As immunotherapy moves to first-line cancer therapy, it is important to understand the long-term consequences of these agents and who is at higher risk of developing high-grade adverse events.


Immune-related adverse events (IRAEs) have emerged as a serious clinical problem with the use of immune checkpoint inhibitors in the treatment of various types of cancer; however, the cause of, and risk factors for, these potentially life-threatening adverse events remain unknown.

“Compared with men, women are more likely to develop autoimmune disorders, ranging from auto-immune hypothyroidism to systemic lupus erythematous, due to stronger innate and adaptive immune responses,” says Narjust Duma, MD. “With the introduction of immune checkpoint inhibitors to the cancer treatment armamentarium, immune-related events have become commonly seen adverse events in the clinic. A recent meta-analysis suggested that gender may influence the magnitude of benefit from these agents, but data regarding gender differences in tolerability to anti-PD1 therapy—a form of checkpoint inhibition—is lacking.” For a study presented at the 2018 ASCO Annual Meeting, Dr. Duma and colleagues assessed gender differences in tolerability to anti-PD1 therapy.


Key Findings

The researchers identified all patients with metastatic melanoma who were treated with anti-PD1 therapy at the Mayo Clinic from 2014 to 2017. Patients were reviewed individually, and those with ocular melanoma, prior treatment with ipilimumab, or history of autoimmune disorders were excluded. Although the goal was to study an overall homogenous population, a disproportionate number of women were admitted to the hospital for IRAEs, ranging from colitis to diabetic ketoacidosis. Data regarding demographics, tumor characteristics, response to therapy and all adverse events were collected. The cohort was separated into pre-menopausal (younger than 52) women, post-menopausal women, and men, who were compared based on IRAE rates.

Among participants, 60% were men, 12% were premenopausal women, and 27% were postmenopausal women. Baseline characteristics were similar among groups (Table). Premenopausal women were more likely to experience IRAEs (67%) than both postmenopausal women (60%) and men (46%). Premopausal women were also more likely than men to experience endocrinopathies (35% vs 10%) and cutaneous reactions (25% vs 15%). All cases of diabetic ketoacidosis were observed in premenopausal women. No differences in grade 3 or greater toxicities were observed across groups. Patients with IRAEs were more likely than those without IRAEs to have a radiographic response to anti-PD1 therapy regardless of gender (68% vs 44%).

“Pre-menopausal women with metastatic melanoma were more likely to develop IRAEs and discontinue treatment due to toxicity,” says Dr. Duma. “We also observed improved progression-free survival in male patients who experienced IRAEs compared with male patients who did not develop these adverse events (16.5 months vs 9.7 months). Unfortunately, our sample of pre-menopausal women was small, limiting our opportunity to observe differences in progression-free survival between those with and without IRAEs.”


Looking Ahead

While Dr. Duma and colleagues observed significant gender-specific associations with IRAEs, she suggests that further research is needed before applying their findings to daily practice. “We want to bring attention to our observations to hopefully allow clinicians to better understand the gender-specific differences in IRAEs and consider closer monitoring to the patients who are at risk of these potentially life-threating adverse events,” says Dr. Duma.

Dr. Duma and colleagues are currently conducting further analyses and hope to conduct a large and prospective study that would help understand the risk factors associated with IRAEs. While they are expanding their study to include non-small cell lung cancer patients, other malignances have adopted anti-PD1 therapy as standard of care. Similar studies in renal cell carcinoma and head and neck malignancies, for example, would help shed more light on the role of intrinsic tumor characteristics and the development of IRAEs.

“The field of cancer therapeutics is advancing rapidly, with promising new agents and combinations,” says Dr. Duma. “As immunotherapy moves to first-line therapy, it is important to understand the long-term consequences of these agents and who is at higher risk of developing high-grade adverse events.