Combination immunotherapy: The latest revolution in cancer treatment

An analysis of the clinical landscape

The present focus in the treatment of cancer is immunotherapy, in particular immunotherapies that are trialed in a combination regimen. By combining immuno-oncology (IO) agents with other IO agents and/or standard of care (SoC) therapies, the aim is to expand the range of responders and to improve the quality and durability of clinical benefit in patients beyond what can be achieved with monotherapy alone. The promising future for immunotherapy combinations is resulting in an explosive, extensively evolving and complex clinical trial landscape.

Immunotherapy combinations have been of great interest in clinical trials in the recent years. Since its approval in 2011, the first checkpoint inhibitor ipilimumab has been increasingly tested in combination with other cancer treatments. Ipilimumab is an example of many other immunotherapies, which are progressively trialed in a combinatorial approach¹. There are even more combination regimens planned in the coming years. The vast possibilities of combining multiple agents results in a chaotic trial landscape. This uproar overwhelms even the most experienced clinical investigators², calling need for classification and structuring the complex landscape of the different combination approaches arises.

Allucent is specialized in early phase oncology trials as well as providing expert advice and strategic consulting in oncology drug development. The progress in the field of combination immunotherapies warrants a structured analysis of the field to keep on top of the changing scenery. In this study, SMS-oncology used secondary desk research to analyze this volatile landscape. GlobalData, a global competitive intelligence database, was used to gather the relevant information and analyze the clinical trial landscape to identify new developments in the vast field of combination immunotherapies. Data was collected from 776 combination immuno-oncology trials initiated between January 2014 until March 2018. All trials are categorized based on their modality and tumor type. With this extensive dataset, multiple parameters were analyzed to visualize interesting trends not limited to clinical trial design, sponsor type, tumor types and drug modality combinations. A small selection and broad overview of the whole analysis is presented in this blog.

The landscape analysis

The field of IO combinations trials has developed at an exponential rate in only a few years. The number of combination trials initiated in 2017 is almost six times the number of trials that started in 2014. These trials investigate 866 combinations of which 171 combination regimens are a unique combination of the categorized agents. Consequently, some trials investigate more than one combination and the same categorized combination can be investigated by multiple trials.

These unique combinations are displayed in figure 1, with the top 5 most studied combination visualized on the left. These five combinations dominate the landscape as they comprise over half of the total landscape. This means that the other combinations account for the other half of the field – the empty green squares. Furthermore, 60% of the unique combinations are only investigated once. These combinations are mostly complex regimens, for example cell-based therapies and cancer vaccines. Overall, ICI combinations strike as the most trialed combinations among all IO combinations. A staggering 80% of all trialed combinations including one or more ICIs.

These ICIs are investigated across all tumor types and mostly in lung cancer – more than one in five ICI combination trials are performed for lung cancer. When looking at other categories like cancer vaccines or cell based therapies, lung cancer is often not the most trialed tumor type. For example, results showed that cancer vaccines are trialed mostly for pancreas cancer, prostate cancer and CNS cancer. An overview of indications of the IO combination trials is displayed in figure 2.

Future developments

At this time, only 4% of the 766 trials are completed, which means that analysis of results regarding efficacy will be revealed in the next 5-year period. The effects on patients and tumor response regarding these combination regimens are other key elements to be analyzed in the coming years. Still, the outcomes of our research have given a tool to better understand the status and developments in combination immunotherapies. This knowledge is essential to guide the operational aspects of clinical trials such as the major contemporary trends in clinical trial design, duration and the use of immunotherapy modalities. Combining IO agents does not only result in a complex field but also affects clinical trial design at its core. Use of innovative clinical trial design might be the means to accelerate route of the right combination of agents to the right patients. These novel and complex designs require collaboration between sponsors to contribute multiple therapy options to one trial. Partners and governance of these trials are also of vital importance to ensure correct data use, handle publication rights and manage the timing of regulatory submissions³.

References

1. Ledford, H. The perfect blend; The next frontier in cancer immunotherapy lies in combining it with other treatments. Scientists are trying to get the mix just right. Nature; News Feature 2–4 (2016).
2. Tang, J., Shalabi, A. & Hubbard-Lucey, V. M. Comprehensive analysis of the clinical immuno-oncology landscape. Ann. Oncol. 29, 84–91 (2018).
3. Woodcock, J. & LaVange, L. M. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N. Engl. J. Med. 377, 62–70 (2017).