational oncolytic immunotherapy designed to treat high grade gliomas. Upon tumor injection, DNX-2401 sets off a chain reaction of tumor cell killing by selectively replicating within glioma cells (but not normal cells), causing tumor destruction and further spread of the oncolytic virus to adjacent tumor cells. This process can also trigger an anti-tumor immune response. DNX-2401 is currently being investigated in several clinical studies and has been well tolerated in all settings. Compelling results from Phase I clinical studies in recurrent glioblastoma indicate that DNX-2401 can (1) replicate in human brain tumors for a period of weeks to months (2) trigger immune cell infiltration into the tumor (3) cause ongoing tumor destruction detectable by MRI and (4) induce durable responses to therapy. In these studies, patient survival has been prolonged in a subset of patients, including in those achieving a complete response.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Kite Pharma Announces Peer-Reviewed Publication of T Cell Receptor Based Product Candidate to Treat HPV-Associated Cancers

On October 1, 2015 Kite Pharma, Inc., (NASDAQ:KITE), a clinical-stage biopharmaceutical company focused on developing engineered autologous cell therapy (eACT) products for the treatment of cancer, reported the publication of non-clinical findings describing the discovery and characterization of a novel T cell receptor (TCR) product candidate targeting HPV-16 E6 (Press release, Kite Pharma, OCT 1, 2015, View Source [SID:1234507623]).

The findings published online by Clinical Cancer Research (a publication of the American Association for Cancer Research (AACR) (Free AACR Whitepaper)), doi:10.1158/1078-0432.CCR-14-3341, show that this TCR is highly selective and has high affinity for the HPV-16 E6, an oncoprotein that is associated with the majority of HPV-mediated cancers. The study also showed T cells engineered with HPV-16 E6 TCR selectively destroyed HPV-16 positive tumor cells. The National Cancer Institute (NCI) is conducting a Phase 1/2 clinical trial of this TCR product candidate under a Cooperative Research and Development Agreement (CRADA) between Kite and the NCI.

"HPV-16 E6 is a viral oncogene that is causally associated with cervical and other HPV-related cancers. Because E6 protein is expressed in cancer cells and absent in normal, healthy tissues, a TCR product candidate with high selectivity for this oncogene has the potential to become a novel cellular therapy directed against HPV-16 positive cancers," commented David Chang, M.D., Ph.D., Executive Vice President R&D and Chief Medical Officer. Dr. Chang added, "Kite is encouraged by the results of this important research, which has formed the basis for translating this novel approach to the clinic."

"HPV infection, responsible for diverse urogenital cancers and the fastest-growing type of cancers of the head and neck, represents an area of compelling unmet medical needs for patients," stated Arie Belldegrun, M.D., FACS, Kite’s President and Chief Executive Officer. "Peer-reviewed publications, such as in AACR (Free AACR Whitepaper)’s Clinical Cancer Research, continue to add significant validation for our broad, advancing pipeline of candidates to treat patients with solid tumors."

In December 2014, Kite signed an exclusive, worldwide license with the National Institutes of Health (NIH) for the rights to develop and commercialize intellectual property related to TCR-based product candidates directed against HPV-16 E6 and E7 oncoproteins for the treatment of HPV-related cancers. Kite expects to file an IND for a Company-sponsored clinical trial of HPV-16 E6 TCR product candidate in the first half of 2016.

About HPV-Associated Cancers

There were over 500,000 new cases of and 275,000 deaths attributable to cervical cancer worldwide in 2008.1 Human papillomavirus (HPV) is the most common viral infection of the reproductive tract, and HPV-16 is believed to cause about 50-60% of cervical cancers. HPV-16 is also implicated in additional urogenital and head and neck cancer types,2 and is believed to cause 90% of HPV-mediated oropharyngeal cancers and the majority of HPV-mediated anal, penile, vaginal and vulvar cancers.

About TCR-based Immunotherapy

Kite’s broadly enabling eACT technology platform allows a patient’s T cells to be genetically modified to express cancer-targeting receptors, including TCRs. Engineered TCR T cells express alpha and beta chains of the T cell receptor, which recognize and bind to MHC-presented tumor antigens. Once modified, the T cells can traffic directly to tumor sites and become activated upon engagement with the target tumor antigen, selectively eradicating the tumor cells.

Bristol-Myers Squibb Receives Approval from the U.S. Food and Drug Administration for the Opdivo (nivolumab) + Yervoy (ipilimumab) Regimen in BRAF V600 Wild-Type Unresectable or Metastatic Melanoma

On October 1, 2015 Bristol-Myers Squibb Company (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab) in combination with Yervoy (ipilimumab), for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma (Press release, Bristol-Myers Squibb, OCT 1, 2015, View Source [SID:1234507621]).1 Today’s announcement marks the first and only FDA approval of a Regimen of two Immuno-Oncology agents in cancer. This indication is approved under accelerated approval based on tumor response rate and durability of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

The approval is based on data from the pivotal study, CheckMate -069, which was the first to report outcomes of the Opdivo + Yervoy Regimen in previously untreated patients with unresectable or metastatic melanoma. Results from the trial demonstrated a statistically significant (p<0.001) increase in confirmed objective response rate – the study’s primary endpoint – in patients with BRAF wild-type melanoma treated with the Opdivo + Yervoy Regimen [60% (95% CI: 48-71; p<0.001)] compared to those treated with Yervoy monotherapy [11% (95% CI: 3-25)]. Complete responses were seen in 17% of patients. Partial responses were seen in 43% of the Regimen group and 11% of the Yervoy monotherapy group. The Opdivo + Yervoy Regimen demonstrated a 60% reduction in the risk of progression vs. Yervoy alone (HR=0.40; 95% CI: 0.22-0.71; p<0.002). Median PFS was 8.9 months with the Regimen (95% CI: 7.0, NA) and 4.7 months with Yervoy alone (95% CI: 2.8-5.3).1 This trial provides clinical rationale for targeting the immune system with two Immuno-Oncology agents in metastatic melanoma.

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, other adverse reactions; infusion reactions; and embryofetal toxicity.1 Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.

"Targeting the immune system in the treatment of cancer has been of interest to the oncology community for decades,4 and our first Immuno-Oncology agent, Yervoy, was approved in 2011 for metastatic melanoma. Opdivo reinforced the power of the immune system in the fight against cancer, and is quickly becoming a foundational component in how the oncology community treats this devastating disease," said Giovanni Caforio, chief executive officer, Bristol-Myers Squibb. "Today’s approval of the Opdivo + Yervoy Regimen marks another first for our research in Immuno-Oncology and represents our unwavering commitment to continually redefine cancer care, and offer patients new treatment options with the goal of improved outcomes."

About the Opdivo + Yervoy Regimen: Advancing Metastatic Melanoma Treatment
CheckMate -069 is a Phase 2, double-blind, randomized study which enrolled 140 patients with previously untreated unresectable or metastatic melanoma,1 and included patients with both BRAF wild-type and BRAF mutation-positive melanoma.2 The primary endpoint was objective response rate (ORR) in patients with BRAF wild-type tumors.1 Additional efficacy outcome measures were investigator-assessed duration of response and progression-free survival (PFS) in patients with BRAF V600 wild-type melanoma. Randomization was stratified by BRAF mutation status.2 The Regimen includes four cycles of the Opdivo + Yervoy combination followed by Opdivo monotherapy.1 In the clinical study, patients in the Opdivo + Yervoy Regimen group received Opdivo 1mg/kg plus Yervoy 3mg/kg every 3 weeks for 4 doses during the combination phase, followed by Opdivo 3mg/kg every 2 weeks during the monotherapy phase. Treatment was continued until progression or unacceptable toxicity.1 In the Yervoy monotherapy group, patients were treated with Yervoy 3mg/kg every 3 weeks for 4 doses with matched placebo.1 Of the 95 patients randomized to receive the Opdivo + Yervoy Regimen, 50% were 65 years or older and 13% were 75 years or older.3 Fifty-nine percent of patients completed all 4 doses in the initial combination phase over a median of 9.1 weeks (range: 9.0 weeks to 26.3 weeks).1

Among patients (n=109) with BRAF wild-type melanoma, the Regimen demonstrated a significantly superior response rate of 60% (95% CI: 48-71; p<0.001) vs. Yervoy alone, 11% (95% CI: 3-25).1 Seventeen percent of patients experienced a complete response in the BRAF wild-type population.1 Partial responses were seen in 43% of the Regimen group and 11% of the Yervoy monotherapy group.1 Seventy-nine percent (34/43) of patients had ongoing responses of at least 6 months at the time of analysis. Of these patients, 14 had a duration of response of at least 6 months but less than 9 months, and 20 patients had a duration of response of at least 9 months. The remaining 21% (9/43) of patients had a duration of response ranging from 3 to 7 months and have progressed after response, died, or received subsequent therapy.1 Along with higher ORR and more complete responses, the Opdivo + Yervoy Regimen demonstrated a 60% reduction in the risk of progression among BRAF wild-type patients vs. Yervoy alone (HR=0.40, 95% CI: 0.22-0.71; p<0.002).1 Median PFS was 8.9 months with the Regimen (95% CI: 7.0, NA) and 4.7 months with Yervoy alone (95% CI: 2.8-5.3).1

"Historically, metastatic melanoma has been a difficult disease to treat.6 Now, a new treatment option based on the combination of two valued Immuno-Oncology agents demonstrates significant efficacy versus ipilimumab (Yervoy) in metastatic melanoma,"2 said Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. "Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma."

In CheckMate -069, serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delays (47% vs. 22%), and Grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving the Opdivo + Yervoy Regimen compared with those receiving Yervoy alone. In the Opdivo + Yervoy Regimen group, 27% (25/94) of patients did not complete all four cycles of the Opdivo + Yervoy Regimen. The first occurrence of a Grade 3 or 4 adverse reaction was during administration of the Opdivo + Yervoy Regimen in 56 patients (59%), while 9 patients (10%) experienced first occurrence of a Grade 3 or 4 adverse reaction during administration of Opdivo alone.

The most common adverse reactions leading to discontinuation of Opdivo, as compared to Yervoy alone, were colitis (16% vs. 2%), diarrhea not treated with corticosteroids (4% vs. 4%), increased ALT levels (4% vs. 0), pneumonitis (3% vs. 0), and AST increase (3% vs. 0). The most frequent serious adverse events with the Opdivo + Yervoy Regimen, as compared to Yervoy alone, were colitis (17% vs. 9%), diarrhea (9% vs. 7%), pyrexia (6% vs. 7%), and pneumonitis (5% vs. 0). The most common adverse reactions (≥20%) reported in patients receiving the Opdivo + Yervoy Regimen vs. Yervoy alone were rash (67% vs. 57%), pruritus (37% vs. 26%), headache (24% vs. 20%), vomiting (23% vs. 15%), and colitis (22% vs. 11%).

"We are currently witnessing a turning point in cancer history, based on the significant impact Immuno-Oncology is making in the lives of patients with metastatic melanoma. Today’s approval of the first Regimen of two Immuno-Oncology agents, Opdivo and Yervoy, is an exciting moment for our community because it reinforces we are on a positive path forward, providing new approaches which translate into meaningful results for patients," said Tim Turnham, Executive Director, Melanoma Research Foundation.

About the Opdivo + Yervoy Regimen
The scientific rationale for targeting the immune system via dual immune checkpoint inhibition in cancer has formed the basis of a novel approach to the treatment of metastatic melanoma.4

"At Bristol-Myers Squibb, we have been at the forefront of researching the potential of two different immune checkpoint pathways – CTLA-4 and PD-1 – in the treatment of cancer," said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer, Bristol-Myers Squibb. "From initial pre-clinical research, to pivotal studies resulting in regulatory approval of Yervoy and Opdivo as monotherapies, to today’s FDA approval, we are proud to be leading the way in bringing a dual Immuno-Oncology Regimen to cancer patients for the first time."

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack.4 Opdivo and Yervoy are immune checkpoint inhibitors that target separate, distinct and complementary checkpoint pathways (PD-1 and CTLA-4).4 The mechanism of action involves dual immune checkpoint inhibition resulting in increased anti-tumor activity.5 Yervoy blockade of CTLA-4 has been shown to augment T-cell activation and proliferation,4 while Opdivo restores the active T-cell response directed at the tumor.4 This may affect healthy cells and result in immune-mediated adverse reactions, which can be severe and potentially fatal.4

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA in other indications, including metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Bristol-Myers Squibb has a broad, global development program to study the combination of Opdivo and Yervoy consisting of more than 14 trials in which more than 2,000 patients have been enrolled worldwide through September 2015.

About Metastatic Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.6 Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to other organs.6 The incidence of melanoma has been increasing for at least 30 years.6 An estimated 73,870 melanoma cases will be diagnosed in the U.S. in 2015.6 Melanoma is mostly curable when treated in its early stages.6 However, in its late stages, 5-year and 10-year survival rates in the U.S. average 15-20% and 10-15%, respectively.6

About Bristol-Myers Squibb’s Patient Support Programs
Bristol-Myers Squibb remains committed to helping patients access our medicines. For support and assistance, patients and physicians may call 1-855-OPDIVO-1. This number offers one-stop access to a range of support services for patients and healthcare professionals alike.

About Bristol-Myers Squibb’s Access Support
Bristol-Myers Squibb is committed to helping patients access the Opdivo + Yervoy Regimen and offers BMS Access Support to support patients and providers in gaining access. BMS Access Support, the Bristol-Myers Squibb Reimbursement Services program, is designed to support access to BMS medicines and expedite time to therapy through reimbursement support including Benefit Investigations, Prior Authorization Facilitation, Appeals Assistance, and assistance for patient out-of-pocket costs. BMS Access Support assists patients and providers throughout the treatment journey – whether it is at initial diagnosis or in support of transition from a clinical trial. More information about our reimbursement support services can be obtained by calling 1-800-861-0048 or by visiting www.bmsaccesssupport.com. For healthcare providers seeking specific reimbursement information, please visit the BMS Access Support Product section by visiting www.bmsaccesssupportopdivo.com.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) and thyroid function tests at baseline and before each dose.

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

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO as a single agent; no cases occurred in Checkmate 063. In Checkmate 063, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO as a single agent including five Grade 3 and two Grade 2 cases. Across the clinical trial experience in 188 patients with melanoma who received OPDIVO in combination with YERVOY, in Checkmate 069 (n=94) and an additional dose-finding study (n=94), fatal immune-mediated pneumonitis occurred in 0.5% (1/188) of patients. In Checkmate 069, there were six additional patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and Grade 2 (n=3).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 063, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO as a single agent. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. In Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and Grade 1 (n=5).

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

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 063, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%) in patients receiving OPDIVO as a single agent. In Checkmate 069, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).

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

Immune-Mediated Dermatitis

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

Immune-Mediated Neuropathies

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

Immune-Mediated Endocrinopathies:

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

In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2 (n=10). In Checkmate 069, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 069, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with YERVOY. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with YERVOY. In Checkmate 063, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO as a single agent. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case.

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

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 063, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients receiving OPDIVO as a single agent. In Checkmate 069, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. One patient died without resolution of renal dysfunction.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 069, immune-mediated rash occurred in 37% (35/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=6), Grade 2 (n=10), and Grade 1 (n=19).

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In Checkmate 063, the following clinically significant immune-mediated adverse reactions occurred in <2% of single-agent OPDIVO-treated patients: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered as a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: diabetes mellitus, diabetic ketoacidosis, and myasthenic syndrome. In Checkmate 069, the following additional immune-mediated adverse reactions occurred in 1% of patients treated with OPDIVO in combination with YERVOY: Guillain-Barré syndrome and hypopituitarism. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: uveitis, sarcoidosis, duodenitis, pancreatitis, and gastritis.

Infusion Reactions

Severe infusion reactions have been reported in <1% of patients in clinical trials of OPDIVO. In Checkmate 069, Grade 2 infusion reactions occurred in 3% (3/94) patients receiving OPDIVO in combination with YERVOY. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO 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 OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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 OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Checkmate 063, serious adverse reactions occurred in 59% of patients receiving OPDIVO as a single agent. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

In Checkmate 069, serious adverse reactions occurred in 62% of patients receiving OPDIVO; the most frequent serious adverse events with OPDIVO in combination with YERVOY, as compared to YERVOY alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0).

Common Adverse Reactions

In Checkmate 063, the most common adverse reactions (≥20%) reported with OPDIVO as a single agent were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). In Checkmate 069, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO in combination with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

In a separate YERVOY Phase 3 study, 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%).