Research

JAMA Oncology | Original Investigation

Association of Patient Sex With Efficacy

of Immune Checkpoint Inhibitors
and Overall Survival in Advanced Cancers
A Systematic Review and Meta-analysis
Christopher J. D. Wallis, MD, PhD; Mohit Butaney, MD; Raj Satkunasivam, MD, MS; Stephen J. Freedland, MD;
Sandip P. Patel, MD; Omid Hamid, MD; Sumanta K. Pal, MD; Zachary Klaassen, MD

Supplemental content
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 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 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 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 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 (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 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.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Christopher
J. D. Wallis, MD, PhD, Division of
Urology, Department of Surgery,
University of Toronto, 149 College St,
JAMA Oncol. 2019;5(4):529-536. doi:10.1001/jamaoncol.2018.5904 Room 503G, Toronto, ON M5T 1P5,
Published online January 3, 2019. Canada (wallis.cjd@gmail.com).

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 Research Original Investigation Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers
W
omen and men differ in their immunologic
response to both foreign and self-antigens, with
women typically having stronger innate and adap-
tive immune responses.1 Compared with men, women not only
experience a higher prevalence of systemic autoimmune
disease1,2 but also have a greater response to vaccination
and a lower severity and prevalence of many infectious
conditions.1,3,4 In oncology, differences in immune response
have been postulated to underlie observed differences in preva-
lence and mortality from many cancers.5,6
Immune checkpoint inhibitors targeting cytotoxic
T-lymphocyte antigen-4 (CTLA-4) and programmed cell death
1 (PD-1) have demonstrated higher efficacy than standard of
care (SOC) chemotherapeutic approaches in several malig-
nant neoplasms. Sex hormone modulation of the PD-1/
programmed cell death 1 ligand 1 (PD-L1) pathway has been
demonstrated in animal models.7,8 Thus, it has been postu-
lated that the advantages of immunotherapy may vary accord-
ing to patient sex.9 Recently, Conforti et al10 found in a meta-
analysis of randomized clinical trials that men derived greater
value from immune checkpoint inhibitors compared with
women (hazard ratio [HR], 0.72 [95% CI, 0.65-0.79] vs 0.86
[95% CI, 0.79-0.93]; P = .002). However, another recent analy-
sis has presented conflicting data: No difference in advan-
tages between nivolumab and everolimus was seen among
men and women with metastatic renal cell carcinoma.11
The Conforti et al10 meta-analysis demonstrated a difference
between patient sex, which presents a number of limitations that
preclude strong conclusions from being drawn from the data set.
First, the meta-analysis included a limited subset of approved im-
munotherapeutic agents. Second, several comprehensive and up-
dated studies that met the inclusion criteria, including those with
a more robust representation of female patients, have been pub-
lished since the Conforti et al10 literature review.
To address these concerns, we performed a systematic
review and meta-analysis that examine the association of pa-
tient sex with the advantages of immunotherapy in patients
with advanced cancer. We used a more contemporary and com-
prehensive literature search strategy.
Methods
This systematic review and meta-analysis followed the Pre-
ferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) guidelines. 12 The study protocol was
registered with PROSPERO.
Types of Studies
We included randomized clinical trials. Observational stud-
ies (whether cohort or case-control in design), editorials, com-
mentaries, and review articles were excluded. Publications that
were not subject to peer review (ie, reports of data from the
National Vital Statistics System and dissertations or theses)
were also excluded. To prevent the duplication of patients used
in our analyses, we selected 1 study (when more than 1 was pub-
lished about the same patient cohort), on the basis of contem-
porary timing, cohort size, and granularity of data reported.
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Key Points
Question Do women derive less advantage from immune
checkpoint inhibitors, compared with standard systemic therapy,
in the treatment of advanced solid-organ malignant neoplasm?
Findings In this systematic review and meta-analysis of 23
randomized clinical trials of immunotherapy for advances
solid-organ cancers including 9322 men and 4399 women, overall
survival from immunotherapy was found in both men and women,
with no statistically significant differences between the sexes.
Meaning The response to immune checkpoint inhibitors does not
appear to differ on the basis of patient sex.
We included studies that compared immunotherapy for
metastatic cancers with other systemic treatment regimens,
including chemotherapy-based regimens and those that used
other targeted therapies. Analyses that examined immuno-
therapy-chemotherapy combinations compared with chemo-
therapy alone were also included. However, studies that com-
pared various immunotherapy regimens were excluded.
Outcome and Exposure of Interest
The outcome of interest was overall survival (OS) and whether
OS was reported as the primary or secondary outcome of the
original study. Studies that reported other measures of onco-
logic response, including progression-free survival and objec-
tive response rate (without OS data) were excluded as these
may not be comparable across histologic subtypes.
We sought to examine whether patient sex modified the
association between immunotherapy (compared to chemo-
therapy) and OS. Studies that did not report analyses strati-
fied by sex in the original trials were excluded. Furthermore,
to exclude ecologic bias, we excluded studies that reported
subgroup analyses for 1 sex only.
Search Strategy and Review Method
To perform this present analysis, we updated a previous rele-
vant systematic review by Conforti et al10 that used MEDLINE
(PubMed), Embase, and Scopus from inception of these databases
to November 30, 2017, to identify phase 2 or 3 randomized clini-
cal trials for the agents ipilimumab, tremelimumab, nivolumab,
and pembrolizumab. In this update, we expanded the literature
search for previously included agents from November 30, 2017,
to October 2, 2018. We expanded the search criteria to include
atezolizumab, durvalumab, and avelumab and searched the rele-
vant databases from inception to October 2, 2018. References from
review articles, editorials, and included studies were reviewed
and cross-referenced to ensure completeness. No limitations were
placed regarding publication language or publication year. After
the literature search, we excluded all duplicates. References from
review articles, commentaries, editorials, included studies, and
conference publications of relevant medical societies were
reviewed and cross-referenced to ensure completeness.
We (M.B. and Z.K.) performed study selection independently,
and we resolved disagreements by consensus with the primary
author (C.J.D.W.). Titles and abstracts were used to screen for
initial study inclusion. Full-text reviews were performed if the
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 Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers
abstracts were insufficient for determining if the studies met
the inclusion or exclusion criteria. We (C.J.D.W., M.B., and Z.K.)
developed a data extraction form by consensus. One of us (M.B.)
performed all of the data extraction, and two of us (C.J.D.W. and
Z.K.) conducted independent verification.
Study characteristics, including first author, year of pub-
lication, study design, phase, type of therapy (anti–PD-L1 or
anti–CTLA-4), line of therapy, underlying malignant neo-
plasm, and baseline demographic characteristics were
extracted. In addition, outcome information, including the HR
(with 95% CI) for death, stratified by patient sex, was
abstracted. A risk-of-bias assessment was conducted using the
Cochrane Collaboration tool for assessing risk of bias.13
Assessment of Heterogeneity and Statistical Analysis
We identified heterogeneity using the Q test. Heterogeneity was
estimated using the DerSimonian-Laird method and was quan-
tified using I2 values.14
Meta-analysis was performed using Review Manager, version
5.3 (Nordic Cochrane Centre). We used the inverse variance tech-
nique for meta-analysis of HRs. Because of the clinical heteroge-
neity inherent in the data, we used random-effects models for all
meta-analyses.Toassessthedifferencesbetweenthesexesineach
study while accounting for study-level associations, we made cal-
culations using log HR and then assessed whether the variations
differed from the null using the χ2 test.14 All reported P values are
2-sided, and P = .05 was used to indicate statistical significance.
Subgroup Analyses
We performed a number of prespecified subgroup analyses to
assess the potential association of oncologic and methodologic
factors in effect modification of patient sex with immunotherapy
efficacy. We considered subgroups, including disease site (mela-
noma, non–small cell lung cancer [NSCLC], and other tumor
sites), line of therapy (first line and subsequent), class of immu-
notherapy (anti–CTLA-4, anti–PD-1, and anti–PD-L1), and study
methodology (various immunotherapies vs chemotherapy
alone, immunotherapy-chemotherapy combination vs chemo-
therapy alone).
To assess the degree to which the relative underrepresen-
tation of women in these trials may contribute to the previ-
ously observed differences in outcome between women and
men, we performed a stratified analysis according to the pro-
portion of women in each study. We categorized the included
studies according to whether women represented less than 20%,
20% to 30%, 30% to 40%, or 40% or more of the study cohort.
Results
Literature Search Results
The literature search identified 57 unique references. After a
full-text review of 17 studies, we identified 7 relevant clinical
trials for inclusion, in addition to 16 trials included from the
Conforti et al10 meta-analysis. Thus, a total of 23 trials15-37 were
included in the present meta-analysis (Figure 1). All trials in-
cluded a subgroup analysis, stratified by sex, that compared the
intervention group with the control group, with an HR for OS.
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Original Investigation Research
Figure 1. PRISMA Diagram
20 Records identified 59 Records identified
from Conforti et al10 from databases
57 Remained after
duplicates removed
40 Excluded after abstract
review
4 Excluded
2 IO vs IO 17 Underwent full-text
1 IO vs vaccine review
1 Conference abstract
40 Excluded after full-text
review
7 No OS subgroup for sex
1 Review manuscript
1 RFS end point
1 PFS end point
16 Included 7 Included
23 Studies included in
meta-analysis
IO indicates immunotherapy; OS, overall survival; PFS, progression-free
survival; RFS, relapse-free survival.
Characteristics of Identified Trials
Table 1 lists the main characteristics of the 23 trials. In total,
13 721 patients were included, of which 9322 (67.9%) were men
and 4399 (32.1%) were women; the age of most patients was
in the 70s. All studies enrolled patients within the past de-
cade, and most trials were published in the past 3 years. Only
2 studies18,29 (9%) evaluated OS as a secondary end point (the
primary end point was progression-free survival), both of which
allowed crossover to immunotherapy at the time of disease
progression. There were 11 trials (48%) for patients with
NSCLC,16-18,20-22,29,31,34-36 4 (17%) for melanoma,24,30,32,33 2 (9%)
for clear cell renal cell carcinoma,26,27 2 (9%) for SCLC,28,37 and
1 (4%) each for urothelial carcinoma,15 head and neck squa-
mous carcinoma,19 mesothelioma,25 and gastric or gastro-
esophageal carcinoma. 23 Most trials evaluated immuno-
therapy after previous systemic therapy failure; however, 11
trials (48%) assessed the efficacy for OS in the first-line
setting.18,20,21,27-30,32,33,35,37 Most trials used a PD-L1 or PD-1
inhibitor as the immunotherapy agent, whereas 6 trials (26%)
used a CTLA-4 inhibitor.21,25,27,28,30,32 Most study designs in-
cluded immunotherapy vs SOC, but 6 trials20,21,28,32,35,37 (26%)
were designed as immunotherapy and SOC vs SOC alone.
Several trials had unique designs that may warrant further
explanation. The KEYNOTE 010 trial22 was unique in that it tested
2 doses of pembrolizumab (2 mg/kg and 10 mg/kg) vs docetaxel
among patients with NSCLC, with an overall pooled HR for OS of
0.67 (95% CI, 0.56-0.80). In the CheckMate 214 study, Motzer
et al27 randomized 1096 patients with advanced clear cell renal
cell carcinoma to receive both an anti–PD-1 (nivolumab) and an
anti–CTLA-4 (ipilimumab) agent vs sunitinib; however, Motzer
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 Research Original Investigation Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers

Table 1. Characteristics and Outcomes of the 23 Trials Included in the Meta-analysis

Age,
Median Follow-up,
Control (Range Median
Disease Lines of Intervention Treatment or IQR), (Range or Sex, No. Overall Survival HR (95% CI)
Source Site Trial Name Therapy (No.) (No.) y IQR), mo Men Women Overall Men Women
Antonia NSCLC PACIFIC >1 Durvalumab Placebo 64 25.2 500 213 0.68 0.78 0.46
et al,34 (476) (237) (23-90) (0.2-43.1) (0.47- (0.59- (0.30-
2018 0.998) 1.03) 0.73)
Barlesi NSCLC JAVELIN >1 Avelumab (396) Docetaxel Int: 64 18.3 (IQR, 367 162 0.90 0.83 1.08
et al,36 Lung 200 (396) (58-69); 13.2-22.7) (0.72- (0.64- (0.74-
2018 Cont: 63 1.12) 1.08)a 1.59)a
(57-69)
Bellmunt Urothelial KEYNOTE >1 Pembrolizumab ICC (272) 66 14.1 402 140 0.73 0.73 0.78
et al,15 carcinoma 045 (270) (26-88) (9.9-22.1) (0.59- (0.56- (0.49-
2017 0.91) 0.94) 1.24)
Borghaei NSCLC CheckMate >1 Nivolumab Docetaxel 62 13.2 (NR) 319 263 0.73 0.73 0.78
et al,16 057 (292) (290) (21-85) (0.59- (0.56- (0.58-
2015 0.89) 0.96) 1.04)
Brahmer NSCLC CheckMate >1 Nivolumab Docetaxel 63 11.0 (NR) 208 64 0.59 0.57 0.67
et al,17 017 (135) (137) (39-85) (0.44- (0.41- (0.36-
2015 0.79) 0.78) 1.25)
Carbone NSCLC CheckMate 1 Nivolumab ICC (270) 64 13.5 (NR) 332 209 1.02 0.97 1.15
et al,18 026 (271) (29-89) (0.80- (0.74- (0.79-
2017 1.30) 1.26) 1.66)
Ferris Head & CheckMate >1 Nivolumab ICC (121) 60 5.1 300 61 0.70 0.65 0.93
et al,19 neck 141 (240) (28-83) (0-16.8) (97.73% CI, (0.48- (0.47-
2016 squamous 0.51-0.96) 0.88) 1.85)
carcinoma
Gandhi NSCLC KEYNOTE 1 Pembrolizumab Placebo + Int: 65 10.5 363 253 0.49 0.70 0.29
et al,20 189 + platinum platinum (34-84); (0.2-20.4) (0.38- (0.50- (0.19-
2018 (410) (206) Cont: 64 0.64) 0.99) 0.44)
(34-84)
Govindan NSCLC NR 1 Ipilimumab + Placebo + 64 Int: 12.5 635 114 0.91 0.85 1.33
et al,21 paclitaxel + paclitaxel + (28-85) (NR); (0.77- (0.71- (0.84-
2017 carboplatin carboplatin Cont: 11.8 1.07) 1.02) 2.11)
(388) (361) (NR)
Herbst NSCLC KEYNOTE >1 Pembrolizumab Docetaxel 63 (IQR, 13.1 (IQR, 634 399 Pooled: 0.65 0.69
et al,22 010 2 mg/kg (345); (343) 54-70) 8.6-17.7) 0.67 (0.52- (0.51-
2016 pembrolizumab (0.56- 0.81) 0.94)
10 mg/kg (346) 0.80)
Horn SCLC IMpower133 1 Atezolizumab Placebo + Int: 64 13.9 (NR) 261 142 0.70 0.74 0.65
et al,37 + carboplatin + carbo- (28-90); (0.54- (0.54- (0.42-
2018 etoposide (201) platin + Cont: 64 0.91) 1.02) 1.00)
etoposide (26-87)
(202)
Kang Gastric or ATTRACTION-2 >1 Nivolumab Placebo 62 (IQR, Int: 8.87 348 145 0.63 0.59 0.83
et al,23 gastroeso- (330) (163) 53-69) (IQR, (0.51- (0.46- (0.56-
2017 phageal 6.57-12.37); 0.78) 0.75) 1.23)
junction Cont: 8.59
carcinoma (IQR,
5.65-11.37)
Larkin Melanoma NR >1 Nivolumab ICC (133) 61 苲 261 144 0.95 0.85 1.07
et al,24 (272) (23-88) 24 (NR) (0.73- (0.62- (0.69-
2018 1.24) 1.17) 1.65)
Maio Meso- DETERMINE >1 Tremelimumab Placebo 67 (IQR, NR 434 137 0.92 0.91 1.12
et al,25 thelioma (382) (189) 60-73) (0.76- (0.73- (0.72-
2017 1.12) 1.13) 1.75)
Motzer ccRCC CheckMate >1 Nivolumab Everolimus 62 14 (NR) 619 202 0.73 0.73 0.84
et al,26 025 (410) (411) (18-88) (98.5% CI, (0.58- (0.57-
2015 0.57-0.93) 0.92) 1.24)
Motzer ccRCC CheckMate 1 Nivolumab + Sunitinib Int: 62 25.2 (NR) 615 232 0.63 0.71 0.52
et al,27 214 ipilimumab (422) (26-85); (99.8% CI, (0.55- (0.34-
2018 (425) Cont: 51 0.44-0.89) 0.92) 0.78)
(21-85)
Paz-Ares NSCLC KEYNOTE 1 Pembrolizumab Placebo + Int: 65 7.8 455 104 0.64 0.69 0.42
et al,35 407 + ICC (278) ICC (281) (29-87); (0.1-19.1) (0.49- (0.51- (0.22-
2018 Cont: 65 0.85) 0.94) 0.81)
(36-88)
Reck SCLC NR 1 Ipilimumab + Placebo + 63 Int: 10.5 643 311 0.94 1.07 1.06
et al,28 etoposide + etoposide + (36-85) (NR); (0.81- (0.89- (0.81-
2016 platinum (478) platinum Cont: 10.2 1.09) 1.28) 1.37)
(476) (NR)
Reck NSCLC KEYNOTE 1 Pembrolizumab ICC (151) 65 11.2 187 118 0.60 0.54 0.96
et al,29 024 (154) (33-90) (6.3-19.7) (0.41- (0.36- (0.56-
2016 0.89) 0.80) 1.64)

(continued)

et al27 performed OS analysis on only a sex subgroup among 847 a survival advantage for both sexes (men HR, 0.71 [95% CI, 0.55-
patients with intermediate- or poor-risk disease, demonstrating 0.92]; women HR, 0.52 [95% CI, 0.34-0.78]).

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

Table 1. Characteristics and Outcomes of the 23 Trials Included in the Meta-analysis

Age,
Median Follow-up,
Control (Range Median
Disease Lines of Intervention Treatment or IQR), (Range or Sex, No. Overall Survival HR (95% CI)
Source Site Trial Name Therapy (No.) (No.) y IQR), mo Men Women Overall Men Women
Ribas Melanoma NR 1 Tremelimumab ICC (327) 57 NR 372 283 0.88 (NR); 0.93 0.81
et al,30 (328) (22-90) P = .13 (0.74- (0.62-
2013 1.17) 1.06)
Rittmeyer NSCLC OAK >1 Atezolizumab Docetaxel 64 21 (NR) 520 330 0.73 0.79 0.64
et al,31 (425) (425) (33-85) (0.62- (0.64- (0.49-
2017 0.87) 0.97) 0.85)
Robert Melanoma NR 1 Ipilimumab + Placebo + 56.9 54 (NR) 301 201 0.72 0.70 0.86
et al,32 dacarbazine dacar- (NR) (0.59- (0.55- (0.63-
2011 (250) bazine 0.87) 0.90) 1.17)
(252)
Robert Melanoma CheckMate 1 Nivolumab Dacar- 65 Int: 8.9 246 172 0.42 0.34 0.56
et al,33 066 (210) bazine (18-87) (NR); (0.25- (0.22- (0.33-
2015 (208) Cont: 6.8 0.73) 0.54) 0.95)
(NR)

Abbreviations: ccRCC, clear cell renal cell carcinoma; Cont, control group; HR, hazard ratio; ICC, investigator’s choice of chemotherapy; Int, intervention group;
IQR, interquartile range; NR, not reported; NSCLC, non–small cell lung cancer; PD-L1, programmed cell death 1 ligand 1; SCLC, small cell lung cancer.
a
Sex subgroup analysis performed in population with positive PD-L1.

Table 2. Differences in Efficacy of Immunotherapy in Men and Women by Subgroups

Test for
Study, Participants, No. Pooled HR (95% CI) for IO vs SOC Difference
Variable No. (%) Men Women Men Women I2, % P Value
Overall 23 9322 4399 0.75 (0.69-0.81) 0.77 (0.67-0.88) 38 .60
Disease site
Melanoma 4 (17) 1180 800 0.68 (0.48-0.97) 0.83 (0.68-1.00) 16 .36
NSCLC 11 (48) 4520 2125 0.79 (0.71-0.88) 0.72 (0.56-0.93) 61 .79
Other tumors 8 (35) 3622 1474 0.76 (0.66-0.89) 0.83 (0.69-1.00) 0 .47
Line of therapy
First line 11 (48) 4410 2139 0.75 (0.64-0.87) 0.73 (0.57-0.94) 58 .92
Subsequent 12 (52) 4912 2260 0.73 (0.66-0.80) 0.79 (0.68-0.91) 2 .38
Class of immunotherapya
Anti–CTLA-4 6 (26) 3000 1278 0.86 (0.76-0.98) 0.91 (0.73-1.13) 26 .62
Anti–PD-1 18 (78) 7198 3495 0.70 (0.65-0.77) 0.70 (0.60-0.83) 44 .94
Abbreviations: CTLA-4, cytotoxic
Study methodology
T-lymphocyte antigen-4; HR, hazard
Non-IO + IO vs non-IO 6 (26) 2658 1125 0.80 (0.68-0.94) 0.69 (0.45-1.07) 69 .55 ratio; IO, immunotherapy;
IO vs non-IO 17 (74) 6664 3274 0.73 (0.66-0.80) 0.79 (0.69-0.89) 14 .33 NSCLC, non–small cell lung cancer;
Proportion of women, % PD-1, programmed cell death 1;
<20 3 (13) 1390 279 0.75 (0.63-0.90) 0.82 (0.41-1.64) 58 .65 SOC, standard of care chemotherapy.
a
20-30 7 (30) 3126 1133 0.72 (0.64-0.81) 0.72 (0.57-0.91) 33 .93 Motzer et al27 included both classes
31-39 8 (35) 3205 1815 0.81 (0.70-0.94) 0.88 (0.73-1.06) 0 .52 of immunotherapy in subgroups as
agents from both categories used in
≥40 5 (22) 1601 1172 0.67 (0.52-0.87) 0.63 (0.44-0.90) 71 .76
the exposure arm.

The median age of patients included was typically in the 70s;
however, in 2 trials, the median age was in the 60s.30,32 Most stud-
ies tended to have short follow-up, although 3 trials (13%) had a
median follow-up of 24 months or more.24,27,34 Overall, all but
7 studies18,21,24,25,28,30,36 (30%) showed an OS advantage for pa-
tients who received immunotherapy compared with the control
group. In subgroup analyses, 14 studies15-17,19,20,22,23,26,27,29,31-33,35
(61%) demonstrated a survival advantage from immunotherapy
among men and 7 studies20,22,27,31,33-35 (30%) showed this advan-
tage among women.
Risk of Bias
Risk of bias of the included trials is shown in the eTable in the
Supplement. All trials included random-sequence generation and
were at low risk for selection bias. There was intermittent report-
ing of allocation concealment; several studies were at risk for se-
lection bias because of this criterion. Generally, all studies were
at low risk for attrition and reporting bias. Several studies were
unblinded and were thus at risk for performance and detection
bias; however, for the outcome of OS, such a lack of blinding is
likely inconsequential as blinding is unlikely to affect the outcome.
Primary Analysis
Meta-analysis of the available literature demonstrated a statis-
tically significant advantage in OS for patients who received
immunotherapy compared with other systemic therapies
(HR, 0.75, 95% CI, 0.70-0.81; P < .001; I2 = 61%). Compared with
SOC systemic therapy, an OS advantage of immunotherapy
was observed for both men (HR, 0.75; 95% CI, 0.69-0.81;
P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002);
however, we found no statistically significant difference
in OS advantage between the sexes (P = .60; I2 = 38%) (Table 2,

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

Figure 2. Forest Plot of Association Between Overall Survival and Immunotherapy (IO) and Standard of Care (SOC) Stratified by Patient Sex

A Overall survival for men B Overall survival for women

Source
Antonia et al,34 2018a
Barlesi et al,36 2018a
Bellmunt et al,15 2017
Borghaei et al,16 2015
Brahmer et al,17 2015
Carbone et al,18 2017
Ferris et al,19 2016
Gandhi et al,20 2018a
Govindan et al,21 2017
Herbst et al,22 2016
Horn et al,37 2018a
Kang et al,23 2017
Larkin et al,24 2018
Maio et al,25 2017
Motzer et al,26 2015
Motzer et al,27 2018a
Paz-Ares et al,35 2018a
Reck et al,28 2016
Reck et al,29 2016
Ribas et al,30 2013
Rittmeyer et al,31 2017a
Robert et al,32 2011
Robert et al,33 2015
HR (95% CI) Favors IO Favors SOC HR (95% CI) Favors IO Favors SOC
0.78 (0.59-1.03) 0.46 (0.30-0.73)
0.83 (0.64-1.08) 1.08 (0.74-1.59)
0.73 (0.56-0.94) 0.78 (0.49-1.24)
0.73 (0.56-0.96) 0.78 (0.58-1.04)
0.57 (0.41-0.78) 0.67 (0.36-1.25)
0.97 (0.74-1.26) 1.15 (0.79-1.66)
0.65 (0.48-0.88) 0.93 (0.47-1.85)
0.70 (0.50-0.99) 0.29 (0.19-0.44)
0.85 (0.71-1.02) 1.33 (0.84-2.11)
0.65 (0.52-0.81) 0.69 (0.51-0.94)
0.74 (0.54-1.02) 0.65 (0.42-1.00)
0.59 (0.46-0.75) 0.83 (0.56-1.23)
0.85 (0.62-1.17) 1.07 (0.69-1.65)
0.91 (0.73-1.13) 1.12 (0.72-1.75)
0.73 (0.58-0.92) 0.84 (0.57-1.24)
0.71 (0.55-0.92) 0.52 (0.34-0.78)
0.69 (0.51-0.94) 0.42 (0.22-0.81)
1.07 (0.89-1.28) 1.06 (0.81-1.37)
0.54 (0.36-0.80) 0.96 (0.56-1.64)
0.93 (0.74-1.17) 0.81 (0.62-1.06)
0.79 (0.64-0.97) 0.64 (0.49-0.85)
0.70 (0.55-0.90) 0.86 (0.63-1.17)
0.34 (0.22-0.54) 0.56 (0.33-0.95)

0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 0 0.25 0.50 0.75 1.00 1.25 1.50 1.75
HR (95% CI) HR (95% CI)

HR indicates hazard ratio.

a
New studies included in this meta-analysis.

Figure 2). Statistically significant heterogeneity was demon-
strated among both men (tau2 = 0.02; χ2 = 51.67; P = .003;
I2 = 57%) and women (tau2 = 0.07; χ2 = 62.29; P < .001; I2 = 65%).
Subgroup Analysis
We performed a number of subgroup analyses according to dis-
ease site, line of therapy, class of immunotherapy, and study
methodology. No statistically significant differences in the ef-
ficacy of immunotherapy were found between men and
women in any of these analyses (Table 2). Finally, we exam-
ined for the effect of the prevalence of women in the study co-
hort. Again, no statistically significant differences were dem-
onstrated among these subgroups (Table 2).
Discussion
Contrary to the published meta-analysis by Conforti et al,10 which
suggested a greater immunotherapy advantage compared with
SOC systemic therapy for men than women, the present analy-
sis found no difference in OS from immune checkpoint inhibi-
tors when comparing the efficacy of these treatments between
the sexes. Furthermore, when assessing several subgroup analy-
ses, including disease site, line of therapy, class of immuno-
therapy, and study methodology, we could not demonstrate any
significant sex-associated differences in efficacy.
These conflicting results may be explained in a number of
ways. First, we excluded 3 trials, which were included in Conforti
et al,10 that compared various immunotherapy regimes.38-40 By
including only those trials that compared an immunotherapy
group with a nonimmunotherapy control, we were able to specif-
ically assess the association of sex with response to immuno-
therapy.Second,weexpandedthesearchcriteriatoincludeimmu-
notherapy agents that were not considered in Conforti et al.10 The
resulting search included a trial of atezolizumab in patients with
NSCLC.31 This trial demonstrated a greater net value of immuno-
therapy for women (HR, 0.64; 95% CI, 0.49-0.85) than for men
(HR, 0.79; 95% CI, 0.64-0.97). Because this trial was large (n =
850 patients), it contributed considerably to the pooled HR effect.
Third, we updated the search previously performed and
identified 7 recent large trials that have been published since
the end date for inclusion in the Conforti et al 10 meta-
analysis. Gandhi et al20 in KEYNOTE 189 tested pembroli-
zumab plus platinum chemotherapy (n = 410) vs pla-
cebo plus platinum chemotherapy (n = 206) in the first-line
setting among patients with NSCLC. KEYNOTE 189 included
363 men and 253 women and noted a strong OS advantage from
immunotherapy among women (HR, 0.29; 95% CI, 0.19-
0.44) compared with men (HR, 0.70; 95% CI, 0.50-0.99).
Motzer et al27 in CheckMate 214 tested nivolumab plus ipili-
mumab (n = 425) and the tyrosine-kinase inhibitor sunitinib
(n = 422) in the first-line setting among intermediate- and poor-

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

risk patients with clear cell renal cell carcinoma. CheckMate
214 had 615 men and 232 women and also found a strong OS
advantage from immunotherapy among women (HR, 0.52;
95% CI, 0.34-0.78) compared with men (HR, 0.71; 95% CI,
0.55-0.92). KEYNOTE 407 tested first-line pembrolizumab vs
saline placebo (plus carboplatin and either paclitaxel or
nanoparticle albumin-bound paclitaxel) among patients with
NSCLC.35 Although women made up only 18.6% of partici-
pants in KEYNOTE 407, they had a remarkable immuno-
therapy treatment advantage (HR, 0.42; 95% CI, 0.22-0.81)
compared with men (HR, 0.69; 95% CI, 0.51-0.94). Taken to-
gether, the present meta-analysis provides a more specific
assessment of the research question while including a greater
number of immunotherapy agents and an updated search.
Small samples sizes may result in an elevated false discov-
ery rate41 or even false-positive results.42 Meta-analyses of such
trials may propagate such findings by enhancing the statistical
power of these small subgroup analyses. To explore the final hy-
pothesis that the representation of women in a study may me-
diate observed differences in immunotherapy efficacy between
men and women, we performed a stratified analysis. We found
no statistically significant difference in outcomes between men
and women regardless of the proportion of women in the study
cohort. The effect estimates favored men in studies with study
cohorts composed of less than 20% women, but the results were
very comparable in the other subgroups. Trials with an under-
representation of women may present spurious results for
sex-specific subgroup analyses, as evidenced by the wide CIs
when less than 20% of the cohort represented is women.
Six20,27,31,34,36,37 of the 7 trials included in this meta-analysis but
not included in the Conforti et al10 study had more than 27%
women representation, with 2 trials20,31 having more than 38%
women inclusion.
Strengths and Limitations
The strengths of this meta-analysis include the strict methodo-
logic inclusion criteria that required the comparison between an
immunotherapy group and a nonimmunotherapy control group;
the broad inclusion of all approved immunotherapy agents; and
the rigorous, up-to-date search strategy. As a result, this analy-
sis provides a comprehensive assessment of the association of
patient sex with response to immunotherapy compared with
nonimmunotherapy, including data on more than 13 000 pa-
tients. Furthermore, we undertook several subgroup analyses
in an attempt to ascertain any differences in immunotherapy ef-
ficacy between the sexes.
This analysis has several limitations. First, it relies on pub-
lished clinical trial subgroup HRs and not on individual patient-
level data. Second, residual confounding is possible in that dif-
ferences other than sex contribute to immunotherapy response
and OS. Third, differences in outcomes between men and wom-
en may be ascribed to other factors (including differences in life-
style, comorbidities, incidence of autoimmune diseases, and
other factors) that are unaccounted for in clinical trials. Fourth,
as in all clinical trials, the included studies are at risk for having
nongeneralizable results (the so-called efficacy-effectiveness gap)
because of referral bias and strict inclusion criteria, among other
factors, that result in the underrepresentation of uninsured, low-
income, and minority populations. Meta-analysis of these trials,
such as the one we performed, is subject to the same limitations.
Finally, the trials that we excluded because of a lack of published
sex-subgroup analyses may demonstrate sex differences if ana-
lyzed in this fashion.
Conclusions
In this contemporary meta-analysis of all available immuno-
therapy clinical trials across all disease sites, we found no
difference in immunotherapy efficacy or OS between
women and men. Contrary to findings of a previous analysis,
we found no evidence that sex should be considered when
deciding whether to offer immunotherapy to patients with
advanced cancers.

ARTICLE INFORMATION
Accepted for Publication: October 10, 2018.
Published Online: January 3, 2019.
doi:10.1001/jamaoncol.2018.5904
Author Affiliations: Division of Urology,
Department of Surgery, University of Toronto,
Toronto, Ontario, Canada (Wallis); School of
Medicine, Royal College of Surgeons in Ireland,
Dublin, Ireland (Butaney); Center for Outcomes
Research, Department of Urology, Houston
Methodist Hospital, Houston, Texas
(Satkunasivam); Division of Urology, Department of
Surgery, Cedars-Sinai Medical Center, Los Angeles,
California (Freedland); Urology Section, Durham VA
Medical Center, Durham, North Carolina
(Freedland); Moores Cancer Center-La Jolla,
Department of Medicine, University of California,
San Diego, La Jolla (Patel); Translational Research &
Immunooncology, The Angeles Clinic & Research
Institute, Los Angeles, California (Hamid);
Department of Medical Oncology and Experimental
Therapeutics, City of Hope Comprehensive Cancer
Center, Duarte, California (Pal); Division of Urology,
Department of Surgery, Medical College of Georgia
at Augusta University, Augusta (Klaassen); Georgia
Cancer Center, Augusta University, Augusta,
Georgia (Klaassen).
Author Contributions: Drs Wallis and Klaassen had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Wallis, Hamid, Pal, Klaassen.
Acquisition, analysis, or interpretation of data:
Wallis, Butaney, Satkunasivam, Freedland, Patel,
Hamid, Klaassen.
Drafting of the manuscript: Wallis, Patel, Hamid,
Klaassen.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Wallis, Satkunasivam.
Administrative, technical, or material support:
Wallis, Butaney, Patel, Pal, Klaassen.
Supervision: Patel, Pal, Klaassen.
Conflict of Interest Disclosures: Dr Freedland
reported receiving grants from Merck outside of the
submitted work. Dr Patel reported receiving
scientific advisory income from AstraZeneca, BMS,
Illumina, Tempus, and Novartis. Dr Patel's university
receives research funding from Bristol-Myers
Squibb, Eli Lilly, Fate, Incyte, AstraZeneca/
MedImmune, Merck, Pfizer, Roche/Genentech,
Xcovery, Fate Therapeutics, Genocea, and Iovance.
Dr Pal reported receiving personal fees from
Genentech, Pfizer, and BMS outside of the
submitted work. No other disclosures were
reported.
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