Sex Differences in Efficacy of ICIs in NSCLC: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Guillermo Suay Montagud.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC) patients (IB-IIIA) with no targetable driver mutations. Although genetic and physiological factors could suggest a priori differences in response to ICIs regarding sex. It is well established that women have a more proficient immune system; thus, a higher immune editing level is needed to develop metastatic disease, which could explain their better responses in the early phases of disease. Furthermore, the encouraging results observed for metastatic disease have promoted the use of ICIs as neoadjuvant treatments.

  • immune checkpoint inhibitors
  • NSCLC
  • neoadjuvance
  • sex
  • PD-L1
  • immune system

1. Introduction

Non-small cell lung cancer (NSCLC) is one of the main causes of cancer death worldwide, which is attributed to its late stage diagnosis [1,2,3][1][2][3]. Immune checkpoint inhibitors (ICIs) have emerged as a new treatment option in those patients without target mutations. Anti-programmed death receptor-1 (PD-1), anti-programmed death ligand-1 (PD-L1) and anti-cytotoxic T-lymphocyte protein 4 (CTLA4) have been developed to inhibit immune checkpoint pathways in order to prime anti-tumor activity of cytotoxic T-cells. PD-1 is a checkpoint protein and a composition of the CD28 family [4]. It pertains to a family of suppressor T-cell receptors, which is also expressed in B cells, monocytes and dendritic cells [5]. PD-L1 is a type 1 transmembrane glycoprotein of the B7 ligand family, which is not only expressed on activated B cells and T cells, but also on other type of cells [6]. This pathway intervenes to downregulate T cell functions in antigen-presenting cells. T cells recognize tumor cells and kill them, but when tumor cells upregulate the PD-L1 protein, it binds to PD-1 and leads to the apoptosis of T cells [7]. PD-1 and PD-L1 inhibitors interdict the combination between PD-1 and PD-L1 and effectively produce an activation of depleted immune cells, triggering an immune response to the tumor [8]. CTLA4 is a critical immune checkpoint expressed on the surface of activated T cells. It plays a role in early T cell response development. There is a competition for B7 ligands expressed on antigen-presenting cells against CD28. CTLA4 blocks the formation of the immunological synapse between the T cell and the antigen-presenting cell [9]. The role played by this checkpoint involves maintaining self-tolerance and preventing autoimmune reactions. CTLA4 plays a pivotal role as a regulator of the cancer immunity cycle, and the inhibition of this element has shown to lead to an improvement in the immune response to different tumors [10]. The safety profile of ICIs is acceptable in monotherapy or in combination with chemotherapy. The toxicity is different to that of chemotherapy and associated with hyperstimulation of the immune system, including the reactivation of previous autoimmune syndromes [11,12][11][12]. All types of autoimmune diseases have been described, with a preponderance of dermatologic, gastrointestinal, or endocrinological alterations, although clinically significant toxicities are infrequent, and they usually occur in less than 10% of patients [13].
The use of anti-PD1/PD-L1 monotherapy in patients with high tumor PD-L1 expression (≥50%) increased progression-free survival (PFS) and overall survival (OS), as shown in EMPOWER-Lung 1 [14], KEYNOTE-024 [15] and Impower110 [16] trials, which established single-agent immunotherapy as the standard first-line therapy for metastatic NSCLC patients without targeted alterations and high tumor PDL1 expression (≥50%). In contrast, when negative or low PD-L1 expression is observed, the combination of chemotherapy plus anti-PD1/PD-L1 with or without anti-CTLA4 is used, which delivers an increase in both PFS and OS, as shown in the KEYNOTE-189 [17], KEYNOTE-407 [18], IMpower150 [19] and CheckMate 9LA [20] trials. Despite the important clinical benefits reported, the results of phase III clinical trials using ICIs in monotherapy suggested that sex may impact treatment outcomes after observing a worse hazard ratio (HR) for females compared to males [14,15,16][14][15][16]. These results need to be further confirmed, as sex is neither usually considered to be a stratification factor in clinical trials nor included in the clinical guidelines [21,22][21][22].

32. Current Clinical Settings of Neoadjuvance in NSCLC

3.1. The Neoadjuvant Setting in the Pre-ICIs Era

2.1. The Neoadjuvant Setting in the Pre-ICIs Era

The good results achieved in the metastatic setting have promoted the use of ICIs as perioperative treatments. The 5-year OSs of patients who underwent a pulmonary resection are 68%, 60%, 53% and 36% for stages IB, IIA, IIB and IIIA, respectively [36][23]. The new ICIs approaches exploring the neoadjuvant and adjuvant settings aimed to improve the quality of life and OS of these patients. The current use of neoadjuvant chemotherapy in NSCLC is mainly supported by the Meta-Analysis Collaborate Group, which combined 15 randomized controlled clinical trials, showing a significant benefit of pre-operative chemotherapy on survival (HR 0.87; CI 95% 0.78–0.96, p = 0.007) and a 13% decrease in the relative risk of death. These findings represented an absolute survival improvement of 5% after 5 years [37][24].

3.2. The Development of the Neoadjuvant Setting in the ICIs Era

2.2. The Development of the Neoadjuvant Setting in the ICIs Era

32.2.1. Neoadjuvant ICI

The use of neoadjuvant ICIs is mostly supported based on the assumption that this treatment may control micrometastases in early phases. In this sense, it has been shown that T cells are activated via the recognition of the presented tumor antigens and travel through the lymphatic system and the bloodstream to reach primary and metastatic sites. Therefore, it has been assumed that immunotherapy may better control the tumor in the pre-operatory setting because of lymphatic and blood flow integrity between the tumor and regional lymph nodes, which is not present in the adjuvant setting [39][25]. Pre-clinical tests have shown that mice with neoadjuvant ICI therapy had longer survival than those that were treated with adjuvant ICIs [40][26].Based on these results, ICIs have been tested in the neoadjuvant setting in monotherapy or combined with chemotherapy. In 2018, Forde et al. published a pilot trial of nivolumab in resectable NSCLC [24][27]. In this study, patients with stage I-IIIA NSCLC received two doses of nivolumab every 2 weeks, followed by surgery in week 4 after the first dose. In total, 22 patients were enrolled, of whom 21 were eligible for the study. The primary endpoints of the study were safety and feasibility; pathological response, expression of PD-L1, mutational burden and neoantigen-specific T-cell responses were also analyzed. The pathological assessment of the removed tumors showed a major pathological response (MPR; defined as ≤10% viable malignant cells) in nine patients (42.85%). The side effect profile was acceptable and not associated with delays in surgery. The NEOSTAR study was a randomized phase II trial of neoadjuvant nivolumab vs. nivolumab and ipilimumab in operable NSCLC (stage I to IIIA) [25][28]. 

32.2.2. Neoadjuvant ICI Plus Chemotherapy

After observing the good results of the combination of ICI plus chemotherapy in stage IV NSCLC treatment, recent clinical trials have investigated this approach in the neoadjuvant setting, providing promising results [29,30,31,32,33,34,35][29][30][31][32][33][34][35]. One of the first studies, which was published by Shu et al., was a phase II trial in which patients with resectable stage IB-IIIA NSCLC received pre-operative treatment with atezolizumab on day 1 and nab-paclitaxel on days 1, 8 and 15 of 21 [29]. Patients received four cycles before proceeding to surgery. The primary endpoint was MPR. In total, 29 of the 30 patients were enrolled and, thus, received an operation. MPR were observed in 17 patients (57%). Side effects were manageable, with no treatment-related deaths occurring. The SAKK 16/14 study was a phase II trial that explored the neoadjuvant setting in stage IIIA-N2-positive patients with NSCLC [30]. It was a single-arm trial in which patients received cisplatin plus docetaxel on day 1 every 3 weeks for three cycles, followed by two doses of durvalumab every 2 weeks. Patients then proceeded to surgery, and one additional year of durvalumab was administered. The primary endpoint was event-free survival (EFS), and the key secondary endpoints were OS, objective response rate (ORR) after neoadjuvant chemotherapy and immunotherapy, pCR and MPR. In total, 67 patients were analyzed, and 55 patients were resected; the 1-year PFS was 73% (95% CI 63–82%), which met the proposed hypothesis. Three randomized neoadjuvant trials have been published: the Checkmate-816 [32], the NADIM-II [33,34][33][34] and the KEYNOTE-671 [35] trials. The Checkmate-816 study [32] was the only phase III trial published, as well as the largest trial. Patients with resectable IB-IIIA NSCLC were randomized 1:1 to receive either nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by surgery. The primary endpoints were EFS and pCR. The key secondary endpoint was OS. In total, 179 patients were enrolled in each arm of the study. The median EFS was 31.6 months (95% CI 30.2-NR) with the chemotherapy–nivolumab combination versus 20.8 months (95% CI 14–26.7 months) with chemotherapy alone (HR 0.63; 95% CI 0.43–0.91). Median OS was not reached in either the chemotherapy–nivolumab group or the chemotherapy alone groups (HR for death 0.57; 99.67% CI 0.30–1.07). The percentage of patients with MPR was 36.9% in the chemotherapy–nivolumab arm versus 8.9% in the chemotherapy arm, and the pCR was 24% (95% CI 18–31%) in the experimental arm vs. 2.2% (95% CI 0.6–5.6%) in the control arm (OR 13.94; 99% CI 3.49–55.75). Grade 3 or greater treatment-related adverse events occurred in 33.5% of the patients in the experimental group versus 36.9% in the control group. The incidence and characteristics of immune adverse events in the pembrolizumab group were similar to those stated in previous reports. 

3. Sex Differences in Immune Response

In recent years, sex has been identified as one of the main elements that can modulate the immune response [41,42][36][37]. Women usually elicit a stronger immune response than men [43][38], a fact that might explain why autoimmune diseases prevail in this group of patients, as well as why infections are more severe in the male population [39][25]. At the basic level, multiple differences have been found in the innate and adaptive immune systems of both sexes [44,45,46][39][40][41]. In adult humans, there are differences in sex lymphocyte subsets: there is a higher number of CD4+ T cell counts and higher CD4/CD8 ratios in females than in same-age males. Transcriptional analyses have also shown a higher cytotoxic T cell activity in females than in males [41][36]. All of these differences point to sex differences in the immune response triggered against NSCLC, which led to the complete analysis of this phenomena by Conforti et al. [47][42]. This analysis showed important differences in early-stage tumors (stage I–III). In a pooled analysis, it was found that dendritic cells, CD4+ T cells, B cells and Mast cells were more enriched in the tumor microenvironment (TME) of women than in men, with a false discovery rate cut-off ≤0.05. Other cells found to be relevant in this response were regulatory T cells, natural killer T cells, M1 type macrophages, CD8+ T cells and eosinophils. TME in female patients was also significantly enriched in cancer-associated fibroblasts, granulocyte–macrophage progenitors and hematopoietic stem cells, which have been shown to exert immunosuppressive activities in the TME. The T-cell landscape was also analyzed in early-stage tumors [47][42]. The following analyzed T-cell subpopulations were significantly enriched in the TME of women: (1) CD8+ and CD4+ naïve T cells, (2) CD8+ and CD4+ effector T cells, (3) CD8+ and CD4 T-cell subpopulations with an intermediate functional state. Taking all of these results into account, like the lower number of immune cells in TME, the higher T-cell exclusion score, and the smaller TCR clonality, they show that tumors in men have less efficient tumor infiltration via the immune system and less tumor recognition [47][42]. However, because of the efficiency of the immune system of women, NSCLC develops more complex and redundant mechanisms of resistance, as shown by the higher expression of immune checkpoint molecules with inhibitory functions. 

Sex-Based Immune Response to ICI

Despite their being scarce literature addressing sex-based difference response to ICIs, some differences have been reported. Hormones can change the function and expression of PD-1 and mediate autoimmunity [52,53][43][44]. Furthermore, in pre-clinical melanoma murine models, the different efficacy of anti-PD-L1 in relation to the sex has been described [54][45]. In this sense, Conforti et al. [55][46] hypothesize that male patients could have a better benefit from ICI in metastatic disease than female patients due to three considerations: (1) There is sex dimorphism in immunity. Tumors in woman tend to have a better immune surveillance system and need a stronger immune-editing process to produce metastases [55][46]. This process could make the tumors less immunogenic and have more mechanisms to evade the immune system. This issue would make the tumor more resistant to immunotherapy [56][47]. (2) The tumor mutational burden is significantly higher in male patients, irrespective of other factors [57][48]. Finally, (3) there is a lower smoking prevalence in female than male populations, which affects the tumor mutational burden stemming from this behavior [58][49].

4. Summary

The perioperative landscape of NSCLC is continuously evolving and will change the clinical practice of treating this disease in the coming years. The neoadjuvance was relegated to specific settings before the introduction of ICIs [21[21][22],22], but the evidence shows a change in paradigm [24,25,26,27,28,29,30,31,32,33,34,35][27][28][29][30][31][32][33][34][35][50][51][52]. The neoadjuvant approach is quite promising, having an increased number of MPR and pCR [24,25[27][28][29][30][31][32][33][34][35][50][51][52],26,27,28,29,30,31,32,33,34,35], which has led to one of the most important changes in everyday clinical practice with the approval of the CheckMate-816 protocol by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, different approaches in many clinical trials are yet to show the optimal sequence of treatment, such as pre-operative ICIs versus adjuvant ICIs. Moreover, there are still some questions that need to be answered: Might the surgical procedure become more difficult for the thoracic surgeons due to treatment-induced changes? What is the optimal stage at which to use this treatment? Should all patients receive a combination of ICIs plus chemotherapy, or are there some settings in which ICI monotherapy could be enough? According to evidence of the phase III CheckMate-816 and KEYNOTE-671 trials, it seems that surgical complications are the same or less frequent in the ICI plus chemotherapy group than in the chemotherapy alone group [32,35][32][35]. Regarding the optimal stage to select, the phase III CheckMate-816 and KEYNOTE-671 trials [32[32][35],35], which included stage IB (in the CheckMate-816 trial), II, and III patients, showed a global benefit for all of the cohort. However, the benefit was higher in patients with stage IIIA tumors. This effect led studied authors to establish in the SAKK 16/14 [30], NADIM [31] and NADIM-II [33,34][33][34] trials an inclusion criterion, which required the involvement of stage IIIA patients. This point is controversial, as it is argued in the discussion of the CheckMate-816 and KEYNOTE-671 trials that the stage IB or II patients were under-represented, and further research should be performed in that specific setting. Future approaches could include a comparison of neoadjuvant combination of ICIs plus chemotherapy with adjuvant ICIs, like atezolizumab [61][53], in different stages (e.g., IB, II, III). Nevertheless, it seems clear that, with ICIs, it is possible to rescue many stage IIIA patients who would not be operated on in the past, which is a great achievement at such a poor prognostic stage. Another setting that would be interesting to compare is the use of neoadjuvant ICIs, followed by surgery against chemotherapy plus radiotherapy, as a radical treatment in the stage IIIA setting [62][54], particularly in case of N2 disease. Future treatment approaches that could modulate the tumor immune environment are currently being studied, such as the use of metformin-modified chitosan to increase the susceptibility of platin-based chemotherapy and downregulate PD-L1 expression [63][55]. Regarding the optimal regimen and settings that need to be selected, including the addition of chemotherapy, different clinical factors should be considered: One of the most relevant factors, which is obviated in many trials, is sex. Historical series show a better outcome of NSCLC in woman than in men [64,65][56][57], and part of this difference could be explained based on the better immune control of the disease in women in the localized setting. ICIs have changed the paradigm of the neoadjuvant treatment of NSCLC by increasing MPR and pCR, which was unattainable through the use of chemotherapy alone, a fact that led to the neoadjuvant setting being discarded barring some specific situations. Yet, there are many doubts regarding the optimal combinations of drugs that should be used, the stages that benefit from this approach and the relevant factors that should be considered. Data are scarce, but as the analysis shows, sex is a key element. It is known that women have a more proficient immune system, which may help to control disease in localized NSCLC. This fact could enable disease control in non-metastatic NSCLC and induce a better response to ICIs compared to men, most likely due to women’s superior immune capacity to detect and remove tumor cells.

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