Increasingly, over the past decade pharmaceutical companies have sought to enhance the efficacy of Immune checkpoint inhibitors (ICIs) by using these in combination with other ICIs, chemotherapies, small molecules or cell therapies says GlobalData, the leading data and analytics company.

ICIs are very widely used in oncology and include blockbuster drugs Merck & Co.’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab). ICIs inhibit immune checkpoint molecules that would otherwise dampen down an immune response by switching off T-cells. The hope is that they enhance the patient’s own immune response to a tumor by preventing this dampening down process.

It has been hypothesized that the addition of the combination drug could enhance tumor immunogenicity, and therefore improve overall response rates. However, recent analysis from researchers at Harvard Medical School suggests that positive results may not necessarily be attributed to synergistic activities.

Jessica McCormack, PhD, Oncology and Hematology Analyst at GlobalData, comments: “Undoubtedly, combining ICIs with another therapy has shown great results in many trials. It is important to note that synergism is not a prerequisite for success since the use of multiple therapies can increase the likelihood that a patient will receive a therapy that works for them, but there are downsides to this approach.

“Typically, combination regimens are more toxic, meaning they may not be suitable for all patients, or patients may be more likely to need to skip doses. Secondly, the addition of multiple therapies increases the total cost of therapy dramatically. The burden on healthcare systems for oncology therapeutics is already considerable.”

Approximately, 90% of ongoing or planned Phase II to III clinical trials in the US, Europe, and China are combination trials. This figure is relatively stable between regions. Overall, Keytruda  is the most investigated molecule, but there are regional differences, with the Chinese domestically-developed PD-1 inhibitor camrelizumab featuring in the most trials in China. Exploring novel combinations is an important strategy for pharmaceutical companies, which will begin facing patent expiries of the leading ICIs in the coming decade.

While efficacy has been demonstrated in many cases, whether this combination approach results in synergistic activity has not been clear. New data now suggests that in fact efficacy is most often derived from the activities of the individual drugs. In just one of the 13 Phase III trials investigated by the researchers was a synergistic effect suggested.

McCormack concludes: “It will be interesting to see how the Harvard group’s model holds up over a larger sample size, and if it does, if this could impact the strategies of pharmaceutical companies regarding clinical trial design. Any sort of predictive model that could estimate expected response rates of combinations based on the individual drugs’ activities could be highly useful for companies looking to the future.”