Do Immune-Based Cancer Drugs Work Better in Men?

December 3, 2021
Ernie Mundell and Robert Preidt HealthDay Reporters

Women are two times more likely than men to die after receiving a combination of cancer immunotherapy drugs called checkpoint inhibitors, but it's not clear if that difference is due to side effects or because the treatment isn't working, researchers say.

This new class of highly targeted drugs -- which includes pembrolizumab (Keytruda), nivolumab (Opdivo) or ipilimumab (Yervoy) -- has revolutionized cancer care. They work by triggering the immune system to combat cancer, but they can also cause severe, sometimes life-threatening side effects, researchers at Thomas Jefferson University in Philadelphia explained.

Gender might also play a role in patient outcomes, the new research showed.

"This is the first large population-based study that demonstrates a significant difference in outcomes for women treated with two checkpoint inhibitors at the same time," said senior author Grace Lu-Yao. She's associate director for population science at the Sidney Kimmel Cancer Center at Jefferson Health.

For the study, Lu-Yao's group analyzed data from more than 1,300 patients who were diagnosed with advanced melanoma skin cancer between 1991 and 2015. All were treated with one or several checkpoint inhibitors, such as pembrolizumab, nivolumab or ipilimumab.

There were no differences in survival between men and women treated with a single checkpoint inhibitor, but the risk of death more than doubled for women compared to men when a combination of nivolumab and ipilimumab was used.

The baseline rate of death for both men and women taking PD-1 inhibitors (checkpoint inhibitor drugs that target the PD-1 protein, such as pembrolizumab and nivolumab) was 40%, the study found.

However, for those who received a combination of both anti-PD1 and anti-CTLA-4 inhibitors (such as ipilimumab), the death rate remained at 40% for men but jumped to 65% for women, according to the study published online Dec. 2 in JAMA Network Open.

"Are women more likely to die because the therapy isn't working, or because of side effects? We don't know yet, but this is a powerful signal in real-world data that we need to investigate further," Lu-Yao said in a university news release.

There are slight differences in male and female immune systems, the study team noted. For example, women are at greater risk of autoimmune diseases, but also tend to have stronger immune responses against infection than men.

Despite these known differences, men are over-represented in clinical trials of cancer immunotherapy. When trial results are analyzed it's often assumed that findings apply similarly to women, but that may not be the case, the researchers said.

"This data is a wake-up call based on the experience of hundreds of patients on these drugs," Lu-Yao said. "This real-world data demonstrates that the results derived from men might not be applicable to women and it is critical to design studies with sufficient power to evaluate treatment effectiveness by sex."

Dr. Michele Green is a dermatologist who treats skin cancers at Lenox Hill Hospital in New York City. She wasn't involved in the new research, but said it "underlies a very important element to researching cancer treatments in general, and in this case advanced malignant melanoma."

The finding that survival was poorer for women with certain drug combinations "is very important," Green said, "as men and women may have different outcomes and may not be able to be given the same treatments for the same diseases."

It all comes back to the need for gender parity in clinical trials, she believes.

"When future trials of new medications or drugs are performed, gender must be included in these studies, since men and women can have different outcomes from the same treatment," Green said.

Study author Lu-Yao and her team said they plan to investigate whether the findings seen in this group of melanoma patients are echoed in patients with other types of cancers.

More information

The American Cancer Society has more on immunotherapy.

SOURCES: Michele S. Green, MD, dermatologist, Lenox Hill Hospital, New York City; Thomas Jefferson University, news release, Dec. 2, 2021

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