Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

Grassadonia, Antonino; Sperduti, Isabella; Vici, Patrizia; Iezzi, Laura; Brocco, Davide; Gamucci, Teresa; Pizzuti, Laura; Maugeri‐Saccà, Marcello; Marchetti, Paolo; Cognetti, Gaetana; Tursi, Michele De; Natoli, Clara; Barba, Maddalena; Tinari, Nicola

doi:10.3390/jcm7120542

Cited by 75 publications

(44 citation statements)

References 65 publications

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“…For example, highest lung cancer and melanoma incidence rates have been recognized in men (Vavalà et al, 2016;Smalley, 2018). Furthermore, our result should be related to the hypothesized but still debated (Postow et al, 2018) correlation between irADRs onset and immunotherapy efficacy (Haratani et al, 2018;Sato et al, 2018), the latter seems to be superior in men (Conforti et al, 2018;Grassadonia et al, 2018;Wu et al, 2018). Since ICIs act on the immune system, irADRs can involve any tissue and organ, probably due to activation of autoreactive T cells damaging host tissues (Sanchez et al, 2019).…”

Section: Discussionmentioning

confidence: 54%

“…Sex-based immunological differences, expressed in different immune responses to infections as well as in different predisposition to develop autoimmune diseases are reported in literature (Taneja, 2018). However, the gender-influence on the efficacy and safety of immunotherapy treatments seems to be controversial (D'Amici et al, 2013;Conforti et al, 2018;Grassadonia et al, 2018;Wallis et al, 2019). What we have found should be related to gender differences in incidence rates of diseases representing therapeutic indications of ICIs treatment.…”

Section: Discussionmentioning

confidence: 63%

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Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database

et al. 2020

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Background: The introduction of immune checkpoint inhibitors (ICIs) in clinical practice has brought significant benefits for patients. Seven ICIs are available in Europe: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, and ipilimumab. Despite their proven clinical efficacy, these innovative drugs may cause serious immune-related adverse drugs reactions (irADRs). Given the significance of these ADRs for patients' health, we analyzed individual case safety reports (ICSRs) related to ICIs, focusing on those reporting irADRs, collected in the Italian spontaneous reporting database. Methods: We analyzed ICI-induced irADRs collected in the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza [RNF]) from January 1, 2002, to February 28, 2019, focusing on those reported in the Campania Region. We retrieved from an open-access Italian pharmacovigilance system, the RAM system (for national safety data), and from the RNF (for Campania safety data) all ICSRs reporting ADRs related to ICIs authorized until the analysis date. Focusing on irADRs, we performed descriptive and disproportionality analyses through the reporting odds ratio (ROR) with 95% confidence interval. Results: National results. Among 2,088 ICI-related ICSRs, 801 reported irADRs. The majority of such ADRs occurred in male patients reporting gastrointestinal and skin toxicities. Nivolumab and pembrolizumab were drugs most commonly reported as suspect drugs. Compared to other ICIs, ROR was statistically significant for pembrolizumab and ipilimumab. Campania Region results. Out of 253 ICI-related ICSRs sent to Regional Pharmacovigilance Center of Campania Region, 121 reported at least one ICI-induced irADR. These were serious in 37.2% of cases and had an unfavorable outcome in 32.2% of cases. Overall, out of 8 ICSRs reported ADR with a fatal outcome, four reported irADRs. From disproportionality analyses on Campania Region ICSRs, statistically significant ROR emerged only for ipilimumab.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 63%

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database

et al. 2020

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“…The complexity is further augmented by disparities between the ICI agents, for example, the anti-CTLA4 antibodies being more sex-related than the anti-PD-1 ones. Indeed, sex-related differences seem more relevant to overall survival in melanoma patients than in other cancers [208,209].…”

Section: Sex Differences and Response To Therapiesmentioning

confidence: 99%

Sex and Gender Disparities in Melanoma

Bellenghi

Puglisi

Pontecorvi

et al. 2020

Cancers

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Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more frequent on the trunk in men and on the lower limbs in women. A debated issue is if—and to what extent—melanoma development can be attributed to gender-specific behaviors or to biologically intrinsic differences. In the search for factors responsible for the divergences, a pivotal role of sex hormones has been observed, although conflicting results indicate the involvement of other mechanisms. The presence on the X chromosome of numerous miRNAs and coding genes playing immunological roles represents another important factor, whose relevance can be even increased by the incomplete X chromosome random inactivation. Considering the known advantages of the female immune system, a different cancer immune surveillance efficacy was suggested to explain some sex disparities. Indeed, the complexity of this picture emerged when the recently developed immunotherapies unexpectedly showed better improvements in men than in women. Altogether, these data support the necessity of further studies, which consider enrolling a balanced number of men and women in clinical trials to better understand the differences and obtain actual gender-equitable healthcare.

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“…The higher discriminatory power was observed for the tumor localization. There is also a relationship between tumor localization and sex, as melanomas in the extremities occur more frequently in females, and females have a less favorable response to immunotherapy than males [32][33][34]. Accordingly, sex was a significant risk factor in the univariate analysis but not in the multivariate analysis.…”

Section: Discussionmentioning

confidence: 95%

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Amaral

Seeber

Mersi

et al. 2020

Cancers

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Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

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Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

Cited by 75 publications

References 65 publications

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database

Sex and Gender Disparities in Melanoma

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

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