A research team from Cleveland Clinic Genomic Medicine share insights from an early set of 19,000 patients to receive immune checkpoint inhibitor treatments for colorectal cancer in the U.S.

The report comes from the laboratory of Stephanie Schmit, PhD, MPH, and was published in JAMA Network Open. It serves as an opportunity to better understand how immune checkpoint inhibitor treatments, including PD-1 and PD-L1 inhibitors, work in a larger population that reflects real-world settings. Dr. Schmit collaborated with a team of researchers that included Moffitt Cancer Center.

The results showed immune checkpoint inhibitors greatly improved survival rates for patients living with metastatic microsatellite instable (MSI-H) colorectal cancer, in line with clinical trials. Investigators also found certain conditions that may improve the therapy’s effectiveness against a specific type of difficult-to-treat tumour called a microsatellite stable (MSS) tumour under certain conditions, building on the initial clinical trial results.

“Because clinical trials have strict inclusion criteria, their findings are not always generalisable to the greater population,” says data scientist and study first author Marco Matejcic, PhD. “We wanted to ensure that the treatment works the same in routine clinical practice as it did in clinical trials. There is always a possibility that there are factors unexamined in clinical trials that may influence treatment outcomes.”

Immune checkpoints act as a brake to keep immune cells from attacking normal, healthy cells. Immune checkpoint inhibitors work to remove this brake, which boosts the immune system’s ability to attack tumours and other cancerous cells.

Immune checkpoints can include molecules located on the surface of immune cells that act as "scanners”, and molecules located on the surface of all other healthy cells that act as “barcodes.” If a cell does not have immune checkpoint proteins it is generally either unhealthy or a pathogen, so the immune system will attack it.

Many colorectal cancer tumours have specific mutations that let them produce and display a lot of immune checkpoint proteins. In this way, the tumour can disguise itself as a normal, healthy part of the body.

In 2017, the FDA approved six immune checkpoint inhibitors to be used for treatment of colorectal cancer patients with MSI-H tumours. The therapies had great success as a treatment for metastatic colorectal cancer in clinical trials, but the study team used an international database from healthcare technology company Flatiron Health to learn how a large group of patients responded to the treatment in typical, routine clinical practice.

Dr Matejcic, who works in Dr Schmit’s lab, teamed up with co-first author Shahla Bari, MD, an oncologist who formerly worked at Moffitt, to analyse electronic health records of almost 19,000 individuals who received treatment for their colorectal cancer between 2013 and 2019. He analysed the records to identify factors that correlated with a specific treatment outcome for patients treated with or without the immune checkpoint inhibitors.

The team’s results supported the earlier clinical trial findings, showing that immune checkpoint inhibitors greatly improved survival rates for patients living with MSI-H metastatic colorectal cancer.

Interestingly, they also identified different factors that could influence how well the treatments worked in patients with MSS tumours. MSS tumours are generally not very responsive to immune checkpoint inhibitor therapy, so the FDA currently approves the treatment for MSI-H tumours.

“While most of the individuals with MSS tumours we observed responded poorly, there actually were some MSS tumours with durable responses,” Dr. Schmit says. “Factors like enzyme levels, microbiome activity, additional medications and more each played a small role in determining an MSS tumour’s response to immune checkpoint therapy, though we can’t make any specific recommendations until we do more research.”

Many physicians prescribe chemotherapy or immunotherapy based on their patient’s tumour status. Because individuals with MSS tumours did not respond as well to the therapy in clinical trials, physicians are less likely to prescribe immune checkpoint inhibitors to these patients. The researchers' additional findings indicate there are more options.

“Our study may provide new guidelines/changes in guidelines for MSS tumors that have generally been unresponsive to immune checkpoint inhibitors in clinical trials, although our findings need to be replicated in larger studies,” Dr Matejcic says. “We hope that our findings will contribute to improving the survival outcome of MSS colorectal cancer patients who are currently unresponsive to immunotherapy.”