Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers

Abstract

IMPORTANCE Sex-associated differences in immune response are known, but a meta-analysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subsequent trials have placed these results in doubt.OBJECTIVE To perform an updated, comprehensive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex. DESIGN, SETTING, AND PARTICIPANTSA systematic review of studies (n = 23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was conducted. Randomized clinical trials that compared immunotherapy with standard of care in the treatment of advanced solid-organ malignant neoplasms were included if overall survival was reported as an outcome and if data stratified by patient sex were available. Observational studies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens, studies that reported other measures of oncologic response, and studies that reported subgroup analyses for 1 sex only were excluded. MAIN OUTCOMES AND MEASURESOverall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immunotherapy exists by patient sex.RESULTS This meta-analysis included 23 randomized clinical trials that reported on 9322 men (67.9%) and 4399 women (32.1%); the age of most patients was in the 70s. An overall survival benefit of immunotherapy was found for both men (hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002). Random-effects meta-analysis of study-level differences in response to immunotherapy demonstrated no statistically significant difference between the sexes (I 2 = 38%; P = .60). Subgroup analyses according to disease site, line of therapy, class of immunotherapy, study methodology, and representation of women recapitulated these findings. CONCLUSIONS AND RELEVANCEStratified analyses demonstrated no statistically significant association of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome.

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?

“…The pooled reduction of risk of death was double the size for male patients compared with female patients. However, a recent systematic review conducted by Wallis et al of 23 randomized ICI clinical trials demonstrated no statistically significant association between sexes and response to therapy. Although these studies are hypothesis generating, the use of patients’ individual data could provide us with more specific answers and include other factors such as comorbidities and health care delivery characteristics that were not accounted in these meta‐analyses.…”

Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non‐small cell lung cancer

“…In the study of only included OS analysis performed by Conforti and colleagues, the pooled overall survival HR was lower from six RCTs of 3482 patients in male patients than female patients . Recently, Wallis et al found in the subgroup analysis of 11 RCTs including 4520 men and 2125 women that female had the better OS benefit from immunotherapy compared to male in NSCLC . Small sample sizes may lead to an increased false discovery rate or even false‐positive outcomes.…”

“…Five different meta‐analysis have been reported to investigate the efficacy of immune checkpoint inhibitors according to the sex of cancer patients . In the previous meta‐analysis conducted by Botticelli and colleagues, there was no significant improvement of overall survival in male cancer patients treated with anti‐PD‐1 or anti‐CTLA‐4 antibodies.…”

“…However, Graham et al presented that no difference in survival advantages for both men and women receiving the immune checkpoint inhibitors in patients with metastatic renal cell carcinoma . Wallis et al reported women derived greater value from the immunotherapy in NSCLC (male: HR 0.79, 95% CI 0.71‐0.88; female: 0.72, 95% CI 0.56‐0.93) …”

“…12 Wallis et al reported women derived greater value from the immunotherapy in NSCLC (male: HR 0.79, 95% CI 0.71-0.88; female: 0.72, 95% CI 0.56-0.93). 13 The previous studies indicated that the role of sex in ICI trials in cancers were controversial. How sex associates with ICI efficacy is incompletely elucidated.…”