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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 238-243

Impact of sex of the patient on efficacy and safety of cancer immunotherapy: A retrospective audit


1 Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center & Homi Bhabha Cancer Hospital, Tata Memorial Center, Varanasi, Uttar Pradesh, India
2 Department of Medical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Homi Bhabha National Institute, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission17-May-2021
Date of Decision27-May-2021
Date of Acceptance11-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Dr. E. Borges Road, Parel East, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_111_21

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  Abstract 


Background: It has been established that women usually mount a stronger immune response than men of the same age. Data for the efficacy of immune checkpoint inhibitors (ICIs) based on the patient's' sex are scarce.
Objectives: We aimed to evaluate the impact of the patients' sex on the efficacy and toxicity of ICIs.
Materials and Methods: Aretrospective audit of a prospectively collected database of patients receiving ICIs for advanced solid tumors between August 2015 and November 2018 was performed at the Tata Memorial Hospital in Mumbai, India. The categorical and continuous variables were evaluated using descriptive statistics. The Kaplan–Meier estimator was used to analyze the progression-free survival (PFS) and overall survival (OS).
Results: Atotal of 155 patients were included in the study, of which 36 (23.2%) were female and 119 (76.8%) were male. The median PFS was 2.8 months (95% confidence interval [CI], 1.4–4.2) for the male patients and 1.9 months (95% CI, 1.0–2.8) for the female patients (hazard ratio [HR], 1.06; 95% CI, 0.69–1.66; P = 0.764). The median OS was 5.9 months (95% CI, 1.5–10.2) for the male patients and 4.2 months (95% CI, 1.1–7.3) for the female patients (HR, 1.27; 95% CI, 0.77–2.12; P = 0.342). The rates of all toxicities, except for pneumonitis, were similar between the male and female patients. All-grade pneumonitis occurred in a total of 7 (5.8%) male patients, while it was not reported in any female patients. All-grade immune-related adverse effects occurred in 24 (20.2%) male and 4 (18.1%) female patients (P = 0.216).
Conclusions: This study shows that the efficacy and toxicity of ICIs are similar in the male and female patients. However, future trials with a balanced number of male and female patients are required to ensure an unbiased estimation of the efficacy and safety of ICIs.

Keywords: Checkpoint inhibitor, gender, real-world data, survival


How to cite this article:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Mahajan A, Janu A, Prabhash K. Impact of sex of the patient on efficacy and safety of cancer immunotherapy: A retrospective audit. Cancer Res Stat Treat 2021;4:238-43

How to cite this URL:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Mahajan A, Janu A, Prabhash K. Impact of sex of the patient on efficacy and safety of cancer immunotherapy: A retrospective audit. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 24];4:238-43. Available from: https://www.crstonline.com/text.asp?2021/4/2/238/320141




  Introduction Top


Immune checkpoint inhibitors (ICIs) are included in the management of most of the solid tumors.[1] However, only a small proportion of the patients respond favorably to ICIs; the majority progress while on therapy.[1] Therefore, the search for appropriate biomarkers to identify patients who are likely to benefit from ICIs continues. Some of these biomarkers include the programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability, and tumor-infiltrating lymphocytes.[2] A potential biomarker for predicting the response to ICIs which does not require any testing and is gradually being recognized is the sex of the patient.

It is well established that women usually mount stronger innate and adaptive immune responses compared to men of the same age.[3] As a result, women can clear infections faster and can develop stronger immunity in response to vaccination.[4] This also explains the higher incidence of autoimmune diseases in women. In fact, up to 80% of the patients with autoimmune diseases are women.[5] Researchers have attempted to find a biological explanation for the difference in the immune response elicited by men and women. Preclinical studies have shown that the toll-like receptor gene, because of its presence on the X chromosome, is more highly expressed in women. This also leads to greater production of interferons in women.[6] Cook et al. have reported the age-adjusted mortality rates for most cancers to be higher in men than women; the highest male-to-female mortality rate ratios have been recorded for lip cancers (5.51), followed by esophageal (4.08) and urinary bladder cancers (3.36).[7] This can be attributed to the hormones, body mass index, carcinogen susceptibility, and access to and utilization of health-care facilities.[6],[7] Thus, it appears that men have lower immune responses and higher risk of mortality from cancers.

There are data to suggest that TMB is significantly higher in men, at least in those with melanomas and non-small cell lung cancers (NSCLCs).[8] This difference in the TMB persists even after adjusting for other confounding variables, such as age, disease stage, and addictions. In addition, studies on animal models have suggested that estrogen can regulate the expression and thus the function of the programmed cell death protein 1 (PD-1) and PD-L1 leading to a possible modulation of the death receptor pathway.[9] These findings suggest that therapies which can lead to potentiation of the immune response could be relatively more beneficial for men as compared to women. Real-world data for the efficacy of ICIs based on the sex of the patient are scarce.[1] Therefore, we performed a retrospective audit of patients who received ICIs to assess the impact of the patient's sex on the efficacy and toxicity of ICIs.


  Materials and Methods Top


General study details

This retrospective audit of a prospectively collected database of patients receiving ICIs between August 2015 and November 2018 was performed at the Tata Memorial Hospital, a tertiary cancer care center in Mumbai, India. The study was approved by the Institutional Ethics Committee [Supplementary Appendix 1]. The need for obtaining a written informed consent was waived as the study was retrospective in nature and did not involve any direct contact between the researchers and the patients. The study was not registered in a public clinical trials registry given the retrospective nature of the study. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki and the Indian Council of Medical Research.

Participants

All consecutive patients with advanced solid tumors from the thoracic, urology, and head-and-neck disease management groups who were planned to receive at least one dose of an ICI were evaluated for inclusion in the study. The patients for whom no details were available for the actual administration of ICIs were excluded from the study.

Variables

The primary endpoint of the study was progression-free survival (PFS). The secondary endpoints were overall survival (OS) and toxicities.

Study methodology

Data related to the patient demographics, sites of metastases, type of PD-1 inhibitor used (nivolumab or pembrolizumab), and use of antibiotics and steroids were extracted from the prospective database and the electronic medical records. The patient identifiers were removed from the dataset before the analysis. As the analysis was based on sex, the patients were categorized as males and females.

Significant antibiotic use was defined as the use of oral and/or intravenous antibiotics for a duration of at least 5 days from 2 weeks prior to the start of treatment with ICI to the end of ICI therapy.[10] Significant steroid use was defined as the use of prednisolone or other steroids at an equivalent dose of ≥10 mg per day for any duration.[11] Nivolumab and pembrolizumab were administered in standard doses, and treatment was provided in accordance with the standard institutional protocol. The Immune Response Evaluation Criteria in Solid Tumors were used for evaluating the response to therapy, and imaging was performed once every 8–12 weeks or when signs of clinical progression appeared. The Common Terminology Criteria for Adverse Events version 4.02 were used for documenting the adverse effects of the therapy.

Definitions

PFS was defined as the time in months from the date of start of treatment with ICI to the date of progression or death due to any cause, in case death occurred before disease progression. OS was defined as the time from the date of the first cycle of ICI to the date of death. Patients who were alive at the time of the last follow-up were censored.

Statistics

Sample size calculation was not performed for this study as it involved a retrospective analysis of the data, and all consecutive patients who fulfilled the eligibility criteria were enrolled. Descriptive statistics were used to evaluate the categorical variables. Kaplan–Meier analysis was performed for determining the median PFS and OS with 95% confidence intervals (CIs). The Cox proportional model was used to generate the hazard ratios (HRs). P <0.05 was considered statistically significant. The Statistical Package for the Social Sciences (SPSS) for Windows version 20 (Armonk, NY, USA, IBM Corp.) was used to perform the statistical analysis. The interaction analysis curve was generated using the Interaction (NOT InterAction) application version 1.7 Fullerton, CA 92831 USA (Available from https://www.danielsoper.com/interaction/).


  Results Top


A total of 161 patients were screened for eligibility, of which 155 were included in our study. There were 36 (23.2%) female and 119 (76.8%) male patients [Figure 1]. The baseline characteristics of the patients are shown in [Table 1]. All the clinicodemographic characteristics were similar for the male and female patients, except for the Eastern Cooperative Oncology Group performance status (ECOG PS). The most common site of the primary tumor was the lung (50%), followed by the head and neck (around 30%) in both the sexes. ICIs were used as first- or second-line therapy in around 60% of the patients in both the sexes. The median follow-up duration was 9.5 months (95% CI: 6.8–12.2). The median PFS was 2.8 months (95% CI: 1.4–4.2) for the male patients and 1.9 months (95% CI: 1.0–2.8) for the female patients (HR, 1.06; 95% CI, 0.69–1.66; P = 0.764). The median OS was 5.9 months (95% CI: 1.5–10.2) for the male patients and 4.2 months (95% CI: 1.1–7.3) for the female patients (HR, 1.27; 95% CI, 0.77–2.12; P = 0.342) [Figure 2]. The 1-year survival rate was 38% for the male patients and 30% for the female patients. The median OS in the female patients was 1.9 months (95% CI: 1.6–2.2) for those who received concomitant steroids (≥10 mg of prednisolone equivalent; n = 7) and 4.2 months (95% CI: 1.5–6.8) for those who did not receive steroids (n = 29), P = 0.458 [Table 2]. Among the male patients, the median OS was 6 months (95% CI: 0.9–11.1) for those who received concomitant steroids (n = 31) and 3.9 months (95% CI: 0–10.9) for those who did not (n = 88, P = 0.304). The median OS was 1.9 months (95% CI: 1.7–2.1) for the female patients who received antibiotics any time during treatment with ICI (n = 12) versus 9.2 months (95% CI: 0.4–18.1) for those who did not (n = 24) (P = 0.104). The median OS in the male patients was 1.0 month (95% CI: 2.4–6.4) for those who received antibiotics (n = 58) versus 9.2 months (95% CI: 4.7–13.6) for those who did not (n = 61), P = 0.665. An interaction analysis was performed to check for the possibility of an association between the sex, ECOG performance score, and OS of the patients. The Levene's test for equality of variances revealed homogeneity of variances, P = 0.066. Moreover, the survival was higher for male patients with a PS of 0–1, however, the curves overlapped for patients with a PS of 2–4 (P = 0.049) [Figure 3].
Table 1: Baseline characteristics of the male and female patients receiving immune checkpoint inhibitors

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Table 2: Comparison of the overall survival for male and female patients as per the baseline characteristics

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Figure 1: Flowchart for patient recruitment

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Figure 2: Kaplan–Meier curve for overall survival of male and female patients receiving immune checkpoint inhibitors

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Figure 3: Interaction analysis for overall survival for patients with solid tumors receiving immune checkpoint inhibitors; factors included gender and Eastern Cooperative Oncology Group performance status. The survival was higher for male patients with a performance status of 0–1, however, the curves overlapped for patients with a performance status of 2–4 (P = 0.049)

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The adverse effects experienced by the patients are depicted in [Table 3]. The most common adverse effect was fatigue (all grade) which occurred in 17 (14.3%) male and 6 (16.7%) female patients. The rates of all adverse events were similar in male and female patients, except for pneumonitis. All-grade pneumonitis occurred in 7 (5.8%) male patients, while it was not reported in any female patient. All-grade immune-related adverse effects (irAEs) occurred in 24 (20.2%) male and 4 (18.1%) females patients (P = 0.216).
Table 3: Toxicities in the male and female patients receiving immune checkpoint inhibitors

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  Discussion Top


Our study evaluating the real-world data on the outcomes and toxicities of 155 patients with advanced solid tumors receiving ICIs found that the efficacy and toxicity were similar between the male and female patients. Although meta-analyses have , meta-analyses that have reported the beneficial effects of ICIs on PFS and OS were greater for male than female patients:[12],[13],[14] our study finds that these differences were not significant in our patient population treated in the real-world setting.

Most of the baseline characteristics of the male and female patients were not significantly different, but a PS of 0–1 was observed in a significantly greater proportion of the male patients. Even though the outcomes were not statistically different between male and female patients, both the PFS and OS were numerically better in the male patients. This is in agreement with the findings of a meta-analysis by Botticelli et al. in which no statistically significant differences were observed in the PFS and OS with PD-1 inhibitors; however, a similar analysis could not be performed for anti-PD-L1 inhibitors due to the lack of data.[12] Another interesting aspect of Botticelli et al.'s analysis was that they reported superior outcomes with cytotoxic T-lymphocyte antigen-4 inhibitors in male as compared to female patients. In our study, only PD-1 inhibitors (nivolumab in 97.4% and pembrolizumab in the remaining patients) were used. Another large study by Wang et al. involving 9583 patients with NSCLC reported contrary results.[13] The authors observed that PD-1/PD-L1 inhibitors alone or in combination with chemotherapy significantly improved both the PFS and OS in male patients and only the PFS in female patients. However, this study included only patients with NSCLC. A meta-analysis by Conforti et al. including data from 11,000 patients with various solid tumors receiving PD-1 or PD-L1 inhibitors, reported a significant OS benefit for both male and female patients. However, the magnitude of benefit was significantly higher (P = 0.0019) among the male patients (HR, 0.72; 95% CI, 0.65–0.79) as compared to the female patients (HR, 0.86; 95% CI, 0.79–0.93).[14] Graham et al. presented the results of their analysis of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) as a correspondence to the study by Conforti et al.[14] They found that nivolumab (n = 294) led to better OS than everolimus (n = 1436) after adjusting for the IMDC criteria and sex, with no effect of sex on the efficacy of nivolumab.[15] Graham et al. concluded that the effect of sex on the patients' survival could be influenced by the confounding variables.

In our cohort, the toxicity profiles for the male and female patients were similar, except for pneumonitis, which was reported only in the male patients. This is in contrast to the findings from the study by Duma et al., which included patients with metastatic melanoma and NSCLC. This study reported that women were more likely to experience irAEs as compared to men.[16] In addition, the main irAEs that led to the differences in the toxicity profiles for the male and female patients were pneumonitis and endocrinopathies, both being significantly higher in the female patients. However, another recent meta-analysis of findings from 13 studies by Jing et al. reported minimal differences in irAEs based on the sex of the patient.[17] Thus, highly conflicting data are available in the literature for the effect of the sex of the patient on both the efficacy and irAEs of ICIs.

The limitations of our study include the retrospective collection of data and predominance of patients with NSCLCs and head-and-neck cancers in the cohort, thus precluding the application of the study results to all types of solid tumors treated with ICIs. The survival analysis in such a heterogeneous patient population is expected to be of limited value. There were only 36 (25%) women in the study cohort, which is a small number considering that this study was aimed at assessing the subtle differences in the efficacy and toxicity based on the sex. The data for the PD-L1 status were not available in majority of the cases and hence have not been included in the study. However, it should be noted that this study predominantly enrolled patients treated with nivolumab in the second line setting or beyond, where the use of nivolumab is approved without PD-L1 testing. Despite the limitations, our study provides important real-world data on the efficacy and toxicity of ICIs based on the sex of the patients.


  Conclusions Top


Our study shows that the efficacy and toxicity of ICIs are similar in both the male and female patients. Future trials with a balanced number of male and female patients are required to ensure an unbiased estimation of the efficacy and safety of ICIs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: :Supplementary Appendix 1: Study protocol





 
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Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Mahajan A, et al. Concomitant use of antibiotics and immune checkpoint inhibitors in patients with solid neoplasms: retrospective data from real-world settings. Ecancermedicalscience 2020;14:1038.  Back to cited text no. 10
    
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Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Abraham G, et al. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with solid neoplasms: A real-world experience from a tertiary cancer center. Cancer Res Stat Treat 2019;2:204-8.  Back to cited text no. 11
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Botticelli A, Onesti CE, Zizzari I, Cerbelli B, Sciattella P, Occhipinti M, et al. The sexist behaviour of immune checkpoint inhibitors in cancer therapy? Oncotarget 2017;8:99336-46.  Back to cited text no. 12
    
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Wang C, Qiao W, Jiang Y, Zhu M, Shao J, Ren P, et al. Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer Med 2019;8:4023-31.  Back to cited text no. 13
    
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Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients' sex: A systematic review and meta-analysis. Lancet Oncol 2018;19:737-46.  Back to cited text no. 14
    
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Graham J, Abdel-Rahman O, Choueiri TK, Heng DY; International mRCC Database Consortium. Re: Fabio Conforti, Laura Pala, Vincenzo Bagnardi, et al. Cancer immunotherapy efficacy and patients' sex: A systematic review and meta-analysis. Lancet Oncol 2018;19:737-46: Outcomes of metastatic renal cell carcinoma by gender: Contrasting results from the International mRCC Database Consortium. Eur Urol 2018;74:e139-40.  Back to cited text no. 15
    
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Duma N, Abdel-Ghani A, Yadav S, Hoversten KP, Reed CT, Sitek AN, et al. 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? Oncologist 2019;24:e1148-55.  Back to cited text no. 16
    
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Jing Y, Zhang Y, Wang J, Li K, Chen X, Heng J, et al. Association between sex and immune-related adverse events during immune checkpoint inhibitor therapy. J Natl Cancer Inst. 2021 Mar 10:djab035. doi: 10.1093/jnci/djab035. Epub ahead of print  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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