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leaders LIFESCIENCELEADER.COM JANUARY 2015 28 ROUNDTABLE leaders other biomarker technologies as well, such as DNA or RNA-based biomarkers. Narrow or wide applications? With our drug, like others, we are find- ing there are patients with every cancer type who respond. Again, although it is not 100 percent of patients, it is clear that even a single agent is capable of having a response in individual patients with a wide variety of cancer types. F I V E P R I M E T H E R A P E U T I C S Preclinical development of immunotherapies in cancer and other areas. BRIAN WONG, M.D., PH.D. Vice President, Research and Head of Immuno-Oncology Why combinations? Tumors are thought to frequently upreg- ulate multiple immune checkpoints to escape destruction by the immune system, and for that reason, it may be more efficacious in many tumor settings to use combinations of immunotherapies. Indeed, early clinical data with ipilim- umab plus nivolumab (anti-PD-1) suggest that the combination is more effective than ipilimumab alone in the treatment of advanced melanoma. Five Prime will initiate a clinical trial next year combining FPA008, our antibody targeting tumor- associated macrophages (TAMs), with BMS's nivolumab in six cancer indica- tions. TAMs are emerging as key cell types that suppress antitumor immunity. Essential components? This will be specific to each patient's tumor, and molecular profiling of the dys- regulated immune checkpoints will likely be needed to determine the optimal com- bination regimen of immunotherapies to use against the specific cancer in that patient. Two or more checkpoints could be targeted simultaneously by multiple drugs with single specificities, or drugs with multiple specificities such as bispe- cific antibodies could be developed. In M E R C K (Known as MSD outside the United States and Canada) Now marketing an FDA-approved PD-1 inhibitor, Keytruda (pembrolizumab) for advanced melanoma, Merck is pursuing a broad research and development program in immuno-oncology with Keytruda leading the company's research efforts. ERIC RUBIN, M.D. Vice President, Oncology Clinical Research Why combinations? Combinations should be studied, but in certain patients a single agent will be sufficient. That is shown by our data in melanoma, where many of our respond- ing patients have remained in remission at the two-year mark. Though they are not a majority of patients, it is a significant portion. For those patients, there may be no need for additional agents, and that will probably be true of other cancers as well. Essential components? The notion of combination therapy in can- cer is not new, and the lessons from that longtime standard of care can help guide choices of combinations in immunotherapy. Mechanism-based combinations should be prioritized. Given our understanding of the PD-1/PD-L1 pathway, what are the logical drugs we should bring in to combine with an agent like ours? We would need agents that contribute to the synergistic improvement in efficacy of the anti-PD-1 drug without a lot of additional toxicity. There are a number of companies now developing other immuno- therapy approaches they believe will be com- plementary to our agent, and I spend a lot of time talking with such companies. The focus in cancer now is on immunotherapy, as it has been with other areas such as molecular- pathway targeting. Backbone therapy? I do believe anti-PD-1/PD-L1 will be the backbone approach for some time to come. With the extraordinary results we have seen with these agents — many now have breakthrough designations as we do with pembrolizumab in melanoma and lung cancer — it does not seem likely in the near term something else will come in to displace anti-PD-1/PD-L1. There are other checkpoint inhibitor targets under investigation; maybe in a number of years we will see something with results that eclipse those we have with our approach, but for now that is unlikely, and anti-PD-1/PD-L1 will be the backbone immunotherapy. Combo criteria? Although our understanding of the mechanisms of PD-1/PD-L1 in patients is limited, there is an increasing knowl- edge in this space that would allow rational, mechanism-based decisions on what to include in combinations. That would primarily be other immunothera- pies, but there is increasing data that other agents such as chemotherapies can alter the tumor microenvironment in advantageous ways for an anti-PD-1 agent, increasing the immuno-antigen repertoire. Epigenetic inhibitors might also be attractive candidates. That said, some of our best combinations in cancer treatment were discovered somewhat empirically. So we and others will take a broad approach to looking at combi- nations. Much of this will have to be sorted out in the clinic and in randomized clinical trials. Biomarkers add another level of com- plexity. We are interested in applying PD-L1 as a biomarker, because higher levels of PD-L1 expression correspond to higher levels of response, though it is clear some patients with low PD-L1 expression also respond. Our registra- tion trials in lung cancer use an "enrich- ment design," which requires some PD-L1 expression in the tumor for the patient to be eligible. There is an anal- ogy to Herceptin, which may not have ever been approved without use of the HER-2 biomarker in its pivotal trial — to ensure maximum benefit in the selected patient population. That can accelerate initial approval; then we can go back and understand whether we can extend use of the drug to some patients with low biomarker levels. We are also investigating COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein