2012 Annual Report 14 Bristol-Myers Squibb  Immuno-Oncology Over the past several decades, surgery,  radiation, chemotherapy or targeted  agents have represented the existing  pillars of cancer treatment. But, for  many with advanced cancer, long-term  survival accompanied by a positive  quality of life has remained an elu- sive goal. To find new approaches in  treatment and to address this unmet  medical need, Bristol-Myers Squibb is  committed to advancing the science of  immuno-oncology and to developing an  innovative portfolio of cancer immuno- therapies in a broad range of tumors.  Immuno-oncology is a rapidly evolv- ing innovative treatment modality that  offers the possibility of revolutionizing  cancer treatment by directly target- ing the immune system – in effect  harnessing the patient’s own immune  system to fight cancer. As researchers  learn more about how cancer evades  the immune system, we recognize  the potential for immuno-oncology  drugs to work in multiple tumor types,  change survival expectations and the  way patients live with cancer. New data continue to emerge on  Yervoy  (ipilimumab), our company’s  first cancer immunotherapy. Five-year  follow-up results from three explor- atory studies presented at a scientific  meeting in September 2012 added to  the growing body of long-term survival  data for  Yervoy  in metastatic mela- noma. The data confirmed what most  of those working with  Yervoy  already  had come to believe.  “ Yervoy  raised the bar on what it  meant to be successful in treating  metastatic melanoma,” says Robert  LaCaze, senior vice president, Global  Our challenge is to increase the  number of people who can benefit from  Yervoy  through dosing optimization,  sequencing or combinations. Currently  a study is underway to understand the  most efficacious monotherapy dose –  3 mg/kg (currently approved) or 10 mg/ kg – to increase patient survival.  Yervoy is also in Phase III trials in prostate  and lung cancers and in earlier trials in  gastric and ovarian cancers, alone and  in combination with other therapies.  Finally,  Yervoy  is being investigated in  the adjuvant setting, administered after  surgical removal of the melanoma but  before the cancer has had a chance to  spread to other organs, to see if  Yervoy “We are proud to have established  immune-based therapies as a new  modality of effective cancer treatment,  working with the patient’s own immune  system rather than just on the tumor as  occurs with standard approaches,” says  Michael Giordano, M.D., senior vice  president and head of Development for Oncology and Immunosciences.  “ Yervoy  is the first of what will be a  portfolio of cancer immunotherapies  from our company that work in different  parts of the immune system’s biologic  pathways to enhance the body’s own  ability to kill cancer cells. This is unique  from the other therapies we use today.”  Indeed, the introduction of  Yervoy in the U.S. and Europe represents  one of the most successful oncology  launches in the past decade as more  countries approve  Yervoy , creating  more access for patients. Commercialization, Oncology. “We are  now talking about longer-term survival,  providing high value for patients and  for society.”  can actually prevent a relapse into meta- static melanoma.  The next wave of the company’s cancer  immunotherapy investigational com- pounds, Giordano says, begins with  nivolumab (BMS-936558, anti-PD-1),  which in 2012 started five Phase III  registrational studies in difficult-to-treat  cancers: lung cancer, melanoma and  renal cell cancer. In earlier studies,  nivolumab showed durable responses  with acceptable safety data. “As we  think about improving patient outcomes,  we think a new frontier will be to com- bine or sequence different immunothera- pies,” he adds. “That’s where nivolumab  could possibly play a role. Initially, if  approved, we believe it may be used as  a stand-alone therapy, but potentially it  could be given with other treatments or  administered in a sequence.” Nils Lonberg, Ph.D., senior vice president,  Biologics Discovery California, explains  how these agents work. “By targeting  CTLA-4,” he says, “a protein that normally  helps keep immune system cells in check,  Yervoy  unblocks immune responses to  tumor cells to increase the number of  T-cells that recognize and attack can- cers. Nivolumab acts on another nega- tive signaling molecule by targeting the  PD-1 receptor, which otherwise renders  inactive immune system T-cells that could  destroy cancer cells. By blocking PD-1,  we reactivate these T-cells.” Nivolumab  was discovered at Medarex, which Bristol- Myers Squibb acquired in 2009. Medarex  researchers also found synergies between  PD-1 and CTLA-4, leading to early stud- ies combining  Yervoy  and nivolumab.  Those trials are ongoing.  Because Bristol-Myers Squibb is break- ing new ground in immuno-oncology, in 