Immunotherapy Outcomes May Be Better in Older Patients With Melanoma

Older patients with melanoma may respond better to anti-PD-1 immunotherapy treatment than their younger counterparts, according to a recent study published in Clinical Cancer Research, a journal from the American Association for Cancer Research.

Researchers collected melanoma tissue samples from 538 patients from the United States, Australia and Germany. The samples were then divided into two categories: those belonging to people over the age of 62 and those belonging to people younger than 62. All of the patients were treated with the immunotherapy agent, Keytruda (pembrolizumab), which targets and blocks PD-1, making the immune system more likely to identify and attack cancer cells.

Since the study included patients from different parts of the world, it eliminated constitutional bias, taking out factors that could differ between nations — or even treatment centers – such as the methods used to treat patients and administer drugs. The findings were consistent across the board, adding validity to the findings.

Ultimately, the researchers saw a 13 percent decrease of disease progression for every decade of patient age when treated with Keytruda. Half of those under 62 saw seeing no benefit compared to only 37 percent of the older population.

“We were very surprised at the findings,” said Ashani T. Weeraratna, Ph.D., Ira Brind Professor, Co-Program Leader, Immunology, Microenvironment and Metastasis, Melanoma Research Center, The Wistar Institute in an interview with CURE.

A few years ago, Weeraratna conducted research on the differences in outcomes between patients with melanoma treated with a BRAF-targeted agent. In the previous study, she found that younger patients did much better, so she expected similar results when it came to PD-1 inhibition.

But this is not the first study stating that age should not be a determining factor in administering immunotherapy to patients with melanoma.

A mouse model paralleled the human portion of the study and replicated the findings that older female mice (10 months old) had better responses to anti PD-1 therapy than younger female mice (2 months old). The mouse model also showed that tumor mutational burden may not be as important in predicting response, as genetically identical tumors were assigned to young and old mice alike.

“We wanted to know why. It’s one thing to just report the data that older patients respond better, but as a scientist, you want to ask why. Mouse models allowed us to see what in the immune system was changing in the older mice and the younger mice and the tumor microenvironment,” Weeraratna said.

The mouse model showed that T regulatory cells (called Tregs) actually increased in the tumor microenvironment of older mice, making it a better target for immunotherapy.

Since previous studies have shown that older patients do more poorly on chemotherapy — in part due to its toxicities – these findings can lay the groundwork for an exciting new treatment modality for this patient population.

“Our dataset showed that younger patients might have a larger number of toxicities,” Weeraratna said.

Immune-related adverse events are common in patients who receive immunotherapy, regardless of the age. This is because immunotherapy agents such as Keytruda activate a patient’s immune system, which could cause a patient to feel like he or she has the flu. But more severe side effects, such as gastrointestinal issues, must be reported to the health care team as soon as possible.

Looking forward, these findings might lay the groundwork for future studies exploring checkpoint inhibitors in different patient populations.

“What was exciting was, even taking into account the limitations of the study, the results were remarkably consistent. Because we were able to deplete the Tregs in the mice and show that they responded the same way to older mice, it tells us that this can be something we can think about targeting in the future,” Weeraratna said.