First-Line Immune Checkpoint Inhibitors Versus Chemotherapy in Delaying Quality of Life Deterioration in Advanced NSCLC: A Systematic Review and Meta- Analysis

First-Line Immune Checkpoint Inhibitors Versus Chemotherapy in Delaying Quality of Life Deterioration in Advanced NSCLC: A Systematic Review and Meta- Analysis | 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 Research Article First-Line Immune Checkpoint Inhibitors Versus Chemotherapy in Delaying Quality of Life Deterioration in Advanced NSCLC: A Systematic Review and Meta- Analysis Juanyan Shen, Junliang Ma, Shaolin Chen, Qisha Li, Su-Han Jin, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8886255/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Backgroud: Immune checkpoint inhibitors (ICIs) have transformed first-line treatment for advanced non–small-cell lung cancer (aNSCLC). While overall survival(OS) remains the primary endpoint, health-related quality of life (HRQoL) is a key patient-centered outcome. Time to deterioration (TTD) captures the durability of HRQoL over treatment. This study compared TTD in HRQoL between patients receiving ICI-based therapies and chemotherapy, and conducted exploratory analyses to assess the association between trial-level hazard ratios(HRs) for TTD and OS. Method MEDLINE, CENTRAL, and Scopus were systematically searched from inception to September 2025. Eligible studies included phase II or III randomized clinical trials evaluating first-line ICIs–based therapies(ICI monotherapy, dual ICI combinations, or ICIs combined with chemotherapy) for aNSCLC and reporting TTD in HRQoL.The prespecified primary outcome was hazard ratio (HR) for TTD of global QoL between aNSCLC patients treated with ICI–based therapies and those receiving chemotherapy. Secondary outcomes were HR for TTD of physical and emotional functioning and symptomatology. (PROSPERO registration number: CRD420251266405) Result A total of 6555 aNSCLC patients from 13 randomized trials comparing ICI-based therapies with chemotherapy were included. Compared with chemotherapy, ICIs–based therapies delayed deterioration of global QoL ( HR 0.75, 95% confidence interval [CI] 0.71–0.81; p < 0.0001, I ²=0%). Regimen-specific analyses indicated that Immunochemotherapy delayed TTD in Global QoL over chemotherapy(HR 0.74, 95%CI 0.69–0.80; I ²=0%), whereas no significant benefit in TTD of Global QoL was observed with immunotherapy(HR 0.78, 95%CI 0.58–1.05; I ²=0%), with similar patterns for physical functioning. Across symptom outcomes, ICI based therapies delayed deterioration in several symptoms, including fatigue, pain, cough, dyspnea, and the composite endpoint of cough, chest pain, or dyspnea, while no significant difference was observed for appetite loss. Exploratory analyses further suggested an association between trial-level HRs for TTD of HRQoL and HRs for OS, although these findings should be interpreted cautiously. Conclusion Among patients with aNSCLC, first-line ICI-based therapies significantly delayed deterioration of HRQoL compared with chemotherapy. These findings indicate that ICI-based therapies—particularly immunochemotherapy—are associated with more durable preservation of HRQoL in first-line treatment, complementing their established survival benefits. Exploratory analyses further suggested that trial-level HRs for HRQoL deterioration were positively associated with HR for OS. Figures Figure 1 Figure 2 Figure 3 1. Introduction Non-small cell lung cancer(NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading contributor to global cancer mortality[ 1 ]. Despite advances in early detection and screening, the majority of patients are diagnosed with stage III or IV disease[ 2 ], for whom curative treatment is rarely feasible. Even with modern systemic therapies, the 5-year survival rate for metastatic NSCLC remains below 15%[ 3 ], traditional CT, while extending patient survival, often comes with a spectrum of severe toxicities that profoundly impair patients' health related quality of life(HRQoL)[ 4 , 5 ]. Consequently, a critical objective in the management of aNSCLC is to not only prolong life but also to maintain or improve patients' HRQoL. In recent years, immune checkpoint inhibitors(ICIs) targeting programmed cell death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have fundamentally reshaped the first-line therapeutic landscape for aNSCLC[ 6 – 9 ]. By restoring antitumor T-cell responses and reversing tumor-induced immune suppression, ICIs have demonstrated substantial and consistent improvements in overall survival(OS) across multiple phase III trials[ 7 , 10 – 12 ]. Although OS remains the most frequently used primary endpoint in phase III randomized clinical trials(RCTs)[ 13 ], its evaluation requires prolonged follow-up and may be confounded by subsequent lines of therapy[ 14 ]. As a result, surrogate endpoints such as progression-free survival (PFS) have increasingly replaced OS as the primary endpoint in contemporary trials[ 15 , 16 ]. However, PFS does not fully capture patients’ subjective treatment experience or the impact of therapy on daily functioning and well-being.HRQoL is a multidimensional construct encompassing physical, psychological, and social functioning and provides a comprehensive assessment of patients’ lived experiences during treatment [17]. In aNSCLC, preserving HRQoL is increasingly viewed as being as important as prolonging survival, with many patients even prioritizing QoL in treatment decisions[18, 19 ]. Time to deterioration(TTD) of HRQoL, defined as the time from randomization to the first clinically meaningful worsening of HRQoL, has emerged as a robust and clinically interpretable event-based endpoint[20, 21 ]. Reported using hazard ratios analogous to OS and PFS, TTD captures both the timing and durability of HRQoL benefits while mitigating biases related to missing data and informative dropout[22–24]. Prior large-scale meta analyses have demonstrated that TTD of global QoL and physical functioning show a stronger association with OS than with PFS in immunotherapy trials[25], supporting its role as a meaningful complementary endpoint in aNSCLC. However, robust evidence for durable improvements in global QoL remains limited in first-line treatment studies of aNSCLC[26, 27 ]. A recent meta-epidemiological analysis of phase 3 RCTs found that global QoL superiority was rarely reported and concurrent improvements in OS and QoL were even more uncommon[27]. These findings highlight the need for rigorous, disease-specific evaluations of QoL outcomes in aNSCLC, where ICIs are now standard first-line therapy. Current evidence gaps limit clinicians’ ability to balance survival benefits with long-term QoL when making treatment decisions. Therefore, this study aimed to synthesize evidence on TTD in HRQoL among patients with aNSCLC receiving first-line ICI-based therapies and to explore its association with OS. These findings may help clinicians better understand the long-term QoL impact of ICIs and inform patient-centered treatment decisions. 2. Methods This meta-analysis was performed by following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guideline[ 28 ]. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO, CRD420251266405). 2.1 Data Sources and Search Strategy A systematic literature search of Pubmed, Cochrane Library, and Scopus databases was performed to identify full-text articles published from the beginning of the databases' availability until September 2025. The detailed search strategy is reported in eTable 1. To find further studies, the electronic search was combined with manual searches of the reference lists of all review articles and primary studies that had been retrieved. If the main study had not included a full analysis of HRQoL, we searched for exploratory analyses of HRQoL that were published subsequently. When studies were published more than once, only the latest full data were used in the meta-analysis. 2.2 Study Selection Phase II or III RCTs had to meet the following inclusion criteria(1) RCTs evaluating first-line ICI-based therapies (PD-1/PD-L1 inhibitors or CTLA-4 inhibitors, administered as monotherapy, dual ICIs, or in combination with CT) compared with CT alone in patients with aNSCLC. (2)Studies in which the control arm was placebo alone or other anticancer agents, including targeted therapy and other ICIs, were excluded. (3) reported data on the TTD of HRQoL scores assessed by validated questionnaires; and(4) published in the English language. Two individual reviewers (Juanyan Shen and Qisha Li) identified and reviewed full-text articles and abstracts that were deemed relevant by screening the list of titles. In cases of disagreement, a third author (Jianguo Zhou) provided a decisive opinion. 2.3 Data Extraction and Quality Assessment HRs for TTD of HR-QoL and HR for OS with corresponding 95% CI were extracted as effect measures. The following study-level covariates were extracted: study name and/or lead author name, publication year, type of intervention and control arms, type of questionnaire(s) used to evaluate HRQoL, HRQoL items assessed, definition of deterioration of HR-QoL. We also noted if there was an HRQoL analysis in the main article or in a later published exploratory analysis. 2.4 Risk of Bias The Cochrane Collaboration’s tool for assessing the risk of bias in the trial was used which includes the following domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting[ 29 ]. The Consolidated Standards of Reporting Trials (CONSORT) PRO checklist was used to assess the quality of PRO[ 30 ]. Two authors (Juanyan Shen and Qisha Li) independently conducted these assessments. Disagreements were resolved by consulting a third author (Jianguo Zhou) 2.5 Statistical Analysis The primary outcome was HR for TTD of global QoL between aNSCLC patients treated with ICI–based therapies and those receiving CT. The EORTC QLQ-C30 global health status scale or, when unavailable, the EQ-5D visual analogue scale (VAS), was used to evaluate global QoL. Secondary outcomes comprised HR for TTD of physical functioning, emotional functioning and symptom domains(ie, pain, fatigue, appetite loss, insomnia, nausea and/or vomiting, and the composite endpoint of cough and chest pain and dyspnea) between aNSCLC patients treated with ICI–based therapies and those receiving CT assessed using the EORTC QLQ-LC13, the Lung Cancer Symptom Scale (LCSS), and selected symptom subscales of the EORTC QLQ-C30. A subgroup analysis for all outcomes was conducted based on whether ICIs–based therapies were administered with or without concomitant CT(ICT or ICIs). All outcomes were analyzed as time-to-event variables. The definition of these outcomes was consistent with the original studies (eTable 2). Effect estimates were pooled as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). We performed a random-effects meta-analysis, as described by Hartung and Knapp[ 31 ], to estimate summary risk of TTD of HRQoL by calculating the pooled estimates of HRs and their 95% CIs for safety outcomes in aNSCLC patients treated with ICI-based therapies vs CT. Heterogeneity across studies was assessed using the I 2 statistic and I 2 values were calculated using the χ 2 test and degrees of freedom[ 32 , 33 ]. A two-sided P value of < 0.05 was considered statistically significant. To investigate the potential association between HRQoL outcomes and survival benefit, we conducted an exploratory correlation analysis comparing HRs for TTD in various HRQoL domains—including global QoL, physical functioning, emotional functioning and symptom subscales—with corresponding HRs for OS. Pearson’s correlation coefficient (r) was used to assess the linear relationship between log-transformed HRs (log[HR]), and scatterplots were used for visual inspection, with significance set at p < 0.05. Publication bias was visually examined for primary outcomes using a funnel plot, and Egger’s regression test was conducted to statistically assess the bias[ 34 ]. Sensitivity analyses were performed for outcomes with substantial heterogeneity (I² ≥50%)[ 35 ]. We performed outlier detection and influence analyses using the leave-one-out method and reported Baujat plots to graphically display studies that overly contribute to the heterogeneity[ 36 ]. All analyses were performed using the meta package in R, version 4.3.2 (R Project for Statistical Computing). 3. Results 3.1 Study selection The flow diagram of the study selection process is shown in eFigure 1. The search strategy retrieved 1519 unique titles. After we screened titles and abstracts, 1453 studies were excluded for irrelevance. We assessed 69 full-text articles, with 56 studies excluded due various reasons, mostly QoL data not available in either the primary publication or exploratory analyses. After reviewing these studies, 13 phase 3 randomized clinicaltrials[ 12 , 37 – 45 ], enrolling 6555 patients fulfilled the inclusion criteria and were selected for the meta-analysis. All included studies had 2 treatment arms, except from MYSTIC and POSEIDON trial[ 41 , 42 ] which had 3 arms. The CheckMate 227 Part 1[ 46 ] trial included three arms. however, TTDs in HR-QOL were reported only for the nivolumab plus ipilimumab versus CT. 3.2 Study characteristics Characteristics of the included studies can be found in eTable 2. Nine articles originated in the United States of American (USA), two articles conducted in China, one in the Australia, one from Argentina. All trials were conducted between 2014 and 2018 and all articles were published from 2017 to 2025. Furthermore, three trials[ 38 , 43 , 46 ] included patients with PD-L1 TPS of 50% or greater, two trials[ 39 , 47 ] included squamous NSCLC, and two trials[ 40 , 44 ] included non-squamous NSCLC. Patients included in the analysis were randomised to receive pembrolizumab (n = 1; 151 patients), pembrolizumab plus CT (n = 3, 743 patients), atezolizumab (n = 2; 409 patients), durvalumab (n = 1, 163 patients), durvalumab plus CT (n = 1, 326 patients), durvalumab plus tremelimumab (n = 1, 163 patients), durvalumab plus tremelimumab plus CT(n = 1, 325 patients), nivolumab plus ipilimumab (n = 1; 396 patients), nivolumab plus ipilimumab plus CT(n = 1; 361 patients), cemiplimab(n = 1, 265 patients), cemiplimab plus CT(n = 1, 312 patients) and sintilimab plus CT(n = 1, 252 patients) versus standard CT. 5 studies assessed both EORTC-QLQ-C30 and EORTC-QLQ-LC13; 1 study assessed EORTC-QLQ-C30 and LCSS; 5 study assessed EORTC-QLQ-LC13 alone; and only 2 studies studies assessed EQ-5D-3L and LCSS; 12 HR-QoL items were reported in 5 or more studies: global QoL, physical functioning(PF) and fatigue, assessed by EORTC-QLQ-C30; Cough, Pain in arm or shoulder, Pain in chest, assessed by EORTC-QLQ-LC13. four and six studies graded as low risk of bias[ 39 , 40 , 44 , 47 ] and some concerns[ 37 , 38 , 41 , 42 , 45 ], respectively and one study graded as high risk of bias[ 48 ] (eFigure 2). 3.3 Primary outcome 3.3.1 TTD of Global QOL Figure 1 presents the pooled estimates of TTD in global QOL for patients with aNSCLC who received ICIs–based therapies compared to those treated with CT. This meta-analysis encompassed 7 studies involving 4317 aNSCLC patients. Compared with CT, first-line ICI-based therapies were consistently linked to a significantly longer TTD of Global QOL (HR 0.75, 95% CI 0.71–0.80; p < 0.001). The pooled hazard ratio indicated a reduced risk of deterioration in overall perceived health among patients receiving ICI-based therapies, with no evidence of between-study heterogeneity ( p = 0.9359; I ² = 0.0%). Regarding ICIs regimen, ICIs alone did not show a statistically significant difference in TTD of global QOL compared with CT under the random-effects model(HR 0.78, 95%CI 0.58–1.05, I ² = 0.0%), whereas, ICT were associated with a significantly prolonged TTD of global QoL(HR 0.74, 95%CI 0.69–0.80, I ² = 0.0%). In meta-regression analyses, the proportion of squamous cell carcinoma was significantly associated with the treatment effect ( p = 0.02), whereas no significant associations were observed for other examined study-level covariates, including mean age, sex distribution, ethnicity, or the proportion of PD-L1–negative tumors ( p > 0.05). 3.4 Secondary outcomes 3.4.1 TTD of functioning The results of the meta-analysis comparing the TTD in physical and emotional functioning in aNSCLC patients treated with ICI-based therapies versus CT regimens are shown in Fig. 2. This meta-analysis encompassed 5 studies(8 treatment arms) and 4 studies(6 treatment arms) involving 2430 to 2805 aNSCLC patients, respectively. Compared with CT, first-line ICI-based therapies significantly delayed TTD of physical functioning(HR 0.68, 95% CI 0.62–0.74; p < 0.001) and TTD of emotional functioning(HR 0.78, 95% CI 0.63–0.97; p = 0.0325), with low heterogeneity between-study ( I ² = 0.0% for physical functioning; I ² = 26% for emotional functioning). Regarding ICI regimen, ICIs alone did not show a statistically significant difference in TTD of physical functioning(HR 0.59, 95%CI 0.31–1.11, I ² = 0.0%) and TTD of emotional functioning(HR 0.66, 95%CI 0.03–16.7, I ² = 60.1%) compared with CT under the random-effects model, whereas, ICT were associated with a significantly prolonged TTD of physical functioning(HR 0.70, 95%CI 0.64–0.76, I ² = 0.0%) and showed a trend toward delayed emotional deterioration (HR 0.82, 95%CI 0.64–1.05, I ² = 9%), though the latter did not reach statistical significance. 3.4.2 TTD of Symptomatology The results of the meta-analysis comparing the TTD in symptoms in aNSCLC patients treated with ICI-based therapies versus CT regimens are shown in eFigure 3-eFigure 5. The meta-analysis of fatigue encompassed 8 studies involving 4,770 aNSCLC patients, whereas analyses of other symptom domains included 5 to 7 studies, with sample sizes ranging from 1,785 to 4,395 aNSCLC patients. Under the random-effects model, treatment with ICI-based therapies was associated with significantly prolonged TTD of fatigue (HR 0.74, 95% CI 0.67–0.83; p < 0.001, I ² = 25.6%, eFigure 3), pain (HR 0.68, 95% CI 0.56–0.83; p = 0.0019, I ² = 60.2%, eFigure 3), dyspnea (HR 0.76, 95% CI 0.68–0.86; p < 0.001, I ² = 0.4%, eFigure 3), cough (HR 0.79, 95% CI 0.65–0.96; p = 0.0228, I ² = 40.8%, eFigure 4), the composite endpoint of cough, chest pain, or dyspnea (HR 0.76, 95% CI 0.61–0.94; p = 0.0243, I ² = 0.0%, eFigure 4), hemoptysis (HR 0.76, 95% CI 0.59–0.97; p = 0.0327, I ² = 33.2%, eFigure 4), and nausea and/or vomiting (HR 0.55, 95% CI 0.36–0.82; p = 0.0112, I ² = 85%, eFigure 4), compared with CT. For pain, fatigue, and dyspnea, regimen-stratified analyses demonstrated statistically significant delays in deterioration with both ICT and ICIs alone compared with CT. The direction and magnitude of effect were consistent across regimens, and no strong evidence of effect modification by treatment strategy was observed(eFigure 3). In contrast, for cough, hemoptysis, nausea and/or vomiting, the composite endpoint of cough, chest pain, or dyspnea, although overall analyses favored ICI-based regimens, regimen-specific subgroup analyses yielded less consistent or statistically non-significant results, with wider confidence intervals(eFigure 4). Notably, no significant difference in TTD of appetite loss was observed between ICI-based regimens and CT in either the overall analysis(HR 0.75, 95%CI 0.57-1, p = 0.0527, I 2 = 76.9%, eFigure 5) or regimen-stratified analyses, suggesting that appetite-related symptoms may be less sensitive to ICI-based therapies effects. 3.5 Sensitivity analyses There was considerable heterogeneity for appetite loss, pain and nausea and/or vomiting, we identified two studies[ 42 , 43 ] for appetite loss and one study[ 37 ] for pain that were outliers or influential with the leave one out analysis and the Baujat plot(eFigure 6). After excluding the those studies, the remaining studies with a cumulative pooled estimate HR for TTD of appetite loss is 0.88(95% CI 0.71–1.08, I 2 = 49.9%) and HR for TTD of pain is 0.72(95% CI 0.61–0.84, I 2 = 42.3%). In contrast, for nausea and/or vomiting, no individual study significantly influenced the pooled results or heterogeneity, indicating the robustness of the findings for this symptom domain. 3.6 Publication bias Visual inspection of funnel plots revealed no evidence of publication bias for either TTD of global QoL (Fig. 3). This was further supported by Egger’s regression test based on the Pustejovsky and Rodgers method[ 49 ], which did not indicate funnel plot asymmetry for TTD of global QoL ( p = 0.227). 3.7 Exploratory analysis: Correlation Between HRQoL Deterioration and OS Among the available treatment comparisons, a statistically significant positive correlation was observed between the HR for TTD of emotional functioning (r = 0.84, p = 0.035) and TTD of the composite symptom domain of dyspnea, cough, and chest pain (r = 0.88, p = 0.047) and the HR for OS. No significant correlations were observed for global QoL, physical functioning, or other individual symptom domains (eFigure 7). 4. Discussion In this meta-analysis of randomized clinical trials, we synthesized evidence on TTD in HRQoL among patients with aNSCLC receiving first-line ICI–based therapies. Using global QoL as the prespecified primary outcome, and physical functioning, emotional functioning and symptom domains as secondary outcomes, we found that ICI-based therapies significantly delayed global QoL deterioration compared with CT, with minimal between-study heterogeneity. This benefit was primarily driven by ICT, whereas ICIs alone did not show a significant advantage over CT for global QoL or physical functioning. Across symptom outcomes, ICI-based therapies delayed deterioration in several high-burden domains closely related to disease burden, including fatigue, pain, cough, dyspnea, and the composite endpoint of cough, chest pain, or dyspnea, while no significant difference was observed for appetite loss. Several mechanisms may explain the observed delay in global QoL deterioration with ICI-based therapies. Improved and more durable disease control may postpone progression-associated symptom escalation, particularly for symptoms closely linked to tumor burden [ 50 – 53 ].In addition, ICIs have a toxicity profile distinct from that of cytotoxic CT[ 54 , 55 ]. Although immune-related adverse events can be severe, they typically affect a minority of patients and lack the cumulative pattern characteristic of CT-related toxicities[ 53 , 56 ]. Reduced treatment-related burden among responders may further contribute to sustained patient-perceived benefit. These findings are consistent with prior evidence showing that ICIs preserve or improve patient-reported QoL across multiple cancer types[ 57 – 59 ]. Previous meta-analyses have reported delayed QoL deterioration with ICIs compared with standard therapies, including in NSCLC[ 60 ]. Our study expands upon existing literature by focusing on first-line ICI-based therapies in aNSCLC, restricting inclusion to randomized trials that report TTD in HRQoL, and incorporating regimen-specific subgroup analyses to better understand how different treatment strategies—monotherapy versus combination ICT—may differentially affect PROs. Additionally, exploratory analyses were conducted to evaluate whether improvements in HRQoL are associated with survival benefits, providing insight into the clinical relevance of symptom control beyond traditional endpoints. Regimen-specific analyses revealed important differences in global QoL outcomes. ICT was associated with a significant delay in TTD of global QoL, whereas ICIs alone did not confer a statistically significant benefit over CT. This difference may reflect variation in symptom profiles across regimens. While ICIs alone delayed deterioration in several disease-related symptoms(pain, fatigue, and dyspnea), the absence of improvement in appetite loss and variability across certain symptom domains may have attenuated gains at the global level. In contrast, combination regimens appeared to achieve a balance in which improvements in disease-related symptoms outweighed CT-associated toxicities, resulting in net preservation of global QoL. Sensitivity analyses showed that TTD of pain heterogeneity was largely driven by one study[ 37 ], which defined pain worsening as a ≥ 10-point score rise without subsequent improvement, whereas other trials often require confirmation of worsening at two consecutive visits. In other words, many studies count TTD only after back-to-back symptom increases, whereas EMPOWER-Lung-3 did not. This inconsistency in TTD rules can bias pooled results. TTD definition likely made this study the outlier. Excluding it dropped I ² from ≈ 60.2% to nearly 42.3%. Influence analysis for TTD of appetite loss identified two studies[ 42 , 43 ]—both ICI monotherapy trials—as major contributors. Compared to combination regimens, monotherapy may result in less consistent appetite improvement due to slower disease control and distinct toxicity profiles. Excluding these studies reduced heterogeneity ( I ² = 49.9%) and improved estimate precision, suggesting that regimen type (monotherapy vs. combination) may influence appetite-related outcomes through different impacts on inflammation, endocrine function, and symptom relief[ 61 – 63 ]. Exploratory analyses further revealed that HRs for deterioration in composite lung-related symptoms (dyspnea, cough, chest pain) and emotional functioning positively correlated with HRs for OS across trials, indicating that deterioration in high-burden and depression/anxiety-related PROs may serve as early prognostic markers. These findings are consistent with our previous studies showing that unfavorable QoL profiles and emotional distress are associated with poorer survival in advanced NSCLC[ 64 , 65 ], as well as with prior evidence demonstrating that pretreatment emotional distress is associated with inferior responses to immune checkpoint inhibitors[ 66 ]. Collectively, these results reinforce the prognostic relevance of symptom and emotional deterioration captured by PROs. However, the small number of data points (n = 5) precludes definitive conclusions. This underscores the need for more granular, trial-level reporting of both PRO and survival outcomes to validate this potential relationship. This study has several limitations. First, this analysis was based on trial-level summary data rather than individual patient data, precluding adjustment for important patient-level confounders such as baseline performance status, comorbidities, socioeconomic factors, and use of supportive care. Second, definitions of time to deterioration (TTD) and thresholds for clinically meaningful change were not fully uniform across trials, which may have introduced measurement heterogeneity. Third, the exploratory correlation between hazard ratios for PRO deterioration and overall survival was conducted at the study level and is therefore subject to ecological bias; causality at the individual patient level cannot be inferred. Fourth, although multiple symptom and functional domains were included, PRO instruments and assessment schedules varied across studies, potentially affecting the comparability of deterioration patterns. Fifth, the number of eligible trials was relatively limited, which may have reduced statistical power for some subgroup and exploratory analyses and may affect the robustness of certain estimates. Finally, most included trials were conducted in selected trial populations with good performance status, which may limit the generalizability of our findings to real-world patients. Our results endorse integrating TTD of HRQoL into assessing first-line treatments for aNSCLC as significant PROs. ICI-based therapies exhibited superior preservation of HRQoL over time, particularly when combined with ICT. Monitoring TTD may help clinicians and patients better anticipate the timing and pattern of QoL changes associated with different treatment strategies, thereby facilitating shared decision-making. Notably, exploratory analyses suggested that deterioration in lung-related symptoms and emotional functioning may have additional prognostic relevance; however, these observations should be interpreted cautiously and considered hypothesis generating. Future studies should continue to integrate longitudinal PROs and evaluate QoL trajectories in more diverse and representative populations. 5. Conclusion First-line ICI-based treatments significantly extended TTD in QoL, functioning, and symptoms compared to CT among patients with aNSCLC. The combination of ICIs and CT exhibited the longer QoL maintenance. These results underscore the importance of TTD as a patient-focused outcome and advocate for its inclusion in clinical trial assessments. Additional research is needed to validate these outcomes across more diverse patient cohorts. Declarations Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This research was partly supported by grants awarded to Jian-Guo Zhou including the National Natural Science Foundation of China (Grant No. 82504050), Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2023ZD0502105), MOE (Ministry of Education in China) Liberal arts and Social Sciences Foundation (Grant No. 24YJCZH462), Youth Science and Technology Elite Talent Project of Guizhou Provincial Department of Education (Grant No. QJJ-2024-333), Zunyi City Science and Technology Plan Project (Grant Nos. Zunshi Kehe HZ (2023) 142 and Zunshi Kehe HZ (2025) 256), Zunyi City Science and Technology Innovation Team(Grant No. Zun KCTD (2025) 63), Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University (ZYSE 2023-02), Guizhou Province High-Level Overseas-Educated Talents Innovation and Entrepreneurship Selective Funding Program (Grant No. 3) and the Key Program of the Education Sciences Planning of Guizhou Province (Grant No. 2024A007), Zunyi City Science and Technology Plan Project (Grant Nos. Zunshi Kehe HZ Zi (2025) No. 82), Author Contribution Shen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Shen, Zhou. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Shen, Zhou. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Zhou, Chen. Obtained funding: Zhou. Administrative, technical, or material support: Zhou, Ma, Gaipl. Supervision: Zhou. Acknowledgments Not applicable. Data Availability The data underlying this article are available in the article and in its online supplementary material. For further information or assistance please contact corresponding author: [email protected] . References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2024;74(3):229–63. Li C, Wang H, Jiang Y, Fu W, Liu X, Zhong R, et al. Advances in lung cancer screening and early detection. Cancer biology Med. 2022;19(5):591–608. Li H, Harrison EB, Li H, Hirabayashi K, Chen J, Li QX, et al. Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration. Nat Commun. 2022;13(1):2154. 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Cheng Y, Zhang L, Hu J, Wang D, Hu C, Zhou J, et al. Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. JTO Clin Res Rep. 2021;2(10):100225. Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, et al. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(3):387–97. Garon EB, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Kim SW et al. Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Lung cancer (Amsterdam, Netherlands). 2023;186:107422. Garon EB, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, et al. Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Clin Lung Cancer. 2021;22(4):301–e128. Kilickap S, Özgüroğlu M, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, et al. Cemiplimab monotherapy as first-line treatment of patients with brain metastases from advanced non-small cell lung cancer with programmed cell death-ligand 1 ≥ 50. Cancer. 2025;131(10):e35864. Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M et al. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung cancer (Amsterdam, Netherlands). 2025;200:108108. !!! INVALID CITATION !!!. Reck M, Ciuleanu TE, Lee JS, Schenker M, Audigier-Valette C, Zurawski B, et al. First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1. J Thorac oncology: official publication Int Association Study Lung Cancer. 2021;16(4):665–76. Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gümüş M, et al. Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. J Clin oncology: official J Am Soc Clin Oncol. 2020;38(3):271–80. de Marinis F, Giaccone G, Herbst RS, Oprean C-M, Szczesna A, Boukovinas I et al. Patient-reported outcomes (PROs) in the randomized, phase III IMpower110 study of atezolizumab (atezo) vs chemotherapy in 1L metastatic NSCLC. J Clin Oncol. 2020;38. Pustejovsky JE, Rodgers MA. Testing for funnel plot asymmetry of standardized mean differences. Zhang H, Hu Y, Wu T, Chen Y, Yang B, Xie T. Clinical characteristics and novel strategies of immune checkpoint inh. Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Early tumor shrinkage identifies long-term disease control and survival in patients with lung cancer treated with atezolizumab. J Immunother Cancer. 2020;8(1). Butterfield LH, Najjar YG. Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations. Nat Rev Immunol. 2024;24(6):399–416. Chen H, Yang H, Guo L, Sun Q. The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances. MedComm. 2025;6(10):e70412. Rached L, Laparra A, Sakkal M, Danlos F-X, Barlesi F, Carbonnel F et al. Toxicity of immunotherapy combinations with chemotherapy across tumor. Rached L, Laparra A, Sakkal M, Danlos FX, Barlesi F, Carbonnel F, et al. Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations. Cancer Treat Rev. 2024;127:102751. Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Boutros A, Bruzzone M, Tanda ET, Croce E, Arecco L, Cecchi F et al. Health-related quality of life in cancer patients treated with immune checkpoint inhibitors in randomised controlled trials: A systematic review and meta-analysis. Gonzalez BD, Eisel SL, Bowles KE, Hoogland AI, James BW, Small BJ, et al. Meta-Analysis of Quality of Life in Cancer Patients Treated With Immune Checkpoint Inhibitors. J Natl Cancer Inst. 2022;114(6):808–18. Pala L, Sala I, Oriecuia C, De Pas T, Queirolo P, Specchia C, et al. Association of Anticancer Immune Checkpoint Inhibitors With Patient-Reported Outcomes Assessed in Randomized Clinical Trials: A Systematic Review and Meta-analysis. JAMA Netw open. 2022;5(8):e2226252. Liu W, Zhang Q, Zhang T, Li L, Xu C. Quality of life in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: a systematic review and meta-analysis. World J Surg Oncol. 2022;20(1):333. Andreyev J, Adams R, Bornschein J, Chapman M, Chuter D, Darnborough S, et al. British Society of Gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut. 2025;74(7):1040–67. Cappello G, Molea F, Campanella D, Galioto F, Russo F, Regge D. Gastrointestinal adverse events of immunotherapy. BJR open. 2021;3(1):20210027. Choi J, Lee SY. Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors. Immune Netw. 2020;20(1):e9. Shen J, Ma J, Chen S, Jin SH, Xu J, Li Q, et al. Quality-of-life scale machine learning approach to predict immunotherapy response in patients with advanced non-small cell lung cancer. Front Immunol. 2025;16:1600265. Li X, Li Q, Jin S-H, Chen X, Shen J, Ma H et al. Association between pretreatment emotional distress and survival outco. Zeng Y, Hu CH, Li YZ, Zhou JS, Wang SX, Liu MD, et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med. 2024;30(6):1680–8. Additional Declarations No competing interests reported. Supplementary Files SupplementalOnlineContent.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 29 Mar, 2026 Reviewers agreed at journal 10 Mar, 2026 Reviewers invited by journal 17 Feb, 2026 Editor assigned by journal 16 Feb, 2026 Submission checks completed at journal 16 Feb, 2026 First submitted to journal 15 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8886255","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593550586,"identity":"676c1411-b228-4f97-b607-e3d2702ef3df","order_by":0,"name":"Juanyan Shen","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juanyan","middleName":"","lastName":"Shen","suffix":""},{"id":593550587,"identity":"4e5ea5b5-5f6a-4f5d-963d-9625b2ba1241","order_by":1,"name":"Junliang Ma","email":"","orcid":"","institution":"Affiliated Hospital of Zunyi Medical 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13:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8886255/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8886255/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103504525,"identity":"7e6365ea-8221-4e12-af13-98f92f596d25","added_by":"auto","created_at":"2026-02-26 13:20:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41175,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8886255/v1/b61441bc3c3e63de701fdee7.png"},{"id":103177512,"identity":"2375c2e0-302f-48c6-b2f9-801912288a78","added_by":"auto","created_at":"2026-02-22 16:51:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74123,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8886255/v1/6e5435d5de63d455e127aa63.png"},{"id":103177511,"identity":"48a35e19-6b41-41b3-9077-9f722d971195","added_by":"auto","created_at":"2026-02-22 16:51:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":26955,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8886255/v1/bd699e94bf00eed8c4b1d916.png"},{"id":103509239,"identity":"f083db84-33cd-4de8-a5c5-2475cf6d1c22","added_by":"auto","created_at":"2026-02-26 13:57:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":889484,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8886255/v1/1908404c-864d-4439-b986-5748935c5c4d.pdf"},{"id":103177514,"identity":"27197379-fc39-4786-9d08-4a0d1b6e6d21","added_by":"auto","created_at":"2026-02-22 16:51:47","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1852709,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalOnlineContent.docx","url":"https://assets-eu.researchsquare.com/files/rs-8886255/v1/e2cacebd799fd874e320ee4f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"First-Line Immune Checkpoint Inhibitors Versus Chemotherapy in Delaying Quality of Life Deterioration in Advanced NSCLC: A Systematic Review and Meta- Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNon-small cell lung cancer(NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading contributor to global cancer mortality[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advances in early detection and screening, the majority of patients are diagnosed with stage III or IV disease[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], for whom curative treatment is rarely feasible. Even with modern systemic therapies, the 5-year survival rate for metastatic NSCLC remains below 15%[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], traditional CT, while extending patient survival, often comes with a spectrum of severe toxicities that profoundly impair patients' health related quality of life(HRQoL)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Consequently, a critical objective in the management of aNSCLC is to not only prolong life but also to maintain or improve patients' HRQoL.\u003c/p\u003e \u003cp\u003eIn recent years, immune checkpoint inhibitors(ICIs) targeting programmed cell death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have fundamentally reshaped the first-line therapeutic landscape for aNSCLC[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. By restoring antitumor T-cell responses and reversing tumor-induced immune suppression, ICIs have demonstrated substantial and consistent improvements in overall survival(OS) across multiple phase III trials[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although OS remains the most frequently used primary endpoint in phase III randomized clinical trials(RCTs)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], its evaluation requires prolonged follow-up and may be confounded by subsequent lines of therapy[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. As a result, surrogate endpoints such as progression-free survival (PFS) have increasingly replaced OS as the primary endpoint in contemporary trials[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, PFS does not fully capture patients\u0026rsquo; subjective treatment experience or the impact of therapy on daily functioning and well-being.HRQoL is a multidimensional construct encompassing physical, psychological, and social functioning and provides a comprehensive assessment of patients\u0026rsquo; lived experiences during treatment [17]. In aNSCLC, preserving HRQoL is increasingly viewed as being as important as prolonging survival, with many patients even prioritizing QoL in treatment decisions[18, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Time to deterioration(TTD) of HRQoL, defined as the time from randomization to the first clinically meaningful worsening of HRQoL, has emerged as a robust and clinically interpretable event-based endpoint[20, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Reported using hazard ratios analogous to OS and PFS, TTD captures both the timing and durability of HRQoL benefits while mitigating biases related to missing data and informative dropout[22\u0026ndash;24]. Prior large-scale meta analyses have demonstrated that TTD of global QoL and physical functioning show a stronger association with OS than with PFS in immunotherapy trials[25], supporting its role as a meaningful complementary endpoint in aNSCLC. However, robust evidence for durable improvements in global QoL remains limited in first-line treatment studies of aNSCLC[26, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. A recent meta-epidemiological analysis of phase 3 RCTs found that global QoL superiority was rarely reported and concurrent improvements in OS and QoL were even more uncommon[27]. These findings highlight the need for rigorous, disease-specific evaluations of QoL outcomes in aNSCLC, where ICIs are now standard first-line therapy. Current evidence gaps limit clinicians\u0026rsquo; ability to balance survival benefits with long-term QoL when making treatment decisions.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to synthesize evidence on TTD in HRQoL among patients with aNSCLC receiving first-line ICI-based therapies and to explore its association with OS. These findings may help clinicians better understand the long-term QoL impact of ICIs and inform patient-centered treatment decisions.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis meta-analysis was performed by following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guideline[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO, CRD420251266405).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data Sources and Search Strategy\u003c/h2\u003e \u003cp\u003eA systematic literature search of Pubmed, Cochrane Library, and Scopus databases was performed to identify full-text articles published from the beginning of the databases' availability until September 2025. The detailed search strategy is reported in eTable 1. To find further studies, the electronic search was combined with manual searches of the reference lists of all review articles and primary studies that had been retrieved. If the main study had not included a full analysis of HRQoL, we searched for exploratory analyses of HRQoL that were published subsequently. When studies were published more than once, only the latest full data were used in the meta-analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study Selection\u003c/h2\u003e \u003cp\u003ePhase II or III RCTs had to meet the following inclusion criteria(1) RCTs evaluating first-line ICI-based therapies (PD-1/PD-L1 inhibitors or CTLA-4 inhibitors, administered as monotherapy, dual ICIs, or in combination with CT) compared with CT alone in patients with aNSCLC. (2)Studies in which the control arm was placebo alone or other anticancer agents, including targeted therapy and other ICIs, were excluded. (3) reported data on the TTD of HRQoL scores assessed by validated questionnaires; and(4) published in the English language.\u003c/p\u003e \u003cp\u003eTwo individual reviewers (Juanyan Shen and Qisha Li) identified and reviewed full-text articles and abstracts that were deemed relevant by screening the list of titles. In cases of disagreement, a third author (Jianguo Zhou) provided a decisive opinion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Extraction and Quality Assessment\u003c/h2\u003e \u003cp\u003eHRs for TTD of HR-QoL and HR for OS with corresponding 95% CI were extracted as effect measures. The following study-level covariates were extracted: study name and/or lead author name, publication year, type of intervention and control arms, type of questionnaire(s) used to evaluate HRQoL, HRQoL items assessed, definition of deterioration of HR-QoL. We also noted if there was an HRQoL analysis in the main article or in a later published exploratory analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Risk of Bias\u003c/h2\u003e \u003cp\u003eThe Cochrane Collaboration\u0026rsquo;s tool for assessing the risk of bias in the trial was used which includes the following domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The Consolidated Standards of Reporting Trials (CONSORT) PRO checklist was used to assess the quality of PRO[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Two authors (Juanyan Shen and Qisha Li) independently conducted these assessments. Disagreements were resolved by consulting a third author (Jianguo Zhou)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe primary outcome was HR for TTD of global QoL between aNSCLC patients treated with ICI\u0026ndash;based therapies and those receiving CT. The EORTC QLQ-C30 global health status scale or, when unavailable, the EQ-5D visual analogue scale (VAS), was used to evaluate global QoL. Secondary outcomes comprised HR for TTD of physical functioning, emotional functioning and symptom domains(ie, pain, fatigue, appetite loss, insomnia, nausea and/or vomiting, and the composite endpoint of cough and chest pain and dyspnea) between aNSCLC patients treated with ICI\u0026ndash;based therapies and those receiving CT assessed using the EORTC QLQ-LC13, the Lung Cancer Symptom Scale (LCSS), and selected symptom subscales of the EORTC QLQ-C30. A subgroup analysis for all outcomes was conducted based on whether ICIs\u0026ndash;based therapies were administered with or without concomitant CT(ICT or ICIs). All outcomes were analyzed as time-to-event variables. The definition of these outcomes was consistent with the original studies (eTable 2). Effect estimates were pooled as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs).\u003c/p\u003e \u003cp\u003eWe performed a random-effects meta-analysis, as described by Hartung and Knapp[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], to estimate summary risk of TTD of HRQoL by calculating the pooled estimates of HRs and their 95% CIs for safety outcomes in aNSCLC patients treated with ICI-based therapies vs CT. Heterogeneity across studies was assessed using the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e statistic and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e values were calculated using the χ\u003csup\u003e2\u003c/sup\u003e test and degrees of freedom[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. A two-sided P value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eTo investigate the potential association between HRQoL outcomes and survival benefit, we conducted an exploratory correlation analysis comparing HRs for TTD in various HRQoL domains\u0026mdash;including global QoL, physical functioning, emotional functioning and symptom subscales\u0026mdash;with corresponding HRs for OS. Pearson\u0026rsquo;s correlation coefficient (r) was used to assess the linear relationship between log-transformed HRs (log[HR]), and scatterplots were used for visual inspection, with significance set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003ePublication bias was visually examined for primary outcomes using a funnel plot, and Egger\u0026rsquo;s regression test was conducted to statistically assess the bias[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Sensitivity analyses were performed for outcomes with substantial heterogeneity (I\u0026sup2; \u0026ge;50%)[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. We performed outlier detection and influence analyses using the leave-one-out method and reported Baujat plots to graphically display studies that overly contribute to the heterogeneity[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. All analyses were performed using the meta package in R, version 4.3.2 (R Project for Statistical Computing).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eThe flow diagram of the study selection process is shown in eFigure 1. The search strategy retrieved 1519 unique titles. After we screened titles and abstracts, 1453 studies were excluded for irrelevance. We assessed 69 full-text articles, with 56 studies excluded due various reasons, mostly QoL data not available in either the primary publication or exploratory analyses. After reviewing these studies, 13 phase 3 randomized clinicaltrials[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42 CR43 CR44\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], enrolling 6555 patients fulfilled the inclusion criteria and were selected for the meta-analysis. All included studies had 2 treatment arms, except from MYSTIC and POSEIDON trial[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] which had 3 arms. The CheckMate 227 Part 1[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] trial included three arms. however, TTDs in HR-QOL were reported only for the nivolumab plus ipilimumab versus CT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study characteristics\u003c/h2\u003e \u003cp\u003eCharacteristics of the included studies can be found in eTable 2. Nine articles originated in the United States of American (USA), two articles conducted in China, one in the Australia, one from Argentina. All trials were conducted between 2014 and 2018 and all articles were published from 2017 to 2025.\u003c/p\u003e \u003cp\u003eFurthermore, three trials[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] included patients with PD-L1 TPS of 50% or greater, two trials[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] included squamous NSCLC, and two trials[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] included non-squamous NSCLC. Patients included in the analysis were randomised to receive pembrolizumab (n\u0026thinsp;=\u0026thinsp;1; 151 patients), pembrolizumab plus CT (n\u0026thinsp;=\u0026thinsp;3, 743 patients), atezolizumab (n\u0026thinsp;=\u0026thinsp;2; 409 patients), durvalumab (n\u0026thinsp;=\u0026thinsp;1, 163 patients), durvalumab plus CT (n\u0026thinsp;=\u0026thinsp;1, 326 patients), durvalumab plus tremelimumab (n\u0026thinsp;=\u0026thinsp;1, 163 patients), durvalumab plus tremelimumab plus CT(n\u0026thinsp;=\u0026thinsp;1, 325 patients), nivolumab plus ipilimumab (n\u0026thinsp;=\u0026thinsp;1; 396 patients), nivolumab plus ipilimumab plus CT(n\u0026thinsp;=\u0026thinsp;1; 361 patients), cemiplimab(n\u0026thinsp;=\u0026thinsp;1, 265 patients), cemiplimab plus CT(n\u0026thinsp;=\u0026thinsp;1, 312 patients) and sintilimab plus CT(n\u0026thinsp;=\u0026thinsp;1, 252 patients) versus standard CT. 5 studies assessed both EORTC-QLQ-C30 and EORTC-QLQ-LC13; 1 study assessed EORTC-QLQ-C30 and LCSS; 5 study assessed EORTC-QLQ-LC13 alone; and only 2 studies studies assessed EQ-5D-3L and LCSS; 12 HR-QoL items were reported in 5 or more studies: global QoL, physical functioning(PF) and fatigue, assessed by EORTC-QLQ-C30; Cough, Pain in arm or shoulder, Pain in chest, assessed by EORTC-QLQ-LC13. four and six studies graded as low risk of bias[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] and some concerns[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], respectively and one study graded as high risk of bias[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] (eFigure 2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Primary outcome\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1 TTD of Global QOL\u003c/h2\u003e \u003cp\u003eFigure 1 presents the pooled estimates of TTD in global QOL for patients with aNSCLC who received ICIs\u0026ndash;based therapies compared to those treated with CT. This meta-analysis encompassed 7 studies involving 4317 aNSCLC patients. Compared with CT, first-line ICI-based therapies were consistently linked to a significantly longer TTD of Global QOL (HR 0.75, 95% CI 0.71\u0026ndash;0.80; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The pooled hazard ratio indicated a reduced risk of deterioration in overall perceived health among patients receiving ICI-based therapies, with no evidence of between-study heterogeneity (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9359; \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%). Regarding ICIs regimen, ICIs alone did not show a statistically significant difference in TTD of global QOL compared with CT under the random-effects model(HR 0.78, 95%CI 0.58\u0026ndash;1.05, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%), whereas, ICT were associated with a significantly prolonged TTD of global QoL(HR 0.74, 95%CI 0.69\u0026ndash;0.80, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%). In meta-regression analyses, the proportion of squamous cell carcinoma was significantly associated with the treatment effect (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02), whereas no significant associations were observed for other examined study-level covariates, including mean age, sex distribution, ethnicity, or the proportion of PD-L1\u0026ndash;negative tumors (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Secondary outcomes\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1 TTD of functioning\u003c/h2\u003e \u003cp\u003eThe results of the meta-analysis comparing the TTD in physical and emotional functioning in aNSCLC patients treated with ICI-based therapies versus CT regimens are shown in Fig.\u0026nbsp;2. This meta-analysis encompassed 5 studies(8 treatment arms) and 4 studies(6 treatment arms) involving 2430 to 2805 aNSCLC patients, respectively. Compared with CT, first-line ICI-based therapies significantly delayed TTD of physical functioning(HR 0.68, 95% CI 0.62\u0026ndash;0.74; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and TTD of emotional functioning(HR 0.78, 95% CI 0.63\u0026ndash;0.97; p\u0026thinsp;=\u0026thinsp;0.0325), with low heterogeneity between-study (\u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0% for physical functioning; \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 26% for emotional functioning). Regarding ICI regimen, ICIs alone did not show a statistically significant difference in TTD of physical functioning(HR 0.59, 95%CI 0.31\u0026ndash;1.11, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%) and TTD of emotional functioning(HR 0.66, 95%CI 0.03\u0026ndash;16.7, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 60.1%) compared with CT under the random-effects model, whereas, ICT were associated with a significantly prolonged TTD of physical functioning(HR 0.70, 95%CI 0.64\u0026ndash;0.76, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%) and showed a trend toward delayed emotional deterioration (HR 0.82, 95%CI 0.64\u0026ndash;1.05, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 9%), though the latter did not reach statistical significance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2 TTD of Symptomatology\u003c/h2\u003e \u003cp\u003eThe results of the meta-analysis comparing the TTD in symptoms in aNSCLC patients treated with ICI-based therapies versus CT regimens are shown in eFigure 3-eFigure 5. The meta-analysis of fatigue encompassed 8 studies involving 4,770 aNSCLC patients, whereas analyses of other symptom domains included 5 to 7 studies, with sample sizes ranging from 1,785 to 4,395 aNSCLC patients. Under the random-effects model, treatment with ICI-based therapies was associated with significantly prolonged TTD of fatigue (HR 0.74, 95% CI 0.67\u0026ndash;0.83; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 25.6%, eFigure 3), pain (HR 0.68, 95% CI 0.56\u0026ndash;0.83; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0019, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 60.2%, eFigure 3), dyspnea (HR 0.76, 95% CI 0.68\u0026ndash;0.86; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.4%, eFigure 3), cough (HR 0.79, 95% CI 0.65\u0026ndash;0.96; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0228, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 40.8%, eFigure 4), the composite endpoint of cough, chest pain, or dyspnea (HR 0.76, 95% CI 0.61\u0026ndash;0.94; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0243, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 0.0%, eFigure 4), hemoptysis (HR 0.76, 95% CI 0.59\u0026ndash;0.97; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0327, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 33.2%, eFigure 4), and nausea and/or vomiting (HR 0.55, 95% CI 0.36\u0026ndash;0.82; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0112, \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 85%, eFigure 4), compared with CT.\u003c/p\u003e \u003cp\u003eFor pain, fatigue, and dyspnea, regimen-stratified analyses demonstrated statistically significant delays in deterioration with both ICT and ICIs alone compared with CT. The direction and magnitude of effect were consistent across regimens, and no strong evidence of effect modification by treatment strategy was observed(eFigure 3). In contrast, for cough, hemoptysis, nausea and/or vomiting, the composite endpoint of cough, chest pain, or dyspnea, although overall analyses favored ICI-based regimens, regimen-specific subgroup analyses yielded less consistent or statistically non-significant results, with wider confidence intervals(eFigure 4). Notably, no significant difference in TTD of appetite loss was observed between ICI-based regimens and CT in either the overall analysis(HR 0.75, 95%CI 0.57-1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0527, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e= 76.9%, eFigure 5) or regimen-stratified analyses, suggesting that appetite-related symptoms may be less sensitive to ICI-based therapies effects.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Sensitivity analyses\u003c/h2\u003e \u003cp\u003eThere was considerable heterogeneity for appetite loss, pain and nausea and/or vomiting, we identified two studies[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] for appetite loss and one study[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] for pain that were outliers or influential with the leave one out analysis and the Baujat plot(eFigure 6). After excluding the those studies, the remaining studies with a cumulative pooled estimate HR for TTD of appetite loss is 0.88(95% CI 0.71\u0026ndash;1.08, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;49.9%) and HR for TTD of pain is 0.72(95% CI 0.61\u0026ndash;0.84, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;42.3%). In contrast, for nausea and/or vomiting, no individual study significantly influenced the pooled results or heterogeneity, indicating the robustness of the findings for this symptom domain.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Publication bias\u003c/h2\u003e \u003cp\u003eVisual inspection of funnel plots revealed no evidence of publication bias for either TTD of global QoL (Fig.\u0026nbsp;3). This was further supported by Egger\u0026rsquo;s regression test based on the Pustejovsky and Rodgers method[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], which did not indicate funnel plot asymmetry for TTD of global QoL (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.227).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Exploratory analysis: Correlation Between HRQoL Deterioration and OS\u003c/h2\u003e \u003cp\u003eAmong the available treatment comparisons, a statistically significant positive correlation was observed between the HR for TTD of emotional functioning (r\u0026thinsp;=\u0026thinsp;0.84, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035) and TTD of the composite symptom domain of dyspnea, cough, and chest pain (r\u0026thinsp;=\u0026thinsp;0.88, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047) and the HR for OS. No significant correlations were observed for global QoL, physical functioning, or other individual symptom domains (eFigure 7).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this meta-analysis of randomized clinical trials, we synthesized evidence on TTD in HRQoL among patients with aNSCLC receiving first-line ICI\u0026ndash;based therapies. Using global QoL as the prespecified primary outcome, and physical functioning, emotional functioning and symptom domains as secondary outcomes, we found that ICI-based therapies significantly delayed global QoL deterioration compared with CT, with minimal between-study heterogeneity. This benefit was primarily driven by ICT, whereas ICIs alone did not show a significant advantage over CT for global QoL or physical functioning. Across symptom outcomes, ICI-based therapies delayed deterioration in several high-burden domains closely related to disease burden, including fatigue, pain, cough, dyspnea, and the composite endpoint of cough, chest pain, or dyspnea, while no significant difference was observed for appetite loss.\u003c/p\u003e \u003cp\u003eSeveral mechanisms may explain the observed delay in global QoL deterioration with ICI-based therapies. Improved and more durable disease control may postpone progression-associated symptom escalation, particularly for symptoms closely linked to tumor burden [\u003cspan additionalcitationids=\"CR51 CR52\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].In addition, ICIs have a toxicity profile distinct from that of cytotoxic CT[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Although immune-related adverse events can be severe, they typically affect a minority of patients and lack the cumulative pattern characteristic of CT-related toxicities[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Reduced treatment-related burden among responders may further contribute to sustained patient-perceived benefit.\u003c/p\u003e \u003cp\u003eThese findings are consistent with prior evidence showing that ICIs preserve or improve patient-reported QoL across multiple cancer types[\u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Previous meta-analyses have reported delayed QoL deterioration with ICIs compared with standard therapies, including in NSCLC[\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Our study expands upon existing literature by focusing on first-line ICI-based therapies in aNSCLC, restricting inclusion to randomized trials that report TTD in HRQoL, and incorporating regimen-specific subgroup analyses to better understand how different treatment strategies\u0026mdash;monotherapy versus combination ICT\u0026mdash;may differentially affect PROs. Additionally, exploratory analyses were conducted to evaluate whether improvements in HRQoL are associated with survival benefits, providing insight into the clinical relevance of symptom control beyond traditional endpoints.\u003c/p\u003e \u003cp\u003eRegimen-specific analyses revealed important differences in global QoL outcomes. ICT was associated with a significant delay in TTD of global QoL, whereas ICIs alone did not confer a statistically significant benefit over CT. This difference may reflect variation in symptom profiles across regimens. While ICIs alone delayed deterioration in several disease-related symptoms(pain, fatigue, and dyspnea), the absence of improvement in appetite loss and variability across certain symptom domains may have attenuated gains at the global level. In contrast, combination regimens appeared to achieve a balance in which improvements in disease-related symptoms outweighed CT-associated toxicities, resulting in net preservation of global QoL.\u003c/p\u003e \u003cp\u003eSensitivity analyses showed that TTD of pain heterogeneity was largely driven by one study[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], which defined pain worsening as a \u0026ge;\u0026thinsp;10-point score rise without subsequent improvement, whereas other trials often require confirmation of worsening at two consecutive visits. In other words, many studies count TTD only after back-to-back symptom increases, whereas EMPOWER-Lung-3 did not. This inconsistency in TTD rules can bias pooled results. TTD definition likely made this study the outlier. Excluding it dropped \u003cem\u003eI\u003c/em\u003e\u0026sup2; from \u0026asymp;\u0026thinsp;60.2% to nearly 42.3%. Influence analysis for TTD of appetite loss identified two studies[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u0026mdash;both ICI monotherapy trials\u0026mdash;as major contributors. Compared to combination regimens, monotherapy may result in less consistent appetite improvement due to slower disease control and distinct toxicity profiles. Excluding these studies reduced heterogeneity (\u003cem\u003eI\u003c/em\u003e\u0026sup2; = 49.9%) and improved estimate precision, suggesting that regimen type (monotherapy vs. combination) may influence appetite-related outcomes through different impacts on inflammation, endocrine function, and symptom relief[\u003cspan additionalcitationids=\"CR62\" citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExploratory analyses further revealed that HRs for deterioration in composite lung-related symptoms (dyspnea, cough, chest pain) and emotional functioning positively correlated with HRs for OS across trials, indicating that deterioration in high-burden and depression/anxiety-related PROs may serve as early prognostic markers. These findings are consistent with our previous studies showing that unfavorable QoL profiles and emotional distress are associated with poorer survival in advanced NSCLC[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], as well as with prior evidence demonstrating that pretreatment emotional distress is associated with inferior responses to immune checkpoint inhibitors[\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Collectively, these results reinforce the prognostic relevance of symptom and emotional deterioration captured by PROs. However, the small number of data points (n\u0026thinsp;=\u0026thinsp;5) precludes definitive conclusions. This underscores the need for more granular, trial-level reporting of both PRO and survival outcomes to validate this potential relationship.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this analysis was based on trial-level summary data rather than individual patient data, precluding adjustment for important patient-level confounders such as baseline performance status, comorbidities, socioeconomic factors, and use of supportive care. Second, definitions of time to deterioration (TTD) and thresholds for clinically meaningful change were not fully uniform across trials, which may have introduced measurement heterogeneity. Third, the exploratory correlation between hazard ratios for PRO deterioration and overall survival was conducted at the study level and is therefore subject to ecological bias; causality at the individual patient level cannot be inferred. Fourth, although multiple symptom and functional domains were included, PRO instruments and assessment schedules varied across studies, potentially affecting the comparability of deterioration patterns. Fifth, the number of eligible trials was relatively limited, which may have reduced statistical power for some subgroup and exploratory analyses and may affect the robustness of certain estimates. Finally, most included trials were conducted in selected trial populations with good performance status, which may limit the generalizability of our findings to real-world patients.\u003c/p\u003e \u003cp\u003eOur results endorse integrating TTD of HRQoL into assessing first-line treatments for aNSCLC as significant PROs. ICI-based therapies exhibited superior preservation of HRQoL over time, particularly when combined with ICT. Monitoring TTD may help clinicians and patients better anticipate the timing and pattern of QoL changes associated with different treatment strategies, thereby facilitating shared decision-making. Notably, exploratory analyses suggested that deterioration in lung-related symptoms and emotional functioning may have additional prognostic relevance; however, these observations should be interpreted cautiously and considered hypothesis generating. Future studies should continue to integrate longitudinal PROs and evaluate QoL trajectories in more diverse and representative populations.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eFirst-line ICI-based treatments significantly extended TTD in QoL, functioning, and symptoms compared to CT among patients with aNSCLC. The combination of ICIs and CT exhibited the longer QoL maintenance. These results underscore the importance of TTD as a patient-focused outcome and advocate for its inclusion in clinical trial assessments. Additional research is needed to validate these outcomes across more diverse patient cohorts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was partly supported by grants awarded to Jian-Guo Zhou including the National Natural Science Foundation of China (Grant No. 82504050), Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2023ZD0502105), MOE (Ministry of Education in China) Liberal arts and Social Sciences Foundation (Grant No. 24YJCZH462), Youth Science and Technology Elite Talent Project of Guizhou Provincial Department of Education (Grant No. QJJ-2024-333), Zunyi City Science and Technology Plan Project (Grant Nos. Zunshi Kehe HZ (2023) 142 and Zunshi Kehe HZ (2025) 256), Zunyi City Science and Technology Innovation Team(Grant No. Zun KCTD (2025) 63), Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University (ZYSE 2023-02), Guizhou Province High-Level Overseas-Educated Talents Innovation and Entrepreneurship Selective Funding Program (Grant No. 3) and the Key Program of the Education Sciences Planning of Guizhou Province (Grant No. 2024A007), Zunyi City Science and Technology Plan Project (Grant Nos. Zunshi Kehe HZ Zi (2025) No. 82),\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eShen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Shen, Zhou. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Shen, Zhou. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Zhou, Chen. Obtained funding: Zhou. Administrative, technical, or material support: Zhou, Ma, Gaipl. Supervision: Zhou.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data underlying this article are available in the article and in its online supplementary material. For further information or assistance please contact corresponding author: [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Clinical characteristics and novel strategies of immune checkpoint inh.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Early tumor shrinkage identifies long-term disease control and survival in patients with lung cancer treated with atezolizumab. J Immunother Cancer. 2020;8(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButterfield LH, Najjar YG. Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations. Nat Rev Immunol. 2024;24(6):399\u0026ndash;416.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen H, Yang H, Guo L, Sun Q. The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances. MedComm. 2025;6(10):e70412.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRached L, Laparra A, Sakkal M, Danlos F-X, Barlesi F, Carbonnel F et al. 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Nat Med. 2024;30(6):1680\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8886255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8886255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackgroud:\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitors (ICIs) have transformed first-line treatment for advanced non\u0026ndash;small-cell lung cancer (aNSCLC). While overall survival(OS) remains the primary endpoint, health-related quality of life (HRQoL) is a key patient-centered outcome. Time to deterioration (TTD) captures the durability of HRQoL over treatment. This study compared TTD in HRQoL between patients receiving ICI-based therapies and chemotherapy, and conducted exploratory analyses to assess the association between trial-level hazard ratios(HRs) for TTD and OS.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eMEDLINE, CENTRAL, and Scopus were systematically searched from inception to September 2025. Eligible studies included phase II or III randomized clinical trials evaluating first-line ICIs\u0026ndash;based therapies(ICI monotherapy, dual ICI combinations, or ICIs combined with chemotherapy) for aNSCLC and reporting TTD in HRQoL.The prespecified primary outcome was hazard ratio (HR) for TTD of global QoL between aNSCLC patients treated with ICI\u0026ndash;based therapies and those receiving chemotherapy. Secondary outcomes were HR for TTD of physical and emotional functioning and symptomatology. (PROSPERO registration number: CRD420251266405)\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eA total of 6555 aNSCLC patients from 13 randomized trials comparing ICI-based therapies with chemotherapy were included. Compared with chemotherapy, ICIs\u0026ndash;based therapies delayed deterioration of global QoL ( HR 0.75, 95% confidence interval [CI] 0.71\u0026ndash;0.81; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=0%). Regimen-specific analyses indicated that Immunochemotherapy delayed TTD in Global QoL over chemotherapy(HR 0.74, 95%CI 0.69\u0026ndash;0.80; \u003cem\u003eI\u003c/em\u003e\u0026sup2;=0%), whereas no significant benefit in TTD of Global QoL was observed with immunotherapy(HR 0.78, 95%CI 0.58\u0026ndash;1.05; \u003cem\u003eI\u003c/em\u003e\u0026sup2;=0%), with similar patterns for physical functioning. Across symptom outcomes, ICI based therapies delayed deterioration in several symptoms, including fatigue, pain, cough, dyspnea, and the composite endpoint of cough, chest pain, or dyspnea, while no significant difference was observed for appetite loss. Exploratory analyses further suggested an association between trial-level HRs for TTD of HRQoL and HRs for OS, although these findings should be interpreted cautiously.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAmong patients with aNSCLC, first-line ICI-based therapies significantly delayed deterioration of HRQoL compared with chemotherapy. These findings indicate that ICI-based therapies\u0026mdash;particularly immunochemotherapy\u0026mdash;are associated with more durable preservation of HRQoL in first-line treatment, complementing their established survival benefits. Exploratory analyses further suggested that trial-level HRs for HRQoL deterioration were positively associated with HR for OS.\u003c/p\u003e","manuscriptTitle":"First-Line Immune Checkpoint Inhibitors Versus Chemotherapy in Delaying Quality of Life Deterioration in Advanced NSCLC: A Systematic Review and Meta- Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 16:51:42","doi":"10.21203/rs.3.rs-8886255/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"210568366624039671595615930801763946340","date":"2026-03-29T13:14:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"177095762070510445572369396823227295648","date":"2026-03-10T13:42:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T04:20:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-16T13:33:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-16T09:29:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2026-02-15T13:15:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ef1bc77-548a-4d30-8466-b9a9a284fb44","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-22T16:51:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 16:51:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8886255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8886255","identity":"rs-8886255","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}