Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Abstract

Background Immune‐related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti‐programmed cell death protein 1 (PD‐1) therapy. Materials and Methods All patients with metastatic melanoma and non‐small cell lung cancer (NSCLC) treated with anti‐PD‐1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan‐Meier method and log‐rank test was used for time‐to‐event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression‐free‐survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune‐related adverse events (irAEs) compared with men when treated with anti‐programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow‐up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment‐related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

Sex differences in cancer mechanisms

“…It has also been shown that tumor mutational burden, rather than PD-L1 expression, has a much better predictive power for female response to ICI compared to male response, in lung cancer patients [322]. Furthermore, women experience more immune-related adverse effects compared with men during treatment with anti-PD-1 drugs [323].…”

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

“…7 Studies so far investigating determinants of anti-PD(L)1 toxicity were of limited sample size with a median of 78 patients at risk (IQR 50-128). [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Here we analysed whether demographic and disease-specific patient characteristics present at start of treatment were associated with an increased risk of severe irAEs using a large dataset from our nationwide melanoma treatment registry.…”

Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients

“…We were also interested in testing sex differences considering it is well known that adult females have stronger innate and adaptive immune responses than males 22 , which theoretically could translate into differential effects of immune system checkpoint inhibitors. A previous retrospective study found that only 12% of male metastatic melanoma discontinued therapy (pembrolizumab or nivolumab) due to immune-related adverse events, compared to 23% of women 23 . In our study, we were unable to detect sex differences in the time to therapy discontinuation.…”