Over the past decade, drug developers have sought to enhance the efficacy of Immune Checkpoint inhibitors by using these in combination with other Checkpoint Inhibitors, chemotherapies, small molecules and/or cell therapies. Some of these therapies with of immune-checkpoint inhibitors in combination with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are underway to test new combinations.

Adam C. Palmer, Ph.D., Department of Pharmacology, Computational Medicine Program, UNC Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The fact is, that Immune Checkpoint inhibitors are very widely used in the treatment of cancer. They included drugs like pembrolizumab (Keytruda®; Merck & Co) and nivolumab (Opdivo®; Birstol Myers Squibb).

Immune Checkpoint inhibitors 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.

Combination therapies
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.

“Undoubtedly, combining Immune Checkpoint Inhibitors 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,” noted Jessica McCormack, Ph.D., Oncology and Hematology Analyst at GlobalData.

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“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,” McCormack added.

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, pembrolizumab is the most investigated molecule, but there are regional differences, with the Chinese domestically-developed PD-1 inhibitor camrelizumab (AiRuiKa™; Jiangsu Hengrui Medicine Co), a programmed cell death 1 (PD-1) inhibitor which received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma and is being investigated as a potential treatment option for patients diagnosed with various other malignancies, including B cell lymphoma, oesophageal squamous cell carcinoma, gastric/gastroesophageal junction cancer, hepatocellular carcinoma, nasopharyngeal cancer and non-squamous, non-small cell lung cancer, featuring in most trials in China.

Exploring novel combinations is an important strategy for pharmaceutical companies, which will begin facing patent expiries of the leading Immune Checkpoint Inhibitors in the coming decade.

Clinical trials with Immune Checkpoint Inhibitors: Mono and Combination Trials per Phase and Region. Source: GlobalData, Pharma Intelligence Center

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 was suggested.[1]

This conclusion is confirmed by researchers in the Department of Pharmacology, Computational Medicine Program, UNC Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina who noted that combining ICIs with other cancer therapies affords predictable and clinically meaningful benefits by providing patients with multiple chances of response to a single agent, however, there exists no evidence in phase III trials that other therapies interact with and enhance the activity of ICIs. And while these findings can inform the design and testing of new combination therapies with immune Checkpoint Inhibitors while emphasizing the importance of developing better predictors (biomarkers) of Immune Checkpoint Inhibitor response, they also are raising questions about concurrent versus sequential therapy or the need for drug combinations in all patients.[1]

The findings further suggest that the focus of translational research into Immune Checkpoint Inhibitors needs to shift from studying drug interaction in atypically sensitive animal models to understanding why response is so variable in humans and how it can be predicted at the level of individual patients.[1]

“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,” McCormack concluded.

Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co)(Prescribing Information)
Nivolumab (Opdivo®; Bristol Myers Squibb/BMS) (Prescribing Information)
Camrelizumab (AiRuiKa™; Jiangsu Hengrui Medicine Co)

[1] Palmer AC, Izar B, Hwangbo H, Sorger PK. Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors. Clin Cancer Res. 2022 Jan 15;28(2):368-377. doi: 10.1158/1078-0432.CCR-21-2275. PMID: 35045958.

Featured Image: Scientist at work in a laboratory. Photo Courtesy: © 2016 – 2022 Fotolia/Adobe. Used with Permission.

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