PracticeUpdate Oncology February 2019

EDITOR’S PICKS 17

Association of GenderWith Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers JAMA Oncology Take-home message • In this systematic review and meta-analysis of 23 randomized clinical trials of immunotherapy for advanced solid-organ cancers including 9322 men and 4399 women, no statistically significant differences in overall survival were found between the two sexes. • The response to immune checkpoint inhibitors does not appear to differ on the basis of gender.

demonstrated no statistically significant asso- ciation of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome. Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers: A Systematic Review and Meta-Analysis. JAMA Oncol 2019 Jan 03;[EPub Ahead of Print], CJD Wallis, M Butaney, R Satkunasivam, et al. www.practiceupdate.com/c/78208 Although the Conforti et al meta-analysis found that men derived greater benefit from immunotherapy than women, the inclusion of more recent studies in this current analysis contributed to the find- ing that gender was not associated with immunotherapy efficacy in advanced solid tumors. Furthermore, an overall survival benefit was seen with immuno- therapy as comparedwith other systemic therapies in both men and women. This contradiction of the previous analysis was due in part to the addition of seven recent large trials, some of which found a strong overall survival advantage from immunotherapy in women compared with men. Despite the inherent limita- tions of this type of analysis, the authors of this contemporary update imply that gender should be a factor considered when deciding whether or not to offer immunotherapy to patients with meta- static solid tumors. Reference 1. Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol 2018; 19(6):737-746. COMMENT By Sumanta Kumar Pal MD I n a recent issue of JAMA Oncology , Wallis and colleagues published a review and meta-analysis of 23 ran- domized clinical trials that compared immunotherapy with standard-of-care regimens in the treatment of metastatic solid tumor cancers to examine the asso- ciation between gender and response to immunotherapy. A similar study from Conforti et al, published in The Lancet Oncology , included data reported prior to November 2017, namely trials for the agents ipilimumab, nivolumab, tremeli- mumab, and pembrolizumab. 1 Due to the magnitude of new information pub- lished since then, the authors of this current study felt that it was important to expand on the analysis and include literature reporting on atezolizumab, dur- valumab, and avelumab.

Abstract IMPORTANCE Sex-associated differences in immune response are known, but a meta-anal- ysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subse- quent trials have placed these results in doubt. OBJECTIVE To perform an updated, comprehen- sive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex. Design, Setting, and PARTICIPANTS A systematic review of studies (n=23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was con- ducted. 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 stud- ies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens,

studies that reported other measures of onco- logic response, and studies that reported subgroup analyses for 1 sex only were excluded. MAIN OUTCOMES AND MEASURES Overall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immuno- therapy exists by patient sex. RESULTS This meta-analysis included 23 ran- domized 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 immuno- therapy demonstrated no statistically significant difference between the sexes (I2=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 RELEVANCE Stratified analyses

VOL. 3 • NO. 1 • 2019