On June 1, 2015 BioInvent International (OMXS: BINV) reported a three-year research collaboration with the University of Southampton (UoS), one of the world’s leading antibody research groups, under the direction of Professor Mark Cragg, BSc, PhD, Professor of Experimental Cancer Research and Director of the Cancer Pathway Integrated Postgraduate Programme (Press release, BioInvent, JUN 1, 2015, http://www.bioinvent.com/media-centre/press-releases/release/?ReleaseID=0E5DCBBC28836A0F [SID:1234506557]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The collaboration, also involving Professor Martin Glennie and Dr Stephen Beers is aimed at developing new immunotherapy treatments for cancer by targeting regulatory T cells (T regs). The program builds on the clinical successes of antibodies to so called T cell checkpoint inhibitors. The collaboration aims to develop novel antibodies and targets that are more specific for the cancer-associated T regs.

This collaboration is separate from two existing research programs in place between the University of Southampton and BioInvent.

Terms of the collaboration are not disclosed, noting that BioInvent will have the option to license any promising results for further development and commercialization. Under the agreement, both parties will contribute to intellectual property generation.

BioInvent has the capacity, through the F.I.R.S.T. platform, to generate a large number of T cell depleting antibodies. UoS has unique capabilities to test and evaluate potential lead candidates in several advanced in vitro and in vivo models. The collaboration between BioInvent and UoS around n-CoDeR antibodies targeting human T regs for cancer therapy utilizes the strengths from both groups.

Professor Cragg commented, "We look forward to building on the strength of our collaborative relationship with BioInvent, which should allow us to remain at the cutting edge of antibody immunotherapy for the benefit of cancer patients worldwide. Both clinical and preclinical data suggests that depletion of T regs can result in efficient anti-tumor T cell responses and tumor eradication. However, current T cell targeting therapeutic antibodies and checkpoint inhibitors were developed based on their abilities to block inhibitory signals. Novel, as yet unidentified targets with broad expression on regulatory T cells in different cancers, such as melanoma, lung cancer etc. and antibody formats with superior T reg depleting activity may have greater activity. We look forward to working with BioInvent’s extensive antibody library and its novel targeting platform to establish several lead candidates for clinical development in this very important area of cancer research."

"We are especially pleased to be undertaking this additional research collaboration with the team at the University of Southampton. This esteemed research center and its renowned clinicians are experts in the fields of immunology and oncology and are at the forefront of unlocking the potential of therapeutic antibodies," said Björn Frendéus, PhD, Chief Scientific Officer of BioInvent and honorary Professor at the University of Southampton. "BioInvent’s phenotypic target and mAb discovery platform, F.I.R.S.T., are ideally suited to identify a great diversity of human mAb with cancer T reg depleting or modulating activity. In collaboration with our colleagues in Southampton, we aim to generate more efficacious and safer immune modulatory antibodies for cancer treatments."

On June 1, 2015 Baxter Ventures, the venture arm of Baxter International Inc. (NYSE:BAX), the Mayo Clinic and Velocity Pharmaceutical Development, LLC ("VPD") reported the formation of Vitesse Biologics, LLC, ("Vitesse") (Press release, Velocity Pharmaceutical Development, JUN 1, 2015, View Source [SID:1234506532]). Vitesse is a unique collaboration model initiated by Baxter Ventures to focus on the development of antibody and protein-based therapeutics in the areas of immunology, hematology, and oncology. Following the spin-off of Baxter BioScience as Baxalta Incorporated, anticipated to take place by mid-2015, the Vitesse relationship will be managed by the planned venture arm, Baxalta Ventures, for the new company.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The collaboration model, which represents a new method of drug development, was designed to incent each partner to advance promising therapies quickly through the development process. Each partner will provide its recognized expertise to enhance the target selection, target optimization, expression and product development process. Baxter BioScience will provide global commercialization, antibody and protein development and manufacturing capabilities; Mayo Clinic researchers will execute the Phase I clinical trials; VPD will be responsible for target identification, selection of early stage drug candidates and will lead the design and execution of pre-clinical and clinical protocols.

"Delivering innovative treatments to address unmet patient needs is at the very core of everything we do and drives our ongoing R&D focus," said Ludwig N. Hantson, Ph.D., president of Baxter BioScience. "By creating Vitesse, our business is executing on a new concept in early stage R&D by leveraging the expertise of industry-leading partners to accelerate the identification and development of novel biologic treatments that could eventually contribute to unmet patient needs while enhancing the Baxalta commercial portfolio."

Vitesse will develop treatments in the fields of hematology, oncology and immunology, which aligns strongly with Baxter BioScience’s therapeutic focus. This innovative model enables Baxter to serve as a hands-on partner in the pursuit of innovative treatments, as Baxter BioScience will be involved in the early-stages of development for all products identified by Vitesse and has an exclusive option to acquire each such product following the completion of the applicable Phase I trials.

"We are excited about the possibilities for this new collaboration, and particularly for this new model for early stage drug development," said Greg Gores, M.D., executive dean for research at Mayo Clinic. "Our goal is to identify new, useful therapeutics to address the unmet needs of our patients."

David Collier, M.D., CEO of VPD, said, "We are fortunate to have world-class partners in this project. We believe that the combination of the development and manufacturing expertise offered by Baxter BioScience and the clinical capabilities of the Mayo Clinic, working in conjunction with our team at VPD, will produce a series of very promising new therapeutics developed in a more rapid and cost-efficient manner."

With research as a key priority of the Destination Medical Center (DMC) initiative, Mayo Clinic is building upon the clinical and research infrastructure further accelerating Mayo Clinic’s ability to conduct some of the most important medical research, eventually to translate these discoveries into therapies for patients from across the globe.

ABOUT VITESSE BIOLOGICS, LLC Vitesse Biologics, LLC, a Delaware Corporation based in South San Francisco, CA, develops antibody and protein-based therapeutics in the areas of immunology, hematology, and oncology.

On June 1, 2015 Janssen Research & Development reported data from the Phase 3 multicenter study SAR3007, which demonstrated a significant improvement in progression-free survival (PFS) with trabectedin (YONDELIS) compared to dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) previously treated with an anthracycline and at least one additional chemotherapy regimen (Press release, Johnson & Johnson, JUN 1, 2015, View Source [SID:1234505209]). SAR3007 is the largest randomized Phase 3 study ever conducted in this patient population. These data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Soft tissue sarcoma (STS) is a type of cancer originating in the soft tissues that connect, support and surround other body structures, such as muscle, fat, blood vessels, nerves, tendons and the lining of joints.[1],[2] LPS and LMS are among the most common types of STS in adults and represent approximately 40-50% of all STS cases.[3],[4]

"Advanced soft tissue sarcomas represent a complex set of rare diseases which, when advanced, are life threatening. Our patients need new treatment options that are effective and reasonably well tolerated, as the treatment landscape has been relatively stagnant for decades," said George Demetri, M.D., Director, Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute and Professor at Harvard Medical School. "In soft tissue sarcomas, disease stabilization is an important metric for evaluating treatment success in patients with advanced disease. The safety data from this trial were consistent with the well-defined adverse events observed in previous clinical trials of trabectedin and in clinical use outside the United States where trabectedin has been approved to treat these aggressive diseases."

Trabectedin is approved in 77 countries in North America, Europe, South America and Asia under the trade name YONDELIS for the treatment of advanced STS as a single agent. Janssen submitted a New Drug Application for YONDELISto the U.S. Food and Drug Administration on November 24, 2014, which was granted Priority Review on February 3, 2015.

"The data presented at ASCO (Free ASCO Whitepaper) underscore the value of trabectedin as a potentially important treatment option for patients with LPS and LMS subtypes of soft tissue sarcoma," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen. "This latest research underlines our long-standing commitment to patients with advanced soft tissue sarcoma. To date, more than 50,000 patients worldwide have been treated with YONDELIS, including approximately 3,000 patients in our Expanded Access Program in the United States."

In this randomized, active-controlled Phase 3 study in patients with advanced LPS or LMS, trabectedin significantly reduced the risk of disease progression or death by 45% compared with those who received dacarbazine (hazard ratio [HR] = 0.550; P< 0.0001; median [M] 4.2 vs. 1.5 months, respectively), with results validated through an audit by independent radiologists. The improved PFS benefit with trabectedin treatment was consistently observed across all clinically relevant subgroups and was further supported by an increased objective response rate (ORR), a longer duration of response (DOR), and a higher clinical benefit response rate as compared to dacarbazine. At the interim analysis for overall survival (OS), the trial had not met the primary endpoint of OS. The study is ongoing to determine the final OS results, which will be presented at a future meeting. The results for the secondary efficacy endpoints are mature.

Safety findings were consistent with the well-characterized safety profiles of both agents, with the most common Grade 3-4 toxicities in the trabectedin versus the dacarbazine groups being decreased absolute neutrophil count (40% vs. 25%), decreased platelets (19% vs. 20%), and transient increases in liver transaminases, including alanine transaminase (ALT) (29% vs. 1%). Drug-related deaths occurred in 2.1% of patients in the trabectedin group versus 0% of patients in the dacarbazine group.

About SAR3007

The Phase 3 multicenter study SAR3007 compared trabectedin with dacarbazine in patients with advanced LPS or LMS previously treated with an anthracycline and at least one additional chemotherapy regimen. The primary endpoint is OS and secondary endpoints included PFS, time to progression (TTP), ORR, DOR, symptom severity and safety. Both treatments were administered via an IV infusion every three weeks with the trabectedin dose of 1.5 mg/m2 given over 24 hours versus dacarbazine dose of 1 g/m2 given over 20-120 minutes. Ninety-four percent of study participants were in the United States.

About Soft Tissue Sarcoma

Soft tissue sarcoma is a type of cancer originating in the soft tissues that connect, support and surround other body structures, such as muscle, fat, blood vessels, nerves, tendons and the lining of joints.1,2 In the United States, nearly 12,000 people will be diagnosed and approximately 4,870 are expected to die of soft tissue sarcomas in 2015.[5] Leiomyosarcoma is an aggressive type of soft tissue sarcoma that occurs in smooth muscles, such as those in the uterus, gastrointestinal tract or lining of blood vessels.[6] Liposarcoma originates in fat cells and most commonly occurs in the thigh and abdominal cavity, though it can occur in fat cells in any part of the body.[7],[8]

About YONDELIS (trabectedin)
YONDELIS (trabectedin) is a novel, multimodal, synthetically produced antitumor agent, originally derived from the sea squirt, Ecteinascidia turbinata. The anti-cancer medicine works by preventing the tumor cells from multiplying and is approved in 77 countries in North America, Europe, South America and Asia for the treatment of advanced soft tissue sarcoma as a single agent, and in 70 countries for relapsed ovarian cancer in combination with DOXIL/CAELYX (doxorubicin HCl liposome injection).

Under a licensing agreement with PharmaMar, a wholly owned member of the Zeltia Group, Janssen Products, LP has the rights to develop and sell YONDELIS globally except in Europe, where PharmaMar SA holds the rights, and in Japan, where PharmaMar has granted a license to Taiho Pharmaceuticals Co., Ltd. If approved in the United States, YONDELIS would be commercialized by Janssen Biotech, Inc.

On Jun 1, 2015 Amphivena Therapeutics, Inc., a developer of cancer immunotherapies, reported positive data from several preclinical studies characterizing the company’s proprietary T-cell redirecting bispecific CD33/CD3-targeting antibodies as potential immunotherapeutics for the treatment of acute myeloid leukemia (AML) (Press release, Amphivena Therapeutics, JUN 1/, 2015, View Source [SID:SID1234515580]). Study findings, which demonstrated potent and specific anti-AML activity for the novel antibodies, were presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Amphivena also announced selection of a development candidate, AMV-564, based on these compelling preclinical data.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A diverse collection of Amphivena’s novel T-cell redirecting, tetravalent, bispecific CD33/CD3-targeting antibodies were evaluated across a rigorous panel of in vitro and in vivo systems in order to identify an optimal candidate for clinical development. The studies, conducted in collaboration with leading researchers at the Fred Hutchinson Cancer Research Center and the Washington University School of Medicine, were designed to examine the antibodies’ stability properties, affinity for CD33 and CD3, and impact on T-cell activation and cytotoxicity against CD33+ AML cells. The ASCO (Free ASCO Whitepaper) poster presentations (abstracts: 3057, 7067 and 7071) can be found on Amphivena’s website at www.amphivena.com.

Key study findings for Amphivena’s CD33/CD3-targeting antibodies included:

Mechanism-based, T-cell activation and proliferation was induced by the tetravalent, bispecific CD33/CD3-targeting antibodies. Importantly, the presence of CD33+ target cells was required for the T-cell activities, demonstrating the potential for minimal off-target safety issues for this antibody platform.

Potent and selective cytotoxic activity against CD33+ AML cell lines and 27 primary CD33+ AML specimens was observed at pM antibody concentrations. This activity was observed in newly diagnosed and relapsed or refractory AML samples, and was independent of disease stage. For the most potent CD33/CD3 antibodies, activity was independent of the level of CD33 expression.

Robust tumor growth inhibition and delay in prophylactic and established AML xenograft models using human cancer cell lines and donor T-cells.

Impressive activity in an AML patient-derived xenograft model with nearly complete elimination of leukemic blasts from all compartments, including bone marrow and spleen, despite the very low number of T-cells present in the patient sample.

"These preclinical studies identified T-cell redirecting bispecific CD33/CD3-targeting antibodies that meet our initial, pre-specified activity and safety profile for an immunotherapeutic clinical candidate for treating AML. Particularly exciting is the breadth and potency of the activity seen in AML patient samples from work done under the direction of Roland B Walter, M.D., Ph.D. at the Fred Hutchinson Cancer Research Center and the impressive level of activity observed in the AML patient-derived xenograft model in research conducted under the direction of John DiPersio, M.D., Ph.D., at the Washington University School of Medicine. Drs. DiPersio and Walter are two prominent, highly-regarded key opinion leaders in the area of hematologic oncology research and having their work support and validate our internal efforts is gratifying," said Jeanmarie Guenot, Ph.D., president and chief executive officer of Amphivena Therapeutics. "These positive preclinical results represent a key milestone for Amphivena, and we are happy to announce selection of a therapeutic candidate, AMV-564, for clinical development. While these studies highlighted promising therapeutic profiles for a number of our novel antibodies, we believe that AMV-564 provides the most rapid opportunity for successful development."

"The potent in vitro and in vivo activity of AMV-564 suggests this tetravalent, bispecific antibody may soon be ready for early phase clinical trials," said Dr. DiPersio, M.D., Ph.D., Chief, Division of Oncology, Deputy Director, Siteman Cancer Center, Washington University School of Medicine.

Dr. Walter, M.D., Ph.D., is Assistant Member, Clinical Research Division at the Fred Hutchinson Cancer Research Center and Associate Professor Medicine, Division of Hematology at the University of Washington.
Under terms of Amphivena’s ongoing agreement with Janssen Biotech, Inc. (Janssen), Janssen has the exclusive right to acquire Amphivena following approval of an Investigational New Drug (IND) application. As part of the agreement, Janssen has provided Amphivena with an initial upfront payment, as well as contingent payments to Amphivena based on achievement of predetermined milestones.

About AMV-564

AMV-564 is one of Amphivena’s proprietary first-in-class, tetravalent, bispecific TandAb antibodies. The novel immunotherapy recruits T-cells to eliminate cancer cells that express CD33, a receptor that is expressed on the majority of acute myeloid leukemias (AMLs) and is present on other hematologic malignancies. AMV-564 is bivalent for both CD33 on AML cells and CD3 on T-cells, forming a T-cell activating complex in the presence of target cancer cells. By maintaining the avidity for antigen as found in typical monoclonal antibodies, AMV-564 mediates potent and efficient tumor cell lysis. AMV-564 also offers pharmacokinetic advantages over smaller, monovalent bispecific constructs due to a molecule size that exceeds renal clearance limits. Amphivena is currently completing IND-enabling studies to advance AMV-564 into clinical development as a treatment for AML.

On June 1, 2015 Merck reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in multiple, difficult-to-treat cancers, including advanced small cell lung cancer (SCLC), esophageal cancer and ovarian cancer from the KEYNOTE-028 Phase 1b study (Press release, Merck & Co, JUN 1, 2015, View Source [SID:1234505182]). These data, which were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, May 29 – June 2, 2015, build upon Merck’s broad and fast-growing immuno-oncology clinical development program for KEYTRUDA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The breadth and depth of the data being shared at ASCO (Free ASCO Whitepaper) reinforces the potential for the broad clinical activity that we have seen with KEYTRUDA in multiple types of cancer," said Dr. Roy Baynes, senior vice president and head of global clinical development, Merck Research Laboratories. "Our goal is to help people with cancer and these data are furthering our understanding of which patients may be more likely to benefit from our anti-PD-1 therapy."

As of ASCO (Free ASCO Whitepaper), data presented has demonstrated anti-tumor activity with KEYTRUDA in 13 different tumor types. Registrational trials are planned or ongoing in eight different tumor types, as monotherapy and in combination with other therapies. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and is currently indicated at a dose of 2 mg/kg administered every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Please see below for complete indication and selected safety information for KEYTRUDA.

About the KEYNOTE-028 Phase 1b Study

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study evaluated patients with PD-L1 positive advanced solid tumors that have not responded to current therapy or for which current therapy is not appropriate.

Early Findings from Advanced Small Cell Lung Cancer Cohort (Abstract #7502)

These early findings from 20 heavily pre-treated patients with advanced SCLC, presented on Saturday, May 30 by Dr. Patrick Ott, Dana-Farber Cancer Institute, demonstrated an overall response rate (ORR) (confirmed and unconfirmed) of 35 percent (n=7/20) (95% CI, 15-59) (per RECIST v1.1). At the time of the analysis, six of seven responses were ongoing. The median follow-up duration for evaluable patients was 21 weeks (range, 2-48). Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 14 patients. Grade 3-4 investigator-assessed, treatment-related adverse events were asthenia (n=1) and blood bilirubin increased (n=1). Some patients experienced adverse events of special interest, including autoimmune thyroiditis (n=1, Grade 2) and colitis (n=1, Grade 5). There was one treatment-related death (colitis).

Early Findings from Advanced Esophageal Cancer Cohort (Abstract #4010)

These early findings from 23 heavily pre-treated patients with advanced esophageal cancer, presented in a clinical science symposium on Sunday, May 31 by Dr. Toshihiko Doi, National Cancer Center Hospital East, Kashiwa, Japan, demonstrated an ORR (confirmed and unconfirmed) of 30.4 percent of patients (n=7/23) (95% CI, 13.2-52.9) (per RECIST v1.1). In patients with squamous cell carcinoma, the ORR was 29.4 percent (n=5/17) and in patients with adenocarcinoma, the ORR was 40 percent (n=2/5). The median duration of response was 40 weeks (0.1+ to 40), with six of seven responses ongoing. Tumor shrinkage was achieved in 52.2 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in nine patients. All investigator-assessed, treatment-related adverse events were Grade 3 and included lymphocyte count decreased (n=2), decreased appetite (n=1), liver disorder (n=1), and pruritic rash (n=1). Some patients experienced adverse events of special interest (Grade 2), including hypothyroidism (n=2) and adrenal insufficiency (n=1). There were no treatment-related deaths.

Early Findings from Advanced Ovarian Cancer Cohort (Abstract #5510)

These early findings from 26 heavily pre-treated patients with advanced ovarian cancer, which will be presented in a clinical science symposium on Monday, June 1 by Dr. Andrea Varga, Gustave Roussy Institute, Villejuif, France, demonstrated an ORR (confirmed and unconfirmed) of 11.5 percent of patients (n=3/26) (95% CI, 2.4-30.2) (per RECIST v1.1). Additionally, there was a disease control rate (DCR) of 34.6 percent (n=9/26) (95% CI, 17.2-55.7). At the time of the analysis, the median duration of response had not been reached (27.9-36.3). Tumor shrinkage was achieved in 23 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 18 patients. One Grade 3-4 treatment-related adverse event occurred (transaminases increased). Some patients experienced adverse events of special interest, including hyperthyroidism (n=2), hypothyroidism (n=3), myositis (n=1) and pancreatitis (n=1). There were no treatment related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) 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 in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks 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.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. 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 for signs and symptoms of hypophysitis. 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.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, 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.

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.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, 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.

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.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥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.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In 2012, there were an estimated 1.8 million new cases of lung cancer diagnosed worldwide. SCLC accounts for about 10-15 percent of all lung cancer cases.

About Esophageal Cancer

Esophageal cancer is a type of cancer that begins in the inner layer (mucosa) of the esophagus and grows outward. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. In 2012, there were an estimated 456,000 new cases of esophageal cancer and 400,000 esophageal cancer deaths worldwide, making it the eighth most common cancer.

About Ovarian Cancer

Ovarian cancer is a type of cancer that begins in the ovaries. There are three main types of ovarian tumors: epithelial ovarian tumors, ovarian germ cell tumors, and ovarian stromal tumors. In 2012, there were an estimated 239,000 new cases of ovarian cancer and 152,000 ovarian cancer deaths worldwide.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung and bladder cancer. High levels of PD-L1 expression are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.