## 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 

Commercialization, Oncology. “We are now talking about longer-term survival, providing high value for patients and for society.” 

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. 

“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.” 

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 

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 

