Immuno-oncology combinations: raising the tail of the survival curve

Abstract

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpointinhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An excitingcomponent of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control formany years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapythrough the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potentialrational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy ormolecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail onthe survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that mayarise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drugpharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novelimmunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistanceand the impact of immuno-oncology on early phase clinical trial design.