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leaders ROUNDTABLE LIFESCIENCELEADER.COM NOVEMBER 2014 38 COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein I n this part and continuing in Part Four next month, we will hear from the leaders of many key companies in the field. Their stake in the race — or is it partnership? — consists of capital, real assets, and other forms of value, including people, knowledge, and a genuine desire to change the ugly vis- age of cancer. In many ways, each one's fate depends on what it does not only to compete against but also to cooperate with the other contenders. We have changed the roundtable for- mat here, from the question-by-ques- tion KOL discussion in Parts One and Two, to a company-by-company pre- sentation — a necessity, given the high number of responding companies. We did our best to invite and include all of the companies now developing cancer immunotherapies, chiefly in the new areas generating the most excitement in the oncology community: checkpoint inhibitors, co-stimulators, and comple- mentary immunostimulators such as cancer vaccines and ablative modali- ties that promote immune-cell produc- tion. We also hear from a few com- panies that believe other approaches deserve a place among the possible cancer immunotherapy combinations the roundtable addresses. T h e q u e s t i o n s w e a s ke d t h e p a n e l i s t s w e r e a s f o l l o w s : W h y c o m b i n a t i o n s ? Do you believe cancer immunotherapies should be used in combinations rather than as single agents, or is it possible to envision a single effective immunothera- peutic agent? E s s e n t i a l c o m p o n e n t s ? In your opinion, if cancer immunothera- py combinations are essential, what are the essential constituents of any combi- nation therapy? B a c k b o n e t h e ra p y ? Will a particular approach such as PD-1/ PD-L1 be the "backbone" of cancer immu- notherapy combinations? Or will consen- sus on a hierarchy of therapies continue yet been maximized in their benefit for patients. Combinations may maximize benefit and potentially enable cure. E s s e n t i a l c o m p o n e n t s ? Aim for synergistic pathways. Three main categories: 1) checkpoint modu- lators with each other to minimize immune suppression; 2) checkpoint modulators with other immunothera- pies to reduce immune suppression and specifically activate immune responses; 3) immunotherapies with targeted thera- pies to leverage immune effects and tar- geted therapy effects (e.g., speed of effect, debulking, immune modulation, etc.). B a c k b o n e t h e ra p y ? In the short term PD-1/PDL-1 and other checkpoint modulators, as they become available, will be the backbone of immu- notherapy combinations based on their clinical efficacy and safety profile and their universal utility. With further evo- lution of other immunotherapy modali- ties, this may shift slowly based on the demonstrated effects. C o m b o c r i t e r i a ? If approved and reimbursed, immuno- therapies will be selected for combina- tions based on their clinical benefit/ risk profile in the respective population. Research addresses rational combina- tion possibilities based on mechanis- tic synergies and characterization of immune effects of non-immunotherapy combination candidates. N a r r o w o r w i d e a p p l i c a t i o n s ? A wide range of benefits is possible depending on the combination; e.g., for targeted therapy/immunotherapy com- binations, most limitations are imposed by the targeted therapy. However, cur- rent development practices dictate development in histology-defined indi- cations. With demonstration of wide benefit across boundaries of histology, it may be possible to modify these stan- dards over time. P e r s o n a l o r b r o a d ? Immunotherapies should be as broadly to evolve with the growth of scientific understanding in ongoing research? C o m b o c r i t e r i a ? By what criteria will physicians select specific immunotherapy combinations for individual patients or patient groups? Or will regulatory and reimbursement realities dictate the combinations? N a r r o w o r w i d e a p p l i c a t i o n s ? Will the most effective immunotherapy combinations be specific to traditional cancer indications (NSCLC, HCC, etc.) or tend to have general effectiveness against all or a wide range of cancers? P e r s o n a l o r b r o a d ? Do you see limits on the practice model for cancer immunotherapies; i.e., will cell- based approaches remain restricted to a small number of patients in intensive- care or salvage settings? C o m m e r c i a l i z a t i o n c h a l l e n g e s ? What are some of the major hurdles you face in commercializing your cancer immunotherapy product or products, especially considering the science, regulatory pathway, and market are still evolving? G e n e ra l c o m m e n t ? Is there anything else that you believe is critical to understanding how combina- tion immunotherapy or another immu- notherapeutic approach will move into use as the backbone of cancer therapy? T h e f o l l o w i n g a r e t h e r e s p o n s e s : f r o m t h e c o m p a n y l e a d e r s : G L AXO S M I T H K L I N E In early development of numerous cancer immunotherapy candidates with a variety of mechanisms. AXEL HOOS, M.D., PH.D. Vice President, Oncology R&D; W h y c o m b i n a t i o n s ? Some immunotherapies have proven effective as single agents. They have not