Efficacy of immunotherapy in older patients with triple-negative breast cancer: a systematic review

Efficacy of immunotherapy in older patients with triple-negative breast cancer: a systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Efficacy of immunotherapy in older patients with triple-negative breast cancer: a systematic review Carrie Sha, Marie Liu, Ashley Schreier, Roberta Zappasodi, Johanna Goldberg, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7024355/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Immune checkpoint inhibitors (ICI) have emerged as a promising treatment for patients with triple-negative breast cancer (TNBC); however, there exists a notable gap in our understanding of their efficacy within the older patient population. The objective of this systematic review is to evaluate the efficacy of ICI in patients with TNBC who are 65 and older. We conducted a comprehensive systematic search using Medline, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform of randomized controlled trials (RCTs) reporting efficacy of ICI from January 2013 to September 2023. Our systematic review identified 18 full-text papers encompassing 11 unique RCTs. Only four RCTs presented results for patients 65 and older: KEYNOTE 355, KEYNOTE 522, IMPASSION 130, and IMPASSION 131. In these four studies, 602 patients out of 3215 patients (18.7%) were 65 and older. The overall risk of bias was rated low or intermediate in all 11 RCTs. Variations in primary endpoint, cancer stage, and ICI precluded meta-analysis. There is a significant gap in data from RCTs evaluating the efficacy of ICI in older patients with TNBC. The only FDA-approved ICI in TNBC, pembrolizumab, was shown in the early-stage setting to improve pathological complete response (pCR) and event-free survival (EFS) in older patients but was not statistically significant (KEYNOTE 522). In the metastatic setting, pembrolizumab may improve overall survival (OS) in older patients with combined positive score (CPS) ≥ 10 (KEYNOTE 355). Although atezolizumab in the metastatic setting showed initial promise in improving OS in the PD-L1 + population (IMPASSION 130), there was no difference in progression-free survival (PFS) nor OS between atezolizumab and placebo arms in IMPASSION 131. All studies had a limited number of patients 65 and older. These results underscore the need for further research on ICIs in older patients with TNBC. Biological sciences/Cancer Health sciences/Oncology Figures Figure 1 Introduction Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States. 1 Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER) expression, progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification. TNBC accounts for approximately 11–15% of all breast cancers and is more prevalent among younger women, particularly those of African and Hispanic descent. 2 , 3 It is also more common in patients with BRCA1 germline mutations and accounts for 80% of breast cancers in BRCA1 mutation carriers. 4 – 6 Compared to ER-positive breast cancer, TNBC is associated with a higher risk of distant recurrence, higher rates of visceral and central nervous system metastases, earlier time to recurrence, and worsened survival. 6 – 8 The aggressive biology along with the paucity of treatment options for TNBC make this disease difficult to treat, and patients are often faced with a grim prognosis, particularly in the metastatic setting. The treatment of TNBC remains very limited; there are no approved targeted treatments for TNBC with the exception of the poly ADP-ribose polymerase (PARP) inhibitor olaparib in select patients with BRCA1 or BRCA2 mutations. 9 More recently, antibody-drug conjugates sacituzumab govitecan 10 and trastuzumab deruxtecan 11 have been incorporated in the standard-of-care for metastatic TNBC patients, but long term prognosis remains limited. For most patients with TNBC, treatment options continue to rely primarily on cytotoxic chemotherapy, typically with taxane and anthracycline backbones. 7 , 12 – 14 Importantly, a sizable subset of TNBC tumors are immunogenic and can respond to immune checkpoint inhibitors (ICI), which have emerged as a promising treatment option for improving outcomes in patients with TNBC. 15 The PD-1 inhibitor pembrolizumab is currently the only ICI approved by the U.S. Food and Drug Administration (FDA) for treatment of TNBC, and is used in the neoadjuvant setting for locally advanced tumors regardless of PD-L1 status and in the metastatic setting for PD-L1 positive tumors. 16 , 17 Of note, atezolizumab was initially granted accelerated FDA approval based on the results of the IMPASSION 130 trial comparing atezolizumab nab-paclitaxel to placebo nab-paclitaxel; however, the FDA approval was revoked based on the negative findings from the IMPASSION 131 trial comparing atezolizumab paclitaxel to placebo paclitaxel. 18 – 22 While the efficacy of pembrolizumab in combination with chemotherapy has been well documented in these clinical settings, our understanding of its effectiveness among older patients, a demographic often underrepresented in clinical trials, is lacking. Older patients make up a significant portion of patients with TNBC as approximately 35% of newly diagnosed patients with TNBC are age 65 and older. 23 Although head-to-head comparisons of mortality in younger and older patients may be difficult to interpret due to variations in tumor biology, differences in likelihood of undergoing surgical resection and adjuvant radiation and chemotherapy may be responsible for increases in cancer-specific mortality among older patients. 24 , 25 Chemotherapy toxicities are more frequent and longer lasting in the older population. 26 While fewer elderly patients may receive treatment due to comorbidities, diminished physiological reserve, and patient preferences, provider bias may also play a role, emphasizing the need to identify optimal treatment options in this vulnerable population. 25 Reduced dose intensity as a result of dose reductions and delays may compromise the effectiveness of treatment for older patients with breast cancer. 27 Numerous studies have shown that ICIs are effective and safe in elderly patients with other cancer types. A single-center cohort study demonstrated no significant differences in overall survival (OS) and progression-free survival (PFS) between patients older than 65 and younger patients with metastatic solid tumors treated with ICIs. 6 Similarly, a systematic review and meta-analysis in elderly patients with head and neck squamous cell carcinoma reported consistent improvements in OS and PFS with immunotherapy in this population. 28 In metastatic melanoma, enhanced responses to anti-PD-1 therapy were observed among elderly patients, including those in their 80s and 90s, with comparable survival outcomes and similar toxicity profiles to those of younger patients. 29 Additionally, a meta-analysis of advanced non-small cell lung cancer patients revealed no significant differences in OS benefit between patients aged 75 and older and younger patients, suggesting consistent efficacy across age groups. 30 However, there have been no recent studies examining ICI efficacy in elderly patients with TNBC. In elderly patients, the immune system undergoes immunosenescence, which refers to the gradual deterioration of the immune system associated with aging. Immunosenescence can affect the body's ability to mount an effective immune response, potentially altering the efficacy of immunotherapies. 31 Through this process, both innate and adaptive arms of the immune response are affected. Among innate cells, neutrophils decrease their motility, phagocytic, and killing function, macrophages decrease their capacity to clear apoptotic bodies, which can contribute to inflammation, and become more prone to acquire pro-inflammatory phenotypes, and dendritic cells (DCs) reduce their antigen presentation function as the host ages. As part of the adaptive immune system, T lymphocytes are the cell type for which the most profound impact of aging has been described. During aging, thymic involution results in proportional decreases in naïve T cells with consequent increases in memory and effector T cells within the T-cell pool. This ultimately skews the T-cell repertoire toward specificity for previously encountered antigens that remain in the memory T-cell pool, while limiting the body’s capacity to recognize novel antigens to which the host has never been exposed before. In addition, non-naïve T cells are characterized by shorter telomeres due to their history of prior cell divisions, which implies limited proliferation potential. In addition to these functional changes, the elderly show quantitative decreases in adaptive immune cells (T and B cells) with compensatory increases in some innate immune cell subsets (neutrophils and natural killer cells) in peripheral blood. Overall, these changes weaken the ability of the immune system to effectively recognize and react to novel non-self antigens, which can particularly affect tumor immunosurveillance and response to immunotherapy. 32 , 33 Due to these biological factors that may impact the anti-tumor T-cell response, evaluating the effectiveness of ICI in older patients is crucial. This systematic review addresses these knowledge gaps by evaluating randomized controlled trials (RCTs) that specifically explore the response to ICI in older patients with TNBC. Although the focus is on pembrolizumab, we also review the literature on atezolizumab and durvalumab to understand any differences in outcomes for older patients. By concentrating on this subset of the geriatric population, we hope to provide more precise insights into ICI's potential benefits and risks for elderly patients facing this challenging diagnosis, informing clinical practice and guiding future research in this crucial area. Methods Our systematic review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines (see PRISMA checklist). Search Strategy A librarian (JG) designed a search in Medline ALL (Ovid) using subject headers and keywords for three main concepts: (1) immune checkpoint inhibitors, specifically atezolizumab, durvalumab, and pembrolizumab; (2) breast cancer; and (3) randomized controlled trials. The search string for RCTs was based on the RCT / CCT filter from the CADTH (now CDA-AMC) Search Filters Database. 34 , 35 A second librarian performed a PRESS Peer Review of Electronic Search Strategies, and then the search was translated with the aid of the Polygot Search Translator to Embase (Elsevier), Cochrane Central Register of Controlled Trials (Wiley), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP, https://trialsearch.who.int/) . 36,37 All databases were searched on September 7, 2023. In Medline and Embase, the Cochrane filter was used to limit results to humans. 38 Results were also limited to items published in English from January 2013 through the search date. Conference abstracts and conference reviews were excluded in Embase, and review articles were excluded in Medline and Embase. Due to the nature of the databases, Cochrane Central, ClinicalTrials.gov, and the WHO ICTRP searches did not include search strings for RCTs. ClinicalTrials.gov and the WHO ICTRP results were limited to items with results. Search results from all databases were uploaded to the systematic review management tool Covidence (Veritas Health Innovation), which removed duplicates. For the full search strategy, please see Supplementary Data 1. Inclusion and Exclusion Criteria Inclusion criteria included: (1) randomized control trials with 2 + arms (2) study must have included adults with triple-negative breast cancer (3) must have included PD1/PDL1 therapy as intervention (4) must have had some measure of efficacy (PCR, ES, OS, PFS, etc.) (5) must have results published. Studies including population subgroups of larger clinical trials were included. Multiple studies performed at different time points of one clinical trial (e.g., interim, primary, secondary, and final analysis) were included. Exclusion criteria included (1) biomarker/non-interventional studies, (2) studies focused on patient-reported outcomes, and (3) studies without full-text articles. Selection Process Using the Covidence platform, abstract and full-text screening was performed by two independent reviewers (CS and ML) and conflicts were resolved through consensus meetings with both reviewers and a third reviewer (IZ). Data Extraction For each study, data including paper title, author, year of publication, trial name, immunotherapy, TNBC stage (early-stage versus metastatic), chemotherapy backbone, follow-up time, study population (n), average age, population ≥ 65 years (n), primary and secondary outcomes, outcomes for population ≥ 65 years (if available), and risk of bias were collected by two independent reviewers (CS and ML). For synthesis, studies were grouped by TNBC stage (early versus metastatic setting) and ICI (pembrolizumab, atezolizumab, or durvalumab). Risk of Bias Assessment Risk of bias assessment was performed, and overall risk of bias was graded according to Cochrane Risk of Bias. Each study’s risk of bias was assessed based on subcategories, and each reviewer rated each subcategory as either “low,” “intermediate,” or “high.” The subcategories included sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data (for age ≥ 65 years), incomplete outcome data (for overall population), and representation of ≥ 65 years population. Two independent reviewers (CS and ML) rated each study, and conflicts were resolved by a third reviewer (IZ). All three reviewers developed a numerical scale for overall risk of bias: high overall risk of bias correlates with ≥ 4 subcategories “high”; intermediate overall risk of bias correlates with 2–3 subcategories “high”; low overall risk of bias correlates with ≤ 1 subcategories “high.” Effect Measures and Synthesis Effect measures were collected as hazard ratios (HR), odds ratios (OR), or estimated treatment difference, depending on how primary endpoints were presented in the original RCT. Due to differences in primary endpoints (e.g. pCR, OS, EFS, PFS), cancer stage, and ICI used among studies, meta-analysis was not performed. Results were synthesized in a table (Table 1). The primary endpoints were interpreted as either 1) favoring immunotherapy with chemotherapy backbone or 2) no difference between immunotherapy-chemotherapy versus placebo-chemotherapy or chemotherapy alone. Interpretations were color-coded accordingly. Missing and unreported results were denoted N/A. Results Study Selection We identified 1665 studies through a comprehensive search across major databases, including CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and the World Health Organization. After removing duplicates, 1291 studies were identified for title and abstract screening. Based on inclusion and exclusion criteria, 39 studies were selected for full-text screening, of which 18 were identified for data extraction (see Figure 1). Study characteristics Our systematic review identified 18 full-text papers on 11 unique RCTs: NCI-10013; IMPASSION 031; IMPASSION 130; IMPASSION 131; ALICE; SAFIR02-BREAST; KEYNOTE 119; KEYNOTE 355; KEYNOTE 522; GeparNuevo; and NeoTRIP Michelangelo. These studies are summarized in Table 1 and detailed results by study are reported in Supplementary Data 2. Only four of the 11 RCTs (highlighted in the last column of table 1) presented results for the subgroup of patients 65 and older: KEYNOTE 355, KEYNOTE 522, IMPASSION 130, and IMPASSION 131. Of the first three, a total of 530 patients out of 2923 patients (18.1%) were 65 and older. In a subset analysis of IMPASSION 131, 72 out of 292 (24.7%) were 65 and older. Additionally, 3 of the 11 RCTs presented data stratified by another age demarcation: younger than or older than 40 (IMPASSION 031; GeparNuevo) or pre- or post-menopausal (NCI-10013). The remaining 4 RCTs did not present efficacy data stratified by age: NeoTRIP Michelangelo; KEYNOTE 119; SAFIR-02 BREAST; ALICE. Of these 11 RCTs, five were in early-stage TNBC and six in the metastatic setting. The PDL1/PD1 inhibitors studied were pembrolizumab (n = 3), atezolizumab (n = 6), durvalumab (n = 2). Of note, although all 11 RCTs listed toxicities and adverse events, no studies specified the frequency of toxicities or adverse events in patients 65 and older. Table 1. Study characteristics and key findings for selected clinical trials. Result summary Early-Stage Setting Pembrolizumab: Overall population Key clinical trials which specified results for patients 65 and older are noted in Table 1 and are described in more detail in Table 2. KEYNOTE 522 1 examined neoadjuvant and adjuvant pembrolizumab with a 4-drug chemotherapy backbone in the early-stage setting for locally advanced TNBC. 1174 patients were randomized in a 2:1 ratio to receive pembrolizumab or placebo with standard-of-care (SOC) chemotherapy paclitaxel and carboplatin followed by anthracycline plus cyclophosphamide. In the interim analysis with a follow-up of 15.5 months, the primary endpoint of pathological complete response (pCR) was significantly improved in patients in the intention to treat (ITT) population (ICI arm n = 401 patients; control arm n = 201 patients) who received pembrolizumab versus placebo (estimated treatment difference 13.6%, 95% CI 5.4 – 21.8%, p<0.001), with a pCR rate of 64.8% (95% CI 59.9 – 69.5%) vs. 51.2% (95% CI 44.1 – 58.3%) in the pembrolizumab-chemotherapy group vs. control group, respectively. Similarly, in the final analysis at 36 months, patients receiving pembrolizumab-chemotherapy were shown to have a significantly increased EFS compared to those receiving placebo-chemotherapy: 84.5% versus 76.8% respectively, p<0.001; hazard ratio (HR) 0.63 (95% CI 0.48 – 0.82, p<0.001). Pembrolizumab: Patients 65 and older In KEYNOTE 522, 132 of 1174 patients (11.2%) were 65 and older. Of the 602 total patients in the interim analysis, 71 patients (11.8%) were 65 and older (ICI arm n = 46; placebo arm n = 25). In patients older than 65, the treatment difference in pCR was 22.3% and statistically insignificant (95% CI -2.1 – 43.5%, p=N/A). In the final analysis, among the population of patients 65 or older, the HR for event or death was statistically insignificant at 0.79 (0.40 – 1.56, p=N/A). For those < 65, the HR was 0.61 (0.45 – 0.82, p=N/A). P-values were not reported. Atezolizumab and Durvalumab Both atezolizumab and durvalumab were investigated in the neoadjuvant setting as well. No trials specify efficacy data for patients 65 or older. Three studies provided subgroup analysis using alternative age brackets: NCI-10013 classified patients as pre or post-menopausal and both IMPASSION 031 and GeparNuevo divided patients into < 40 or ≥ 40, 40,42,44 making it difficult to delineate results for populations ≥ 65 which is the focus of this review. In IMPASSION 031 2 , neoadjuvant and adjuvant atezolizumab in the early-stage setting was shown to have a significant improvement in the primary endpoint of pCR in the ITT population (ICI arm n = 165; placebo arm n = 168; rate difference of 17%, 95% CI 6–27%, one-sided p=0.0044). NCI-10013 42 showed that adding atezolizumab to carboplatin and paclitaxel backbone improved pCR (estimated treatment difference: 36.8%, 95% CI 8.5 – 56.6%, p=0.018) whereas NeoTRIP Michelangelo 43 found that adding atezolizumab to carboplatin and nab-paclitaxel backbone did not improve pCR (odds ratio (OR) 1.18, 95% CI 0.74 – 1.89, p=0.48). GeparNuevo 44 investigated durvalumab in the neoadjuvant setting, showing that the addition of durvalumab to chemotherapy backbone significantly improved invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and OS regardless of pCR response, although the primary endpoint pCR did not meet statistical significance (iDFS HR 0.48, 95% CI 0.24 – 0.97, p=0.036. DDFS HR 0.31, 95% CI 0.13 – 0.74, p=0.005. OS for durvalumab HR 0.24, 95% CI 0.08 – 0.72, p=0.036. pCR OR 1.45; p=0.287). Metastatic Setting Pembrolizumab: Overall population KEYNOTE 355 46,47 is a pivotal RCT demonstrating the efficacy of pembrolizumab with a chemotherapy backbone in patients with previously untreated locally recurrent inoperable or metastatic TNBC. The results were published in two stages, with the first interim results focused on PFS (26 months median follow-up) and the final results focused on OS (44.1 months median follow-up). In this study, 847 patients underwent randomization in a 2:1 ratio to receive pembrolizumab and investigator’s choice of chemotherapy (nab-paclitaxel or paclitaxel or gemcitabine-carboplatin) or placebo and chemotherapy. KEYNOTE 355 subdivided results based on combined positive score (CPS), defined as the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100. In the interim analysis in patients with PD-L1 CPS ≥10 (ICI arm n = 220 patients; placebo arm n = 103 patients), median PFS was 9.7 months with pembrolizumab-chemotherapy versus 5.6 months with placebo-chemotherapy (HR 0.65, 95% CI 0.49 – 0.86, p=0.0012). PFS was not significantly different between ICI and placebo arms for patients with CPS ≥1. Significance was not tested for the ITT population due to a prespecified hierarchical testing strategy for PFS. In the final analysis, KEYNOTE 355 showed that for a total of 323 patients with CPS ≥10, median OS was 23.0 months in the ICI arm compared to 16.1 months in the placebo arm (HR 0.73, 95% CI 0.55 – 0.95; p=0.0185). OS was not significantly different between ICI and placebo arms for patients with CPS ≥1 and not tested for the ITT population. Other RCTs evaluating pembrolizumab in the metastatic setting in our systematic review include subgroup analyses of KEYNOTE 355 as well as KEYNOTE 119, a randomized, open-label phase 3 trial investigating single-agent pembrolizumab versus investigator’s choice single-drug chemotherapy. Subgroup analyses of KEYNOTE 355, namely the Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis and the Japanese subgroup analysis, found improvement in Q-TWIST and OS respectively in the pembrolizumab-chemotherapy group. 48,49 KEYNOTE 119 showed no difference in median OS between ICI and chemotherapy arms (ITT population; HR 0.86, 95% CI 0.69 – 1.06, p=0.073). 45 Pembrolizumab: Patients 65 and older In KEYNOTE 355, 180 of 847 patients (21.2%) in the total study population and 66 of 323 (20.4%) of the PD-L1 CPS ≥10 population were 65 and older. In the interim analysis, for patients 65 and older with CPS ≥10, median PFS was 10.7 months with pembrolizumab-chemotherapy versus 7.6 months with placebo-chemotherapy (HR 0.67, 95% CI 0.37 – 1.23, p=N/A). For older patients with CPS ≥1, median PFS was 8.2 months with pembrolizumab-chemotherapy versus 6.6 months with placebo-chemotherapy (HR 0.69, 95% CI 0.45 – 1.07, p=N/A). In the older ITT population, median PFS was 9.2 months with pembrolizumab-chemotherapy versus 6.2 months with placebo-chemotherapy (HR 0.72, 95% CI 0.49 – 1.05, p=N/A). In the final analysis, for patients 65 and older with CPS ≥10 (n = 66), median OS was 28.3 months in the ICI arm (n = 42) and 12.6 months in the placebo arm (n= 24) (HR 0.51, 95% CI 0.28 – 0.92, p=N/A). For older patients with CPS ≥1, median OS was 17.7 months with pembrolizumab-chemotherapy versus 12.6 months with placebo-chemotherapy (HR 0.81, 95% CI 0.54 – 1.22, p=N/A). In the older ITT population, median OS was 19.0 months with pembrolizumab-chemotherapy versus 13.0 months with placebo-chemotherapy (HR 0.79, 95% CI 0.56 – 1.12, p=N/A). P-values were not reported in the interim nor final analyses. Other RCTs evaluating the efficacy of pembrolizumab in the metastatic setting did not provide subgroup efficacy data for patients 65 and older. Atezolizumab and Durvalumab: Overall population In the metastatic setting, IMPASSION 130 18,20,51 examined the efficacy of atezolizumab with a chemotherapy backbone for metastatic or unresectable locally advanced TNBC. 902 patients were randomized 1:1 to receive either atezolizumab + nab-paclitaxel or placebo + nab-paclitaxel. In the first interim analysis (median follow-up of 12.9 months), PFS was increased in the ICI arm in both the overall population (7.2 versus 5.5 months, HR 0.81, 95% CI 0.70 – 0.93, p=0.002) and PD-L1 IC-positive population (7.5 versus 5.0 months, HR 0.64, 95% CI 0.51 – 0.80, p=N/A). The PD-L1 IC-positive population was defined by immunohistochemistry as ≥1% PD-L1 expression on tumor-infiltrating immune cells over tumor area. IMPASSION 130 did not report PFS for PD-L1 expression ≥10%. However, atezolizumab has not been shown to significantly improve OS in the ITT population or age-specific groups <65 or ≥65 in the final analysis of IMPASSION 130. Median OS in the ITT population was 21.0 months (95% CI 19.0 – 23.4 months) in the ICI arm and 18.7 months (95% CI 16.9 – 20.8 months) in the placebo arm (HR 0.88, 95% CI 0.76 – 1.03, p = 0.077). In the PD-L1 IC-positive population of 369 patients, the ICI arm (n = 185) had significantly increased OS at 25.4 months compared to the placebo arm (n = 184) at 17.9 months (HR 0.69, 95% CI 0.54 – 0.88, p=N/A). When subdivided by patients <65 or ≥65, these results were no longer statistically significant. IMPASSION 131 was a negative trial showing no difference in PFS nor OS between atezolizumab and placebo in the PDL1 IC-positive population (PFS: HR 0.84, 95% CI 0.62 –1.14, p=0.20; OS: HR 1.11, 95% CI 0.76 – 1.64). 21 The ALICE trial, which showed slight improvement in PFS in the atezolizumab-chemotherapy arm versus the placebo-chemotherapy arm (HR 0.57, 95% CI 0.33 – 0.99, log-rank p=0.047), did not report study outcomes by age. 22 For durvalumab, the SAFIR-02 BREAST trial (n = 82) showed that durvalumab compared to maintenance chemotherapy improved OS, where median OS was 21.2 (95% CI 16.6 – 27.3) months with durvalumab compared to 14.0 (95% CI 9.5 – 16.1) months with maintenance chemotherapy (HR 0.54, 95% CI 0.30 – 0.97, log-rank test p=0.0377). 50 Atezolizumab and Durvalumab: Patients 65 and older In IMPASSION 130, 219 of 902 (24.3%) patients were 65 and older. In the first interim analysis, the benefit of atezolizumab for PFS was similarly suggested in this older population (HR 0.69, 95% CI 0.51 – 0.94, p=N/A). In the final analysis, for the PD-L1 IC-positive population older than 65 (n = 86), OS was 30.7 months in the ICI arm and 18.7 months in the placebo arm (HR 0.67, 95% CI 0.40 – 1.13). In IMPASSION 131, 72 of 292 (24.7%) of the PDL1 IC-positive population were 65 and older. 21 Similar to the overall population, the older population also had no difference in PFS between the ICI and placebo arms (HR 0.80, 95% CI 0.41 – 1.58). No trials investigating durvalumab in the metastatic setting specify efficacy data for patients older than 65. Table 2. Summary of final endpoints of pivotal clinical trials investigating PD1/PDL1 inhibitors in breast cancer with an analysis of older patients. Study title Subpopulation Overall population Efficacy in patients > = 65 Early-stage (KEYNOTE 522) Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer Pembrolizumab-chemotherapy (n = 784) EFS at 36 months Placebo-chemotherapy (n = 390) EFS at 36 months Hazard ratio Pembrolizumab-chemotherapy (n =84) Placebo-chemotherapy (n = 48) Hazard ratio 84.5% (95% CI 81.7 to 86.9) 76.8% (95% CI 72.2 to 80.7) 0.63** (95% CI 0.48 to 0.82); P<0.001 N/A N/A 0.79** (95% CI 0.40 - 1.56) Metastatic (KEYNOTE 355) Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer Pembrolizumab-chemotherapy (n = 566) median OS in months Placebo-chemotherapy (n= 281) median OS in months Hazard ratio Pembrolizumab-chemotherapy (n = 123) median OS in months Placebo-chemotherapy (n = 57) median OS in months Hazard ratio CPS > = 10 23.0 16.1 0.73* (0.55- 0.95); P=0.0185 28.3 12.6 0.51* (0.28 - 0.92) CPS > 1 17.6 16.0 0.86* (0.72 - 1.04); P=0.1125 17.7 12.6 0.81* (0.54 to 1.22) Intention-to-treat population 17.2 15.5 0.89* (0.76 - 1.05) 19.0 13.0 0.79* (0.56 to 1.12) (IMPASSION 130) First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis Atezolizumab-nab paclitaxel (n = 451) median OS in months Placebo-nab paclitaxel (n = 451) median OS in months Hazard ratio Atezolizumab-nab paclitaxel (n = 104) median OS in months Placebo-nab paclitaxel (n = 115) median OS in months Hazard ratio PDL1 IC-positive 25.4 17.9 0.69 (0.54-0.88) 30.7 18.7 0.67 (0.40-1.13) Intention-to-treat population 21.0 18.7 0.88 (0.76-1.03) 22.6 19.6 0.92 (0.67-1.26) (IMPASSION 131) Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer Atezolizumab-paclitaxel (n = 191) median PFS in months Placebo-paclitaxel (n = 101) median PFS in months Hazard ratio Atezolizumab-paclitaxel (n = 49) median PFS in months Placebo-paclitaxel (n = 23) median PFS in months Hazard ratio PDL1 IC-positive 5.9 5.7 0.84 (0.62-1.14) 9.4 7.7 0.80 (0.41-1.58) Table 2. Summary of final endpoints of pivotal clinical trials investigating PD1/PDL1 inhibitors in breast cancer with an analysis of older patients. *Hazard ratio for death **Hazard ratio for event or death; n = number; CPS: combined positive score; OS: overall survival; PFS: progression-free survival; EFS: event-free survival; CI: confidence interval Risk of bias assessment The overall risk of bias for the 11 included RCTs was rated low or intermediate (Table 3). All except one RCT (SAFIR02-BREAST) had low risk of bias for sequence generation and allocation concealment. Participants and personnel were blinded in 7 of 11 RCTs. Outcome assessors were blinded in 8 of 11 RCTs. There was low risk of incomplete outcome data in the overall population for all trials except the final outcome analyses of KEYNOTE 522, GeparNuevo, KEYNOTE 355 Q-TWiST, and SAFIR02-BREAST. When examining the population aged 65 and older, 10 of 11 RCTs had unclear risk of bias because they did not clearly delineate the number of attritions and exclusions nor the reasons behind attrition and exclusion. Moreover, the representation of patients older than 65 was highly limited. Based on historical data, 20% of patients enrolled in clinical trials in the U.S. are 65 and older, much less than what is seen in the real-world clinical setting. 52 To match historical trials, we defined “adequate” representation as a study population for which greater than or equal to 20% of patients were older than 65, with a ratio of patients in the experimental to placebo group that matched the distribution of the study’s overall population. Using this criterion, 3 of 11 RCTs had adequate representation of patients older than 65. Even among these three trials, statistical analysis was not performed for the subgroup of older patients. Table 3. Risk of bias for selected clinical trials. Author Year Trial name Sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessors Incomplete outcome data (Age ≥ 65) Incomplete outcome data (Overall Population) Representation of > 65 population Overall risk of bias Schmid et al. 2020 KEYNOTE 522 (interim) Low Low Low Low Unclear Low High Low Schmid et al. 2022 KEYNOTE 522 (final) Low Low Low Low Unclear High High Intermediate Mittendorf et al. 2020 IMPASSION 031 Low Low Low Low Unclear Low Unclear Low Saji et al. 2022 IMPASSION 031 (Japanese subpopulation) Low Low Low Low Unclear Low High Low Ademuyiwa et al. 2022 NCI-10013 Low Low High Unclear Unclear Low Unclear Low Gianni et al. 2022 NeoTRIP Michelangelo Low Low High Unclear Unclear Low Unclear Low Loibl et al. 2022 GeparNuevo Low Low Low Low Unclear High Unclear Low Winer et al. 2021 KEYNOTE 119 Low Low High Low Unclear Low High Intermediate Cortes et al. 2020 KEYNOTE 355 (interim) Low Low Low Low Unclear Low Low Low Cortes et al. 2022 KEYNOTE 355 (final) Low Low Low Low Unclear Low Low Low Huang et al. 2022 KEYNOTE 355 Q-TWiST Low Low Low Low Unclear Unclear Unclear Low Hattori et al. 2023 KEYNOTE 355 (Japanese subpopulation) Low Low Low Low Unclear Low Low Low Rossevold et al. 2022 ALICE Low Low Low Low Unclear Low Unclear Low Schmid et al. 2018 IMPASSION 130 (interim 1) Low Low Low Low Unclear Low Low Low Schmid et al. 2020 IMPASSION 130 (interim 2) Low Low Low Low Low Low Low Low Emens et al. 2021 IMPASSION 130 (final) Low Low Low Low High Low Low Low Miles et al. 2021 IMPASSION 131 (interim) Low Low Low Low Unclear Low Low Low Bachelot et al. 2021 SAFIR02-BREAST Unclear High High High Unclear Unclear Unclear Intermediate Table 3. Risk of bias for selected clinical trials. Numerical scale for overall risk of bias: high overall risk of bias correlates with ≥ 4 subcategories “high”; intermediate overall risk of bias correlates with 2-3 subcategories “high”; low overall risk of bias correlates with ≤ 1 subcategories “high.” Discussion Interpretation This systematic review provides a comprehensive evaluation of the efficacy of ICI in older patients with TNBC, highlighting both the potential of ICI to be effective in this population and limitations in our current understanding. Despite the transformative impact of ICIs on TNBC management, this review reveals a significant gap in data specifically addressing efficacy outcomes for patients aged 65 and older, a population frequently underrepresented in clinical trials. Furthermore, there is a lack of understanding of how toxicities and adverse effects from ICI use in the elderly population may impact applicability. The findings in the early-stage setting are inconclusive; while pembrolizumab likely offers clinical benefits in older patients with TNBC given the trends illustrated, statistical significance was not reached in this small subgroup analysis. KEYNOTE 522 demonstrated that pembrolizumab offers an improved pCR and EFS in the overall population, with a trend towards improved outcomes in patients aged 65 and older, although the 95% confidence interval for hazard ratio crossed 1.0. This is likely attributable to the limited sample size of older patients represented in these studies, as they were not powered to detect differences in these different populations. In the metastatic setting, pembrolizumab has shown substantial efficacy for patients with TNBC and PD-L1 CPS ≥10. In the final analysis of KEYNOTE 355, older patients with CPS ≥10 receiving pembrolizumab-chemotherapy experienced an extension in median OS; however, significance was not tested in this subgroup population. This suggests that pembrolizumab may offer an important therapeutic option for older patients in the metastatic setting, especially in those with high PD-L1 expression. While atezolizumab is not FDA approved for TNBC, the initial results of IMPASSION 130, which showed promise with improved PFS in PD-L1 positive populations, was replicated in patients older than 65. The lack of age-stratified data in multiple RCTs involving atezolizumab and durvalumab (IMPASSION 031, NCI-10013, GeparNuevo, SAFIR-O2 BREAST) underscore the need to enroll older patients in therapeutic clinical trials. This review highlights the persistent underrepresentation and underreporting of data on older patients with TNBC, and the lack of stratified age-specific outcomes highlight critical barriers to fully understanding the role of ICIs in this demographic. While KEYNOTE 522, KEYNOTE 355, IMPASSION 130, and IMPASSION 131 provided age-stratified data, the vast majority of RCTs did not report efficacy outcomes by age, underscoring the ongoing need for trials designed to account for age-related physiological and immune changes that may influence the efficacy of ICIs. Of the 11 unique RCTs reviewed, only four included data specific for individuals aged 65 and older, and even within these reported outcomes, the subgroup analyses were limited by small sample sizes and lacked statistical power to draw definitive conclusions. This is particularly concerning in the context of ICI therapy, where age-related changes in immune function, pharmacokinetics, and comorbidities may influence both efficacy and toxicity profiles. Immunosenescence may alter the effectiveness of ICIs in older patients, and future studies should incorporate this factor to more accurately assess immunotherapy outcomes in this population. Although recent studies indicate that tumors in elderly patients may display characteristics typically associated with ICI responses, including elevated tumor mutational burden, increased immune checkpoint expression and interferon gamma signaling, 53 the immune system in these patients may not be sufficiently equipped to recognize and properly respond to tumor neo-antigens arising from the abundant tumor mutations despite the inflammatory context in these tumors. Moreover, some aspects of immunosenescence may be uncoupled from chronological age, including senescence-related phenotypes in T cells that render them dysfunctional. In fact, elevated frequencies of T cells expressing these late-stage differentiation phenotypes (e.g. CD57+KLRG1+TIM3+CD28-) were associated with unfavorable outcomes of ICIs irrespective of age in studies in non-small cell lung cancer and melanoma patients. 54-56 Hence, in future trials, it will be important to incorporate markers of immune senescence in addition to age as factors potentially influencing the response to immunotherapy. Moreover, there is a paucity of data specifically addressing how toxicities manifest and are managed in older adults receiving ICIs. Older patients may have a heightened susceptibility to certain immune-related adverse events (irAEs), 57 which can be challenging to recognize and manage in this population due to overlapping symptoms from comorbid conditions or polypharmacy. Additionally, toxicities may lead to treatment discontinuation or dose modifications, potentially diminishing therapeutic benefit. Strengths and Limitations Our systematic review offers what we believe is the first comprehensive review of ICI in older adults with early-stage and metastatic TNBC. We only included RCTs as the highest level of evidence and the majority of studies had low risk of bias. Some limitations also warrant consideration. As discussed previously, the lack of subgroup efficacy data for patients older than 65 significantly limited our data synthesis. We also only included trials with published results with available full-text articles. More “gray literature” such as abstract publications, commentaries, case series and reports, can be explored in the future for a more comprehensive analysis. Additionally, our review did not stratify patient outcomes based on the line of therapy received, patient comorbidities, tumor markers, or performance status. An understanding of age in the context of a patient’s performance status may elucidate differential outcomes amongst patients of similar ages. Future Directions Future clinical trials should prioritize intentionally including older adults to reflect the real-world patient population. This is especially relevant given the growing geriatric demographic, the increasing percentage of older patients with TNBC, and the increasing use of ICIs in oncology. Older patients face unique challenges, including immunosenescence, comorbidities, and polypharmacy, that can significantly influence treatment efficacy and tolerability. Stratifying outcomes by age and utilizing standardized geriatric assessment tools to evaluate functional status, frailty, and treatment tolerance may yield more nuanced insights into the efficacy and safety of ICIs in this population. Standardizing the reporting of age-reported outcomes across trials would further our ability to draw comparisons and inform treatment strategies. This is particularly relevant as new ICI-based combinations, such as those involving antibody-drug conjugates (ADCs) and other targeted agents, are emerging and immunotherapy is expanding in breast cancer subtypes other than TNBC. With immunotherapy being studied for use in endocrine therapy-resistant ER-positive breast cancer 58 , understanding its impact on older adults will become increasingly urgent. Agents like pembrolizumab, which have demonstrated consistent benefits across disease stages, warrant further investigation into their broader applicability in older populations. Conversely, the mixed results observed with atezolizumab and durvalumab, neither of which are currently approved for use in TNBC, underscore the need for further studies to establish their efficacy in this subtype before their use in elderly populations can be considered. Preliminary retrospective data suggests that pCR for neoadjuvant pembrolizumab with chemotherapy backbone is similar for patients < 65 and ≥65; 59 however, more real-world data is necessary to elucidate the benefits and risks of immunotherapy in older patients with TNBC. The development of tailored therapeutic approaches, such as incorporating biomarkers, personalized dosing strategies, and supportive care frameworks, should be explored to optimize the benefits of ICIs for older adults. Additionally, further research into age-specific adverse effects will help refine clinical decision-making regarding the use of ICIs in this vulnerable and expanding patient group. Conclusions This systematic review underscores the limited availability of age-specific data on the efficacy of ICIs in older patients with TNBC. While pembrolizumab has demonstrated clinical benefits in early-stage and metastatic TNBC, outcomes specific to patients 65 and older remain inconsistently reported and often underpowered to draw definitive conclusions. Trials investigating atezolizumab and durvalumab, currently not FDA approved for TNBC, showed variable results with limited subgroup analyses by age. Given the projected growth of the geriatric population and the expanding role of immunotherapy, further research is warranted. Future studies may benefit from broader age representation, geriatric assessment tools, and standardized reporting of age-stratified efficacy and toxicity data to better inform clinical decision-making for older adults with TNBC. Declarations Author Contribution I.Z., C.S., and M.L. were responsible for project conception and design and performed systematic review.I.Z. provided mentorship throughout project from conception to manuscript submission.C.S. and M.L. wrote main manuscript text. 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02:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7024355/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7024355/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88097504,"identity":"013c4a19-ff03-4362-a1d5-f11dee6eb26c","added_by":"auto","created_at":"2025-08-01 11:04:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":194665,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/6b4077fb495c411f082780d1.png"},{"id":93274637,"identity":"e66b09f9-dceb-427f-a59a-0384ea3722d2","added_by":"auto","created_at":"2025-10-11 01:38:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1160558,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/1660ed8b-4592-4ba3-9257-8784e178c19e.pdf"},{"id":88097501,"identity":"73c6c3d3-8093-440d-9337-3ecf20fab468","added_by":"auto","created_at":"2025-08-01 11:04:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27687,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryData1Fullsearchstrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/d7e8ab73749833929991d3db.docx"},{"id":88099008,"identity":"602488f4-621e-4f8c-bcb6-1a1ed911a8bf","added_by":"auto","created_at":"2025-08-01 11:12:40","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":100270,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryData2Allstudycharacteristics.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/f3b89dc20c6cf33c129b47db.xlsx"},{"id":88099010,"identity":"60b9baa6-c6fb-43b5-8cf0-4ff44b8b991f","added_by":"auto","created_at":"2025-08-01 11:12:40","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":275513,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/29dc3ab234c19ac6a0e9f0e7.docx"},{"id":88097505,"identity":"cf2f532c-ce7f-4aaf-9dc9-7289a422775d","added_by":"auto","created_at":"2025-08-01 11:04:40","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":29859,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7024355/v1/623d7535e3875a0ae7215cd2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of immunotherapy in older patients with triple-negative breast cancer: a systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER) expression, progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification. TNBC accounts for approximately 11–15% of all breast cancers and is more prevalent among younger women, particularly those of African and Hispanic descent.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e It is also more common in patients with BRCA1 germline mutations and accounts for 80% of breast cancers in BRCA1 mutation carriers.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Compared to ER-positive breast cancer, TNBC is associated with a higher risk of distant recurrence, higher rates of visceral and central nervous system metastases, earlier time to recurrence, and worsened survival.\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe aggressive biology along with the paucity of treatment options for TNBC make this disease difficult to treat, and patients are often faced with a grim prognosis, particularly in the metastatic setting. The treatment of TNBC remains very limited; there are no approved targeted treatments for TNBC with the exception of the poly ADP-ribose polymerase (PARP) inhibitor olaparib in select patients with BRCA1 or BRCA2 mutations.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e More recently, antibody-drug conjugates sacituzumab govitecan\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and trastuzumab deruxtecan\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e have been incorporated in the standard-of-care for metastatic TNBC patients, but long term prognosis remains limited. For most patients with TNBC, treatment options continue to rely primarily on cytotoxic chemotherapy, typically with taxane and anthracycline backbones.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eImportantly, a sizable subset of TNBC tumors are immunogenic and can respond to immune checkpoint inhibitors (ICI), which have emerged as a promising treatment option for improving outcomes in patients with TNBC.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The PD-1 inhibitor pembrolizumab is currently the only ICI approved by the U.S. Food and Drug Administration (FDA) for treatment of TNBC, and is used in the neoadjuvant setting for locally advanced tumors regardless of PD-L1 status and in the metastatic setting for PD-L1 positive tumors.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Of note, atezolizumab was initially granted accelerated FDA approval based on the results of the IMPASSION 130 trial comparing atezolizumab nab-paclitaxel to placebo nab-paclitaxel; however, the FDA approval was revoked based on the negative findings from the IMPASSION 131 trial comparing atezolizumab paclitaxel to placebo paclitaxel.\u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e–\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e While the efficacy of pembrolizumab in combination with chemotherapy has been well documented in these clinical settings, our understanding of its effectiveness among older patients, a demographic often underrepresented in clinical trials, is lacking.\u003c/p\u003e\u003cp\u003eOlder patients make up a significant portion of patients with TNBC as approximately 35% of newly diagnosed patients with TNBC are age 65 and older.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Although head-to-head comparisons of mortality in younger and older patients may be difficult to interpret due to variations in tumor biology, differences in likelihood of undergoing surgical resection and adjuvant radiation and chemotherapy may be responsible for increases in cancer-specific mortality among older patients.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Chemotherapy toxicities are more frequent and longer lasting in the older population.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e While fewer elderly patients may receive treatment due to comorbidities, diminished physiological reserve, and patient preferences, provider bias may also play a role, emphasizing the need to identify optimal treatment options in this vulnerable population.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Reduced dose intensity as a result of dose reductions and delays may compromise the effectiveness of treatment for older patients with breast cancer.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNumerous studies have shown that ICIs are effective and safe in elderly patients with other cancer types. A single-center cohort study demonstrated no significant differences in overall survival (OS) and progression-free survival (PFS) between patients older than 65 and younger patients with metastatic solid tumors treated with ICIs.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Similarly, a systematic review and meta-analysis in elderly patients with head and neck squamous cell carcinoma reported consistent improvements in OS and PFS with immunotherapy in this population.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e In metastatic melanoma, enhanced responses to anti-PD-1 therapy were observed among elderly patients, including those in their 80s and 90s, with comparable survival outcomes and similar toxicity profiles to those of younger patients.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Additionally, a meta-analysis of advanced non-small cell lung cancer patients revealed no significant differences in OS benefit between patients aged 75 and older and younger patients, suggesting consistent efficacy across age groups.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHowever, there have been no recent studies examining ICI efficacy in elderly patients with TNBC. In elderly patients, the immune system undergoes immunosenescence, which refers to the gradual deterioration of the immune system associated with aging. Immunosenescence can affect the body's ability to mount an effective immune response, potentially altering the efficacy of immunotherapies.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Through this process, both innate and adaptive arms of the immune response are affected. Among innate cells, neutrophils decrease their motility, phagocytic, and killing function, macrophages decrease their capacity to clear apoptotic bodies, which can contribute to inflammation, and become more prone to acquire pro-inflammatory phenotypes, and dendritic cells (DCs) reduce their antigen presentation function as the host ages. As part of the adaptive immune system, T lymphocytes are the cell type for which the most profound impact of aging has been described. During aging, thymic involution results in proportional decreases in naïve T cells with consequent increases in memory and effector T cells within the T-cell pool. This ultimately skews the T-cell repertoire toward specificity for previously encountered antigens that remain in the memory T-cell pool, while limiting the body’s capacity to recognize novel antigens to which the host has never been exposed before. In addition, non-naïve T cells are characterized by shorter telomeres due to their history of prior cell divisions, which implies limited proliferation potential. In addition to these functional changes, the elderly show quantitative decreases in adaptive immune cells (T and B cells) with compensatory increases in some innate immune cell subsets (neutrophils and natural killer cells) in peripheral blood. Overall, these changes weaken the ability of the immune system to effectively recognize and react to novel non-self antigens, which can particularly affect tumor immunosurveillance and response to immunotherapy.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eDue to these biological factors that may impact the anti-tumor T-cell response, evaluating the effectiveness of ICI in older patients is crucial. This systematic review addresses these knowledge gaps by evaluating randomized controlled trials (RCTs) that specifically explore the response to ICI in older patients with TNBC. Although the focus is on pembrolizumab, we also review the literature on atezolizumab and durvalumab to understand any differences in outcomes for older patients. By concentrating on this subset of the geriatric population, we hope to provide more precise insights into ICI's potential benefits and risks for elderly patients facing this challenging diagnosis, informing clinical practice and guiding future research in this crucial area.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e Our systematic review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines (see PRISMA checklist).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSearch Strategy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA librarian (JG) designed a search in Medline ALL (Ovid) using subject headers and keywords for three main concepts: (1) immune checkpoint inhibitors, specifically atezolizumab, durvalumab, and pembrolizumab; (2) breast cancer; and (3) randomized controlled trials. The search string for RCTs was based on the RCT / CCT filter from the CADTH (now CDA-AMC) Search Filters Database.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e A second librarian performed a PRESS Peer Review of Electronic Search Strategies, and then the search was translated with the aid of the Polygot Search Translator to Embase (Elsevier), Cochrane Central Register of Controlled Trials (Wiley), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trialsearch.who.int/)\u003c/span\u003e\u003cspan address=\"https://trialsearch.who.int/)\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003csup\u003e36,37\u003c/sup\u003e All databases were searched on September 7, 2023.\u003c/p\u003e\u003cp\u003eIn Medline and Embase, the Cochrane filter was used to limit results to humans.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e Results were also limited to items published in English from January 2013 through the search date. Conference abstracts and conference reviews were excluded in Embase, and review articles were excluded in Medline and Embase. Due to the nature of the databases, Cochrane Central, ClinicalTrials.gov, and the WHO ICTRP searches did not include search strings for RCTs. ClinicalTrials.gov and the WHO ICTRP results were limited to items with results.\u003c/p\u003e\u003cp\u003eSearch results from all databases were uploaded to the systematic review management tool Covidence (Veritas Health Innovation), which removed duplicates. For the full search strategy, please see Supplementary Data 1.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInclusion and Exclusion Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eInclusion criteria included: (1) randomized control trials with 2 + arms (2) study must have included adults with triple-negative breast cancer (3) must have included PD1/PDL1 therapy as intervention (4) must have had some measure of efficacy (PCR, ES, OS, PFS, etc.) (5) must have results published. Studies including population subgroups of larger clinical trials were included. Multiple studies performed at different time points of one clinical trial (e.g., interim, primary, secondary, and final analysis) were included. Exclusion criteria included (1) biomarker/non-interventional studies, (2) studies focused on patient-reported outcomes, and (3) studies without full-text articles.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSelection Process\u003c/b\u003e\u003c/p\u003e\u003cp\u003e Using the Covidence platform, abstract and full-text screening was performed by two independent reviewers (CS and ML) and conflicts were resolved through consensus meetings with both reviewers and a third reviewer (IZ).\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Extraction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor each study, data including paper title, author, year of publication, trial name, immunotherapy, TNBC stage (early-stage versus metastatic), chemotherapy backbone, follow-up time, study population (n), average age, population ≥ 65 years (n), primary and secondary outcomes, outcomes for population ≥ 65 years (if available), and risk of bias were collected by two independent reviewers (CS and ML). For synthesis, studies were grouped by TNBC stage (early versus metastatic setting) and ICI (pembrolizumab, atezolizumab, or durvalumab).\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk of Bias Assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRisk of bias assessment was performed, and overall risk of bias was graded according to Cochrane Risk of Bias. Each study’s risk of bias was assessed based on subcategories, and each reviewer rated each subcategory as either “low,” “intermediate,” or “high.” The subcategories included sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data (for age ≥ 65 years), incomplete outcome data (for overall population), and representation of ≥ 65 years population. Two independent reviewers (CS and ML) rated each study, and conflicts were resolved by a third reviewer (IZ). All three reviewers developed a numerical scale for overall risk of bias: high overall risk of bias correlates with ≥ 4 subcategories “high”; intermediate overall risk of bias correlates with 2–3 subcategories “high”; low overall risk of bias correlates with ≤ 1 subcategories “high.”\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect Measures and Synthesis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEffect measures were collected as hazard ratios (HR), odds ratios (OR), or estimated treatment difference, depending on how primary endpoints were presented in the original RCT. Due to differences in primary endpoints (e.g. pCR, OS, EFS, PFS), cancer stage, and ICI used among studies, meta-analysis was not performed. Results were synthesized in a table (Table\u0026nbsp;1). The primary endpoints were interpreted as either 1) favoring immunotherapy with chemotherapy backbone or 2) no difference between immunotherapy-chemotherapy versus placebo-chemotherapy or chemotherapy alone. Interpretations were color-coded accordingly. Missing and unreported results were denoted N/A.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy Selection\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 1665 studies through a comprehensive search across major databases, including CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and the World Health Organization. After removing duplicates, 1291 studies were identified for title and abstract screening. Based on inclusion and exclusion criteria, 39 studies were selected for full-text screening, of which 18 were identified for data extraction (see Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy characteristics\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur systematic review identified 18 full-text papers on 11 unique RCTs: NCI-10013; IMPASSION 031; IMPASSION 130; IMPASSION 131; ALICE; SAFIR02-BREAST; KEYNOTE 119; KEYNOTE 355; KEYNOTE 522; GeparNuevo; and NeoTRIP Michelangelo. These studies are summarized in Table 1 and detailed results by study are reported in Supplementary Data 2. Only four of the 11 RCTs (highlighted in the last column of table 1) presented results for the subgroup of patients 65 and older: KEYNOTE 355, KEYNOTE 522, IMPASSION 130, and IMPASSION 131. Of the first three, a total of 530 patients out of 2923 patients (18.1%) were 65 and older. In a subset analysis of IMPASSION 131, 72 out of 292 (24.7%) were 65 and older. Additionally, 3 of the 11 RCTs presented data stratified by another age demarcation: younger than or older than 40 (IMPASSION 031; GeparNuevo) or pre- or post-menopausal (NCI-10013). The remaining 4 RCTs did not present efficacy data stratified by age: NeoTRIP Michelangelo; KEYNOTE 119; SAFIR-02 BREAST; ALICE.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf these 11 RCTs, five were in early-stage TNBC and six in the metastatic setting. The PDL1/PD1 inhibitors studied were pembrolizumab (n = 3), atezolizumab (n = 6), durvalumab (n = 2). Of note, although all 11 RCTs listed toxicities and adverse events, no studies specified the frequency of toxicities or adverse events in patients 65 and older.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Study characteristics and key findings for selected clinical trials.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResult summary\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eEarly-Stage Setting\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePembrolizumab: Overall population\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKey clinical trials which specified results for patients 65 and older are noted in Table 1 and are described in more detail in Table 2. KEYNOTE 522\u003csup\u003e1\u003c/sup\u003e examined neoadjuvant and adjuvant pembrolizumab with a 4-drug chemotherapy backbone in the early-stage setting for locally advanced TNBC. 1174 patients were randomized in a 2:1 ratio to receive pembrolizumab or placebo with standard-of-care (SOC) chemotherapy paclitaxel and carboplatin followed by anthracycline plus cyclophosphamide. In the interim analysis with a follow-up of 15.5 months, the primary endpoint of pathological complete response (pCR) was significantly improved in patients in the intention to treat (ITT) population (ICI arm n = 401 patients; control arm n = 201 patients) who received pembrolizumab versus placebo (estimated treatment difference 13.6%, 95% CI 5.4 \u0026ndash; 21.8%, p\u0026lt;0.001), with a pCR rate of 64.8% (95% CI 59.9 \u0026ndash; 69.5%) vs. 51.2% (95% CI 44.1 \u0026ndash; 58.3%) in the pembrolizumab-chemotherapy group vs. control group, respectively. Similarly, in the final analysis at 36 months, patients receiving pembrolizumab-chemotherapy were shown to have a significantly increased EFS compared to those receiving placebo-chemotherapy: 84.5% versus 76.8% respectively, p\u0026lt;0.001; hazard ratio (HR) 0.63 (95% CI 0.48 \u0026ndash; 0.82, p\u0026lt;0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePembrolizumab: Patients 65 and older\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn KEYNOTE 522, 132 of 1174 patients (11.2%) were 65 and older. Of the 602 total patients in the interim analysis, 71 patients (11.8%) were 65 and older (ICI arm n = 46; placebo arm n = 25). In patients older than 65, the treatment difference in pCR was 22.3% and statistically insignificant (95% CI -2.1 \u0026ndash; 43.5%, p=N/A). In the final analysis, among the population of patients 65 or older, the HR for event or death was statistically insignificant at 0.79 (0.40 \u0026ndash; 1.56, p=N/A). For those \u0026lt; 65, the HR was 0.61 (0.45 \u0026ndash; 0.82, p=N/A). P-values were not reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAtezolizumab and Durvalumab\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBoth atezolizumab and durvalumab were investigated in the neoadjuvant setting as well. No trials specify efficacy data for patients 65 or older. Three studies provided subgroup analysis using alternative age brackets: NCI-10013 classified patients as pre or post-menopausal and both IMPASSION 031 and GeparNuevo divided patients into \u0026lt; 40 or \u0026ge; 40,\u003csup\u003e40,42,44\u003c/sup\u003e making it difficult to delineate results for populations \u0026ge; 65 which is the focus of this review. In IMPASSION 031\u003csup\u003e2\u003c/sup\u003e, neoadjuvant and adjuvant atezolizumab in the early-stage setting was shown to have a significant improvement in the primary endpoint of pCR in the ITT population (ICI arm n = 165; placebo arm n = 168; rate difference of 17%, 95% CI 6\u0026ndash;27%, one-sided p=0.0044). NCI-10013\u003csup\u003e42\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eshowed that adding atezolizumab to carboplatin and paclitaxel backbone improved pCR (estimated treatment difference: 36.8%, 95% CI 8.5 \u0026ndash; 56.6%, p=0.018) whereas NeoTRIP Michelangelo\u003csup\u003e43\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003efound that adding atezolizumab to carboplatin and nab-paclitaxel backbone did not improve pCR (odds ratio (OR) 1.18, 95% CI 0.74 \u0026ndash; 1.89, p=0.48). GeparNuevo\u003csup\u003e44\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003einvestigated durvalumab in the neoadjuvant setting, showing that the addition of durvalumab to chemotherapy backbone significantly improved invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and OS regardless of pCR response, although the primary endpoint pCR did not meet statistical significance (iDFS HR 0.48, 95% CI 0.24 \u0026ndash; 0.97, p=0.036. DDFS HR 0.31, 95% CI 0.13 \u0026ndash; 0.74, p=0.005. OS for durvalumab HR 0.24, 95% CI 0.08 \u0026ndash; 0.72, p=0.036. pCR OR 1.45; p=0.287).\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eMetastatic Setting\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePembrolizumab: Overall population\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKEYNOTE 355\u003csup\u003e46,47\u003c/sup\u003e is a pivotal RCT demonstrating the efficacy of pembrolizumab with a chemotherapy backbone in patients with previously untreated locally recurrent inoperable or metastatic TNBC. The results were published in two stages, with the first interim results focused on PFS (26 months median follow-up) and the final results focused on OS (44.1 months median follow-up). In this study, 847 patients underwent randomization in a 2:1 ratio to receive pembrolizumab and investigator\u0026rsquo;s choice of chemotherapy (nab-paclitaxel or paclitaxel or gemcitabine-carboplatin) or placebo and chemotherapy. KEYNOTE 355 subdivided results based on combined positive score (CPS), defined as the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the interim analysis in patients with PD-L1 CPS \u0026ge;10 (ICI arm n = 220 patients; placebo arm n = 103 patients), median PFS was 9.7 months with pembrolizumab-chemotherapy versus 5.6 months with placebo-chemotherapy (HR 0.65, 95% CI 0.49 \u0026ndash; 0.86, p=0.0012). PFS was not significantly different between ICI and placebo arms for patients with CPS \u0026ge;1. Significance was not tested for the ITT population due to a prespecified hierarchical testing strategy for PFS.\u003c/p\u003e\n\u003cp\u003eIn the final analysis, KEYNOTE 355 showed that for a total of 323 patients with CPS \u0026ge;10, median OS was 23.0 months in the ICI arm compared to 16.1 months in the placebo arm (HR 0.73, 95% CI 0.55 \u0026ndash; 0.95; p=0.0185). OS was not significantly different between ICI and placebo arms for patients with CPS \u0026ge;1 and not tested for the ITT population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther RCTs evaluating pembrolizumab in the metastatic setting in our systematic review include subgroup analyses of KEYNOTE 355 as well as KEYNOTE 119, a randomized, open-label phase 3 trial investigating single-agent pembrolizumab versus investigator\u0026rsquo;s choice single-drug chemotherapy. Subgroup analyses of KEYNOTE 355, namely the Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis and the Japanese subgroup analysis, found improvement in Q-TWIST and OS respectively in the pembrolizumab-chemotherapy group.\u003csup\u003e48,49\u003c/sup\u003e\u0026nbsp; KEYNOTE 119 showed no difference in median OS between ICI and chemotherapy arms (ITT population; HR 0.86, 95% CI 0.69 \u0026ndash; 1.06, p=0.073).\u003csup\u003e45\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePembrolizumab: Patients 65 and older\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn KEYNOTE 355, 180 of 847 patients (21.2%) in the total study population and 66 of 323 (20.4%) of the PD-L1 CPS \u0026ge;10 population were 65 and older. In the interim analysis, for patients 65 and older with CPS \u0026ge;10, median PFS was 10.7 months with pembrolizumab-chemotherapy versus 7.6 months with placebo-chemotherapy (HR 0.67, 95% CI 0.37 \u0026ndash; 1.23, p=N/A). For older patients with CPS \u0026ge;1, median PFS was 8.2 months with pembrolizumab-chemotherapy versus 6.6 months with placebo-chemotherapy (HR 0.69, 95% CI 0.45 \u0026ndash; 1.07, p=N/A). In the older ITT population, median PFS was 9.2 months with pembrolizumab-chemotherapy versus 6.2 months with placebo-chemotherapy (HR 0.72, 95% CI 0.49 \u0026ndash; 1.05, p=N/A).\u003c/p\u003e\n\u003cp\u003eIn the final analysis, for patients 65 and older with CPS \u0026ge;10 (n = 66), median OS was 28.3 months in the ICI arm (n = 42) and 12.6 months in the placebo arm (n= 24) (HR 0.51, 95% CI 0.28 \u0026ndash; 0.92, p=N/A). For older patients with CPS \u0026ge;1, median OS was 17.7 months with pembrolizumab-chemotherapy versus 12.6 months with placebo-chemotherapy (HR 0.81, 95% CI 0.54 \u0026ndash; 1.22, p=N/A). In the older ITT population, median OS was 19.0 months with pembrolizumab-chemotherapy versus 13.0 months with placebo-chemotherapy (HR 0.79, 95% CI 0.56 \u0026ndash; 1.12, p=N/A). P-values were not reported in the interim nor final analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther RCTs evaluating the efficacy of pembrolizumab in the metastatic setting did not provide subgroup efficacy data for patients 65 and older.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAtezolizumab and Durvalumab: Overall population\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the metastatic setting, IMPASSION 130\u003csup\u003e18,20,51\u003c/sup\u003e examined the efficacy of atezolizumab with a chemotherapy backbone for metastatic or unresectable locally advanced TNBC. 902 patients were randomized 1:1 to receive either atezolizumab + nab-paclitaxel or placebo + nab-paclitaxel. In the first interim analysis (median follow-up of 12.9 months), PFS was increased in the ICI arm in both the overall population (7.2 versus 5.5 months, HR 0.81, 95% CI 0.70 \u0026ndash; 0.93, p=0.002) and PD-L1 IC-positive population (7.5 versus 5.0 months, HR 0.64, 95% CI 0.51 \u0026ndash; \u0026nbsp;0.80, p=N/A). The PD-L1 IC-positive population was defined by immunohistochemistry as \u0026ge;1% PD-L1 expression on tumor-infiltrating immune cells over tumor area. IMPASSION 130 did not report PFS for PD-L1 expression \u0026ge;10%.\u003c/p\u003e\n\u003cp\u003eHowever, atezolizumab has not been shown to significantly improve OS in the ITT population or age-specific groups \u0026lt;65 or \u0026ge;65 in the final analysis of IMPASSION 130. Median OS in the ITT population was 21.0 months (95% CI 19.0 \u0026ndash; 23.4 months) in the ICI arm and 18.7 months (95% CI 16.9 \u0026ndash; 20.8 months) in the placebo arm (HR 0.88, 95% CI 0.76 \u0026ndash; 1.03, p = 0.077). In the PD-L1 IC-positive population of 369 patients, the ICI arm (n = 185) had significantly increased OS at 25.4 months compared to the placebo arm (n = 184) at 17.9 months (HR 0.69, 95% CI 0.54 \u0026ndash; 0.88, p=N/A). When subdivided by patients \u0026lt;65 or \u0026ge;65, these results were no longer statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIMPASSION 131 was a negative trial showing no difference in PFS nor OS between atezolizumab and placebo in the PDL1 IC-positive population (PFS: HR 0.84, 95% CI 0.62 \u0026ndash;1.14, p=0.20; OS: HR 1.11, 95% CI 0.76 \u0026ndash; 1.64).\u003csup\u003e21\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThe ALICE trial, which showed slight improvement in PFS in the atezolizumab-chemotherapy arm versus the placebo-chemotherapy arm (HR 0.57, 95% CI 0.33 \u0026ndash; 0.99, log-rank p=0.047), did not report study outcomes by age.\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFor durvalumab, the SAFIR-02 BREAST trial (n = 82) showed that durvalumab compared to maintenance chemotherapy improved OS, where median OS was 21.2 (95% CI 16.6 \u0026ndash; 27.3) months with durvalumab compared to 14.0 (95% CI 9.5 \u0026ndash; 16.1) months with maintenance chemotherapy (HR 0.54, 95% CI 0.30 \u0026ndash; 0.97, log-rank test p=0.0377).\u003csup\u003e50\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAtezolizumab and Durvalumab: Patients 65 and older\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn IMPASSION 130, 219 of 902 (24.3%) patients were 65 and older. In the first interim analysis, the benefit of atezolizumab for PFS was similarly suggested in this older population (HR 0.69, 95% CI 0.51 \u0026ndash; 0.94, p=N/A). In the final analysis, for the PD-L1 IC-positive population older than 65 (n = 86), OS was 30.7 months in the ICI arm and 18.7 months in the placebo arm (HR 0.67, 95% CI 0.40 \u0026ndash; 1.13).\u003c/p\u003e\n\u003cp\u003eIn IMPASSION 131, 72 of 292 (24.7%) of the PDL1 IC-positive population were 65 and older.\u003csup\u003e21\u003c/sup\u003e Similar to the overall population, the older population also had no difference in PFS between the ICI and placebo arms (HR 0.80, 95% CI 0.41 \u0026ndash; 1.58).\u003c/p\u003e\n\u003cp\u003eNo trials investigating durvalumab in the metastatic setting specify efficacy data for patients older than 65.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Summary of final endpoints of pivotal clinical trials investigating PD1/PDL1 inhibitors in breast cancer with an analysis of older patients. \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003eStudy title\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eSubpopulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 206px;\"\u003e\n \u003cp\u003eOverall population\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 195px;\"\u003e\n \u003cp\u003eEfficacy in patients \u0026gt; = 65\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 624px;\"\u003e\n \u003cp\u003eEarly-stage\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e(KEYNOTE 522) Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePembrolizumab-chemotherapy (n = 784) \u0026nbsp;EFS at 36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-chemotherapy (n = 390) EFS at 36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePembrolizumab-chemotherapy (n =84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-chemotherapy (n = 48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e84.5% (95% CI 81.7 to 86.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e76.8% (95% CI 72.2 to 80.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.63** (95% CI 0.48 to 0.82); P\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.79** (95% CI 0.40 - 1.56)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 624px;\"\u003e\n \u003cp\u003eMetastatic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 158px;\"\u003e\n \u003cp\u003e(KEYNOTE 355) Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePembrolizumab-chemotherapy (n = 566) median OS in months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-chemotherapy (n= 281) median OS in months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePembrolizumab-chemotherapy (n = 123) median OS in months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-chemotherapy (n = 57) median OS in months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCPS \u0026gt; = 10\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e23.0 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e16.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.73* (0.55- 0.95); P=0.0185\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e28.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.51* (0.28 - \u0026nbsp;0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCPS \u0026gt; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e16.0 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.86* (0.72 - 1.04); \u0026nbsp;P=0.1125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;17.7 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;12.6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.81* (0.54 to 1.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eIntention-to-treat population\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;17.2 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.89* (0.76 - 1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;19.0 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.79* (0.56 to 1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 158px;\"\u003e\n \u003cp\u003e(IMPASSION 130) First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eAtezolizumab-nab paclitaxel (n = 451) median OS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-nab paclitaxel (n = 451) median OS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eAtezolizumab-nab paclitaxel (n = 104) median OS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-nab paclitaxel (n = 115) median OS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003ePDL1 IC-positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e25.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.69 (0.54-0.88)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e30.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.67 (0.40-1.13)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eIntention-to-treat population\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e21.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;18.7\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.88 (0.76-1.03)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e22.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e19.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.92 (0.67-1.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e(IMPASSION 131) Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eAtezolizumab-paclitaxel (n = 191) median PFS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-paclitaxel (n = 101) median PFS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eAtezolizumab-paclitaxel (n = 49) median PFS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo-paclitaxel (n = 23) median PFS in months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eHazard ratio\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003ePDL1 IC-positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.84 (0.62-1.14)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.80 (0.41-1.58)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Summary of final endpoints of pivotal clinical trials investigating PD1/PDL1 inhibitors in breast cancer with an analysis of older patients. \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e*Hazard ratio for death **Hazard ratio for event or death; n = number; CPS: combined positive score; OS: overall survival; PFS: progression-free survival; EFS: event-free survival; CI: confidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias assessment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall risk of bias for the 11 included RCTs was rated low or intermediate (Table 3). All except one RCT (SAFIR02-BREAST) had low risk of bias for sequence generation and allocation concealment. Participants and personnel were blinded in 7 of 11 RCTs. Outcome assessors were blinded in 8 of 11 RCTs. There was low risk of incomplete outcome data in the overall population for all trials except the final outcome analyses of KEYNOTE 522, GeparNuevo, KEYNOTE 355 Q-TWiST, and SAFIR02-BREAST.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; When examining the population aged 65 and older, 10 of 11 RCTs had unclear risk of bias because they did not clearly delineate the number of attritions and exclusions nor the reasons behind attrition and exclusion. Moreover, the representation of patients older than 65 was highly limited. Based on historical data, 20% of patients enrolled in clinical trials in the U.S. are 65 and older, much less than what is seen in the real-world clinical setting.\u003csup\u003e52\u003c/sup\u003e To match historical trials, we defined \u0026ldquo;adequate\u0026rdquo; representation as a study population for which greater than or equal to 20% of patients were older than 65, with a ratio of patients in the experimental to placebo group that matched the distribution of the study\u0026rsquo;s overall population. Using this criterion, 3 of 11 RCTs had adequate representation of patients older than 65. Even among these three trials, statistical analysis was not performed for the subgroup of older patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e \u003cstrong\u003eRisk of bias for selected clinical trials.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eTrial name\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eSequence generation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eAllocation concealment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eBlinding of participants and personnel\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eBlinding of outcome assessors\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eIncomplete outcome data (Age \u0026ge; 65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eIncomplete outcome data (Overall Population)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eRepresentation of \u0026gt; 65 population\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eOverall risk of bias\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eSchmid et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 522 (interim)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eSchmid et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 522 (final)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eMittendorf et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eSaji et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 031 (Japanese subpopulation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eAdemuyiwa et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eNCI-10013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eGianni et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eNeoTRIP Michelangelo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eLoibl et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eGeparNuevo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eWiner et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eCortes et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 355 (interim)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eCortes et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 355 (final)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eHuang et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 355 Q-TWiST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eHattori et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eKEYNOTE 355 (Japanese subpopulation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eRossevold et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eALICE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eSchmid et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 130 (interim 1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eSchmid et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 130 (interim 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eEmens et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 130 (final)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eMiles et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIMPASSION 131 (interim)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eBachelot et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eSAFIR02-BREAST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eUnclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e \u003cstrong\u003eRisk of bias for selected clinical trials.\u003c/strong\u003e Numerical scale for overall risk of bias: high overall risk of bias correlates with \u0026ge; 4 subcategories \u0026ldquo;high\u0026rdquo;; intermediate overall risk of bias correlates with 2-3 subcategories \u0026ldquo;high\u0026rdquo;; low overall risk of bias correlates with \u0026le; 1 subcategories \u0026ldquo;high.\u0026rdquo;\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eInterpretation \u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review provides a comprehensive evaluation of the efficacy of ICI in older patients with TNBC, highlighting both the potential of ICI to be effective in this population and limitations in our current understanding. Despite the transformative impact of ICIs on TNBC management, this review reveals a significant gap in data specifically addressing efficacy outcomes for patients aged 65 and older, a population frequently underrepresented in clinical trials. Furthermore, there is a lack of understanding of how toxicities and adverse effects from ICI use in the elderly population may impact applicability.\u003c/p\u003e\n\u003cp\u003eThe findings in the early-stage setting are inconclusive; while pembrolizumab likely offers clinical benefits in older patients with TNBC given the trends illustrated, statistical significance was not reached in this small subgroup analysis. KEYNOTE 522 demonstrated that pembrolizumab offers an improved pCR and EFS in the overall population, with a trend towards improved outcomes in patients aged 65 and older, although the 95% confidence interval for hazard ratio crossed 1.0. This is likely attributable to the limited sample size of older patients represented in these studies, as they were not powered to detect differences in these different populations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the metastatic setting, pembrolizumab has shown substantial efficacy for patients with TNBC and PD-L1 CPS \u0026ge;10. In the final analysis of KEYNOTE 355, older patients with CPS \u0026ge;10 receiving pembrolizumab-chemotherapy experienced an extension in median OS; however, significance was not tested in this subgroup population. This suggests that pembrolizumab may offer an important therapeutic option for older patients in the metastatic setting, especially in those with high PD-L1 expression.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile atezolizumab is not FDA approved for TNBC, the initial results of IMPASSION 130, which showed promise with improved PFS in PD-L1 positive populations, was replicated in patients older than 65. The lack of age-stratified data in multiple RCTs involving atezolizumab and durvalumab (IMPASSION 031, NCI-10013, GeparNuevo, SAFIR-O2 BREAST) underscore the need to enroll older patients in therapeutic clinical trials.\u003c/p\u003e\n\u003cp\u003eThis review highlights the persistent underrepresentation and underreporting of data on older patients with TNBC, and the lack of stratified age-specific outcomes highlight critical barriers to fully understanding the role of ICIs in this demographic. While KEYNOTE 522, KEYNOTE 355, IMPASSION 130, and IMPASSION 131 provided age-stratified data, the vast majority of RCTs did not report efficacy outcomes by age, underscoring the ongoing need for trials designed to account for age-related physiological and immune changes that may influence the efficacy of ICIs. Of the 11 unique RCTs reviewed, only four included data specific for individuals aged 65 and older, and even within these reported outcomes, the subgroup analyses were limited by small sample sizes and lacked statistical power to draw definitive conclusions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis is particularly concerning in the context of ICI therapy, where age-related changes in immune function, pharmacokinetics, and comorbidities may influence both efficacy and toxicity profiles. Immunosenescence may alter the effectiveness of ICIs in older patients, and future studies should incorporate this factor to more accurately assess immunotherapy outcomes in this population. Although recent studies indicate that tumors in elderly patients may display characteristics typically associated with ICI responses, including elevated tumor mutational burden, increased immune checkpoint expression and interferon gamma signaling,\u003csup\u003e53\u003c/sup\u003e the immune system in these patients may not be sufficiently equipped to recognize and properly respond to tumor neo-antigens arising from the abundant tumor mutations despite the inflammatory context in these tumors. Moreover, some aspects of immunosenescence may be uncoupled from chronological age, including senescence-related phenotypes in T cells that render them dysfunctional. In fact, elevated frequencies of T cells expressing these late-stage differentiation phenotypes (e.g. CD57+KLRG1+TIM3+CD28-) were associated with unfavorable outcomes of ICIs irrespective of age in studies in non-small cell lung cancer and melanoma patients.\u003csup\u003e54-56\u003c/sup\u003e Hence, in future trials, it will be important to incorporate markers of immune senescence in addition to age as factors potentially influencing the response to immunotherapy.\u003c/p\u003e\n\u003cp\u003eMoreover, there is a paucity of data specifically addressing how toxicities manifest and are managed in older adults receiving ICIs. Older patients may have a heightened susceptibility to certain immune-related adverse events (irAEs),\u003csup\u003e57\u003c/sup\u003e which can be challenging to recognize and manage in this population due to overlapping symptoms from comorbid conditions or polypharmacy. Additionally, toxicities may lead to treatment discontinuation or dose modifications, potentially diminishing therapeutic benefit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStrengths and Limitations\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur systematic review offers what we believe is the first comprehensive review of ICI in older adults with early-stage and metastatic TNBC. We only included RCTs as the highest level of evidence and the majority of studies had low risk of bias. Some limitations also warrant consideration. As discussed previously, the lack of subgroup efficacy data for patients older than 65 significantly limited our data synthesis. We also only included trials with published results with available full-text articles. More \u0026ldquo;gray literature\u0026rdquo; such as abstract publications, commentaries, case series and reports, can be explored in the future for a more comprehensive analysis. Additionally, our review did not stratify patient outcomes based on the line of therapy received, patient comorbidities, tumor markers, or performance status. An understanding of age in the context of a patient\u0026rsquo;s performance status may elucidate differential outcomes amongst patients of similar ages.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFuture Directions\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFuture clinical trials should prioritize intentionally including older adults to reflect the real-world patient population. This is especially relevant given the growing geriatric demographic, the increasing percentage of older patients with TNBC, and the increasing use of ICIs in oncology. Older patients face unique challenges, including immunosenescence, comorbidities, and polypharmacy, that can significantly influence treatment efficacy and tolerability. Stratifying outcomes by age and utilizing standardized geriatric assessment tools to evaluate functional status, frailty, and treatment tolerance may yield more nuanced insights into the efficacy and safety of ICIs in this population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStandardizing the reporting of age-reported outcomes across trials would further our ability to draw comparisons and inform treatment strategies. This is particularly relevant as new ICI-based combinations, such as those involving antibody-drug conjugates (ADCs) and other targeted agents, are emerging and immunotherapy is expanding in breast cancer subtypes other than TNBC. With immunotherapy being studied for use in endocrine therapy-resistant ER-positive breast cancer\u003csup\u003e58\u003c/sup\u003e, understanding its impact on older adults will become increasingly urgent.\u003c/p\u003e\n\u003cp\u003eAgents like pembrolizumab, which have demonstrated consistent benefits across disease stages, warrant further investigation into their broader applicability in older populations. Conversely, the mixed results observed with atezolizumab and durvalumab, neither of which are currently approved for use in TNBC, underscore the need for further studies to establish their efficacy in this subtype before their use in elderly populations can be considered. Preliminary retrospective data suggests that pCR for neoadjuvant pembrolizumab with chemotherapy backbone is similar for patients \u0026lt; 65 and \u0026ge;65;\u003csup\u003e59\u003c/sup\u003e however, more real-world data is necessary to elucidate the benefits and risks of immunotherapy in older patients with TNBC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe development of tailored therapeutic approaches, such as incorporating biomarkers, personalized dosing strategies, and supportive care frameworks, should be explored to optimize the benefits of ICIs for older adults. Additionally, further research into age-specific adverse effects will help refine clinical decision-making regarding the use of ICIs in this vulnerable and expanding patient group.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis systematic review underscores the limited availability of age-specific data on the efficacy of ICIs in older patients with TNBC. While pembrolizumab has demonstrated clinical benefits in early-stage and metastatic TNBC, outcomes specific to patients 65 and older remain inconsistently reported and often underpowered to draw definitive conclusions. Trials investigating atezolizumab and durvalumab, currently not FDA approved for TNBC, showed variable results with limited subgroup analyses by age. Given the projected growth of the geriatric population and the expanding role of immunotherapy, further research is warranted. Future studies may benefit from broader age representation, geriatric assessment tools, and standardized reporting of age-stratified efficacy and toxicity data to better inform clinical decision-making for older adults with TNBC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eI.Z., C.S., and M.L. were responsible for project conception and design and performed systematic review.I.Z. provided mentorship throughout project from conception to manuscript submission.C.S. and M.L. wrote main manuscript text. C.S. prepared all figures and tables and revised manuscript.A.S., R.Z., and I.Z. contributed significant additions to the manuscript. J.G. performed systematic review search, provided full search strategy, and wrote significant portion of methods section of manuscript. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eR.Z. is supported by NIH, the Parker Institute for Cancer Immunotherapy, the Starr Cancer Consortium, and the Leukemia \u0026amp; Lymphoma Society.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e\u003cp\u003eThe data in this systematic review were collected from publicly available publications identified through our comprehensive search strategy (see Supplementary Data 1 and 2 for the full search strategy and the list of included studies, respectively).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel, R. L., Miller, K. D., Wagle, N. S. \u0026amp; Jemal, A. Cancer statistics, 2023. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e \u003cstrong\u003e73\u003c/strong\u003e, 17-48 (2023). https://doi.org/10.3322/caac.21763\u003c/li\u003e\n\u003cli\u003eDietze, E. 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H.\u003cem\u003e et al.\u003c/em\u003e Immune-related adverse events in older adults receiving immune checkpoint inhibitors: a comprehensive analysis of the Food and Drug Administration Adverse Event Reporting System. \u003cem\u003eAge Ageing\u003c/em\u003e \u003cstrong\u003e54\u003c/strong\u003e (2025). https://doi.org/10.1093/ageing/afaf008\u003c/li\u003e\n\u003cli\u003eGoldberg, J.\u003cem\u003e et al.\u003c/em\u003e Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor\u0026ndash;positive Breast Cancer. \u003cem\u003eCancer Research Communications\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 496-504 (2024). https://doi.org/10.1158/2767-9764.Crc-23-0244\u003c/li\u003e\n\u003cli\u003ePolidorio, N.\u003cem\u003e et al.\u003c/em\u003e Abstract P5-11-16: Outcomes in Elderly Patients with Triple-Negative Breast Cancer Receiving Neoadjuvant Chemo-immunotherapy and Chemotherapy Alone. \u003cem\u003eClinical Cancer Research\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, P5-11-16-P15-11-16 (2025). https://doi.org/10.1158/1557-3265.Sabcs24-p5-11-16\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7024355/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7024355/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImmune checkpoint inhibitors (ICI) have emerged as a promising treatment for patients with triple-negative breast cancer (TNBC); however, there exists a notable gap in our understanding of their efficacy within the older patient population. The objective of this systematic review is to evaluate the efficacy of ICI in patients with TNBC who are 65 and older. We conducted a comprehensive systematic search using Medline, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform of randomized controlled trials (RCTs) reporting efficacy of ICI from January 2013 to September 2023. Our systematic review identified 18 full-text papers encompassing 11 unique RCTs. Only four RCTs presented results for patients 65 and older: KEYNOTE 355, KEYNOTE 522, IMPASSION 130, and IMPASSION 131. In these four studies, 602 patients out of 3215 patients (18.7%) were 65 and older. The overall risk of bias was rated low or intermediate in all 11 RCTs. Variations in primary endpoint, cancer stage, and ICI precluded meta-analysis. There is a significant gap in data from RCTs evaluating the efficacy of ICI in older patients with TNBC. The only FDA-approved ICI in TNBC, pembrolizumab, was shown in the early-stage setting to improve pathological complete response (pCR) and event-free survival (EFS) in older patients but was not statistically significant (KEYNOTE 522). In the metastatic setting, pembrolizumab may improve overall survival (OS) in older patients with combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;10 (KEYNOTE 355). Although atezolizumab in the metastatic setting showed initial promise in improving OS in the PD-L1\u0026thinsp;+\u0026thinsp;population (IMPASSION 130), there was no difference in progression-free survival (PFS) nor OS between atezolizumab and placebo arms in IMPASSION 131. All studies had a limited number of patients 65 and older. These results underscore the need for further research on ICIs in older patients with TNBC.\u003c/p\u003e","manuscriptTitle":"Efficacy of immunotherapy in older patients with triple-negative breast cancer: a systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-01 11:04:36","doi":"10.21203/rs.3.rs-7024355/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f81f4cc0-e60b-43f8-af63-b6ed436324e7","owner":[],"postedDate":"August 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52325871,"name":"Biological sciences/Cancer"},{"id":52325872,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-10-30T18:08:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-01 11:04:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7024355","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7024355","identity":"rs-7024355","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}