Abstract
Background
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). However, there is limited real-world evidence on their impact in patients with driver mutation-negative or unknown mutation status. This subgroup remains underrepresented in the literature despite having fewer treatment options and a historically poor prognosis. This study aimed to evaluate the long-term impact of ICIs on survival outcomes in this patient population.
Methods
We retrospectively reviewed patients with stage IV NSCLC who were treated at our institution between 2007 and 2024. Patients with driver mutation-negative or unknown mutation status who did not receive molecular-targeted therapies were included. We divided the study cohort into three periods based on the timing of chemotherapy initiation: period 1 [2007–2015], period 2 [2016–2018], and period 3 [2019–2024]. Overall survival (OS) was calculated from the start of chemotherapy to the date of death or last follow-up. Kaplan-Meier curves and Cox regression analysis were used to evaluate survival, with propensity score matching (PSM) conducted for sensitivity analysis.
Results
A total of 762 patients met the inclusion criteria. Patient demographics changed over time, with an increasing median age and a higher proportion of elderly patients (≥75 years) in later periods. The use of ICIs increased significantly over the three periods, from 0% in period 1 to 79.4% in period 3. Median OS (mOS) improved from 11.5 to 20.7 months and then to 19.1 months (P<0.001). In the multivariate Cox regression analysis, ICI use was significantly associated with improved OS [hazard ratio (HR) =0.52; 95% confidence interval (CI): 0.43–0.64; P<0.001], whereas treatment period itself was not an independent prognostic factor. The matched cohort analysis confirmed significant survival gains in periods 2 and 3 compared to period 1.
Conclusions
The widespread adoption of ICIs has significantly improved survival in patients with driver mutation-negative or unknown mutation status in a real-world setting. These findings support the integration of ICI-based regimens into routine clinical practice and underscore the need for ongoing efforts to optimize treatment strategies for patients without actionable mutations.
Keywords: Non-small-cell lung cancer (NSCLC), chemotherapy, immune checkpoint inhibitors (ICIs), survival analysis, driver mutations
Highlight box.
Key findings
• The integration of immune checkpoint inhibitors (ICIs) with chemotherapy significantly improved overall survival (OS) in advanced-stage non-small-cell lung cancer (NSCLC) patients who were driver mutation-negative or had unknown mutation status. The median OS increased from 11.5 months during 2007–2015 to 20.7 months during 2016–2018, coinciding with the expanded use of ICIs.
What is known and what is new?
• Chemotherapy has long been the standard treatment for NSCLC, though survival outcomes have historically been poor. ICIs have demonstrated survival benefits in clinical trials.
• This retrospective cohort study provides real-world evidence that combining ICIs with chemotherapy enhances OS in patients lacking driver mutations. It offers insights into treatment evolution across two decades.
What is the implication, and what should change now?
• ICIs should be firmly integrated into standard treatment strategies for NSCLC. Further investigation into personalized combination regimens is warranted to optimize patient outcomes.
• Broader implementation of ICI-based therapies in clinical practice, expanded real-world research to confirm long-term benefits, and development of novel approaches to meet remaining clinical needs.
Introduction
Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Advanced-stage non-small-cell lung cancer (NSCLC) with driver mutation-negative status has limited treatment options and a historically poor prognosis. Thus, such a condition is particularly challenging to manage (1). Traditionally, platinum-based combination chemotherapy has long been the standard of care for these patients. However, the outcomes have remained unsatisfactory. A major breakthrough in lung cancer treatment has occurred after the approval of immune checkpoint inhibitors (ICIs), starting with nivolumab in Japan in 2015 (2,3), followed by pembrolizumab in 2016 (4), atezolizumab (5), and durvalumab (6) in 2017, and the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody ipilimumab (7) combined with nivolumab in 2020. These drugs have significantly altered therapeutic strategies, particularly in patients without identifiable driver mutations, by improving survival rates. Despite their clinical importance, real-world data on patients with driver mutation-negative or unknown mutation status remain limited. Given the discrepancy between clinical trial populations and real-world patients—who often have worse performance status and more comorbidities—further investigation into real-world treatment outcomes is warranted.
ICIs, including programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have antitumor effects by modulating the interaction between tumor cells and the immune system. These agents are associated with improved outcomes in patients with driver mutation-negative NSCLC. Indeed, both domestic and international clinical trials have consistently shown that ICI treatment prolongs overall survival (OS) and progression-free survival (PFS) compared with conventional chemotherapy. Moreover, combination therapies that integrate ICIs with platinum-based chemotherapy have become a promising treatment approach. Clinical trials, such as the KEYNOTE-189 trial, have revealed that the addition of pembrolizumab to standard chemotherapy significantly improves OS and PFS in patients with advanced-stage NSCLC. Therefore, the combination of ICIs and chemotherapy has been adopted as a standard treatment regimen regardless of PD-L1 expression levels in patients with driver mutation-negative NSCLC (8). The widespread use of this combination therapy can further improve outcomes in patients with advanced-stage, driver-mutation-negative lung cancer. According to the current international treatment guidelines, combination therapy with platinum-based drugs and ICIs is a standard treatment for driver mutation-negative lung cancer regardless of PD-L1 expression (9).
Although clinical trials have confirmed the efficacy of ICIs, they often enroll highly selected patients with preserved performance status and few comorbidities. In contrast, patients in daily clinical practice tend to be older and more heterogeneous in clinical background, and those with unknown mutation status are often underrepresented in trial populations. Furthermore, treatment strategies and molecular testing practices have evolved over time, potentially affecting patient survival. To address these gaps, we conducted a real-world retrospective cohort study to assess survival trends over three distinct treatment eras in patients with advanced-stage NSCLC lacking actionable mutations. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2202/rc).
Methods
Study design and patient selection
This retrospective cohort study was conducted at the Japanese Red Cross Wakayama Medical Center, a general hospital in Japan. We reviewed consecutive patients with histologically or cytologically confirmed stage IV or recurrent NSCLC who received chemotherapy between March 2007 and June 2024. Patients were eligible for inclusion if they had driver mutation-negative or unknown mutation status and had not received molecular-targeted therapies epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Driver mutation-negative status was confirmed using either single-gene or multiplex molecular testing (e.g., Oncomine DxTT), whereas patients who did not undergo molecular testing were categorized as having unknown mutation status.
Patients who received EGFR-TKIs at any point, including after first-line therapy, were excluded. This exclusion was necessary to avoid confounding effects, as patients with unknown EGFR status may have harbored undetected mutations, and subsequent treatment with EGFR-TKIs could have significantly impacted survival outcomes. Patients enrolled in interventional clinical trials or lacking survival data were also excluded.
The total study sample consisted of 762 patients. The sample size reflected all eligible patients treated during the study period and was not determined by an a priori power calculation. Patients were stratified into three treatment periods based on the initiation date of chemotherapy, reflecting key milestones in the adoption of ICIs: period 1 [2007–2015] represented the pre-ICI era; period 2 [2016–2018] reflected early adoption of ICI monotherapy; and period 3 [2019–2024] marked the widespread use of ICI-chemotherapy combination therapy. Follow-up began at the start of first-line chemotherapy and continued until death or the censoring date of September 2, 2024. OS was defined as the time from the initiation of chemotherapy to death from any cause or last known follow-up. Survival data were obtained from hospital medical records.
Data collection
The data collected included demographic characteristics of the patients (age, sex), Eastern Cooperative Oncology Group performance status (ECOG PS) score, smoking history, histological subtype, gene mutation status, disease stage at the start of chemotherapy (including recurrence after surgery or radiotherapy), and the date of death. OS was defined as the duration from the start of chemotherapy until death, with patients still alive at the time of the study being censored as of September 2, 2024. In addition, the usage of ICIs, including nivolumab, pembrolizumab, atezolizumab, durvalumab, and ipilimumab, was recorded.
Patient grouping
The study population was stratified into three groups according to the timing of chemotherapy initiation, as defined in the “Study design and patient selection” section.
Statistical analysis
The characteristics of the patients were compared using the Student’s t-test for continuous variables and the Fisher’s exact test for categorical variables. Kaplan-Meier survival estimates were used to evaluate OS, and the log-rank test was applied to compare survival curves. Age was categorized as <75 and ≥75 years based on its clinical relevance in predicting outcomes in lung cancer treatment, as observed in previous studies. PD-L1 expression levels were categorized into <1%, 1–49%, and ≥50%, reflecting thresholds commonly used in clinical trials to stratify patients for treatment decisions. These categorizations were applied to facilitate subgroup analyses and improve the interpretability of results. Propensity score matching (PSM) was utilized to adjust for potential baseline confounders, including age, sex, smoking history, ECOG PS score, disease stage, and histological subtype. Propensity scores were calculated via logistic regression analysis. Cox proportional hazards regression analysis was conducted to assess the impact of clinical variables on OS, and factors with a P value of <0.05 in the univariate analysis were included in the multivariate analysis. Statistical analyses were performed using the EZR (Easy R) software (Kanda 2013), with a significance threshold of 5% (10).
Ethical considerations
The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the Japanese Red Cross Wakayama Medical Center (approval No. 1314). The need for informed consent was waived because of the retrospective nature of the study, with an opt-out option provided to the patients.
Results
Characteristics of patients
This was a consecutive case series of 1,447 patients with stage IV NSCLC who were treated at our institution. Table 1, which shows the characteristics of the patients, and Figure 1, which illustrates the flow chart of patient selection, were included for reference.
Table 1. Patient characteristics.
| Characteristics | Period 1 [2007–2015] (n=290) | Period 2 [2016–2018] (n=190) | Period 3 [2019–2024] (n=282) | P value |
|---|---|---|---|---|
| Age (years) | 69.5 [40–76] | 70 [35–88] | 72 [43–90] | 0.001 |
| Sex | 0.64 | |||
| Female | 54 (18.6) | 38 (20.0) | 47 (16.7) | |
| Male | 236 (81.4) | 152 (80.0) | 235 (83.3) | |
| Smoking status | 0.24 | |||
| Never smoker | 35 (12.1) | 19 (10.0) | 22 (7.8) | |
| Former or current smoker | 255 (87.9) | 171 (90.0) | 260 (92.2) | |
| Histology | 0.16 | |||
| Non-Sq | 190 (65.5) | 127 (66.8) | 167 (59.2) | |
| Sq | 100 (34.5) | 63 (33.2) | 115 (40.8) | |
| ECOG PS | 0.06 | |||
| 0 or 1 | 261 (90.0) | 158 (83.2) | 239 (84.8) | |
| ≥2 | 29 (10.0) | 32 (16.8) | 43 (15.2) | |
| Stage | 0.047 | |||
| IIIB–IIIC | 35 (12.1) | 19 (10.0) | 15 (5.3) | |
| IV | 168 (57.9) | 103 (54.2) | 167 (59.2) | |
| Recurrence after surgery or radiotherapy | 87 (30.0) | 68 (35.8) | 100 (35.5) | |
| Driver mutation status | 0.002 | |||
| Negative | 201 (69.3) | 150 (78.9) | 230 (81.6) | |
| Unknown | 89 (30.7) | 40 (21.1) | 52 (18.4) | |
| PD-L1 expression | <0.001 | |||
| <1% | 5 (1.7) | 34 (17.9) | 80 (28.4) | |
| 1–49% | 2 (0.7) | 45 (23.7) | 78 (27.7) | |
| ≥50% | 6 (2.1) | 65 (34.2) | 87 (30.9) | |
| Unknown | 277 (95.5) | 46 (24.2) | 37 (13.1) |
Data are presented as median [range] or n (%). ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1; Sq, squamous cell carcinoma.
Figure 1.
Flow chart of patient selection. EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; NSCLC, non-small-cell lung cancer.
We retrospectively included 762 patients with advanced-stage NSCLC and either negative or unknown driver mutation status. Baseline characteristics were evaluated across three distinct treatment periods: 2007–2015, 2016–2018, and 2019–2024. The median age of patients significantly increased from 69.5 years in period 1 to 72 years in period 3 (P=0.001). The proportion of patients aged 75 years or older increased from 32.4% in 2007–2015 to 40.1% in 2019–2024. In terms of histology, the proportions of patients with non-squamous NSCLC were 65.5%, 66.8%, and 59.2% in periods 1, 2, and 3, respectively. The proportions of smokers and histological subtypes were not significantly different across the three periods.
The measurement of PD-L1 expression in period 1 was minimal, with only 1.7% of patients showing expression. However, in period 3, 30.9% of the patients exhibited PD-L1 expression ≥50%, which reflected the increased use of molecular testing (P<0.001).
Treatment regimens and use of ICIs
The treatment regimens changed markedly over time. Table 2 summarizes the distribution of first-line regimens and ICI use across the three periods. In period 1, 76.9% of the patients were treated with platinum doublet chemotherapy. The use of ICI monotherapy increased from 0% in period 1 to 25.2% in period 3. Notably, the use of platinum doublet chemotherapy combined with ICIs increased from 0% in period 1 to 36.9% in period 3 (P<0.001). Monotherapy with ICIs also increased significantly, from 0% in period 1 to 25.2% in period 3. By the end of period 3, 79.4% of the patients had received ICIs at some point during their treatment.
Table 2. Study population treated with chemotherapy.
| Characteristics | Period 1 [2007–2015] (n=290) |
Period 2 [2016–2018] (n=190) |
Period 3 [2019–2024] (n=282) |
P value |
|---|---|---|---|---|
| First-line regimen | <0.001 | |||
| Platinum doublet | 223 (76.9) | 116 (61.1) | 87 (30.9) | |
| Platinum doublet + ICI | 0 (0.0) | 0 (0.0) | 104 (36.9) | |
| ICI only | 0 (0.0) | 53 (27.9) | 71 (25.2) | |
| Cytotoxic | 67 (23.1) | 21 (11.1) | 20 (7.1) | |
| Use of ICI up to the date of confirmation of survival | 27 (9.3) | 132 (69.5) | 224 (79.4) | <0.001 |
| Use of platinum doublet + ICI up to the date of confirmation of survival | 0 (0.0) | 1 (0.5) | 106 (37.6) | <0.001 |
| Use of durvalumab as a consolidation therapy after radiation chemotherapy | 0 (0.0) | 0 (0.0) | 35 (12.4) | <0.001 |
| Observation period (months) | 10.5 | 18.2 | 11.2 |
Data are presented as n (%) or median. ICI, immune checkpoint inhibitor.
OS
The median OS (mOS) was 11.5 months in period 1, increased to 20.7 months in period 2, and slightly declined to 19.1 months in period 3 (P<0.001). The 3-year OS rates improved substantially, rising from 14.2% in period 1 to 34.1% in period 2 and 32.8% in period 3 (Figure 2).
Figure 2.
OS of patients with NSCLC without or unknown driver mutation in each period. CI, confidence interval; m, months; No., number; NSCLC, non-small-cell lung cancer; OS, overall survival.
Propensity score-matched analysis
A propensity score-matched analysis controlled for baseline confounders such as age, sex, smoking status, histological subtype, and ECOG PS score. The detailed baseline characteristics of the matched cohorts are listed in Table S1. The matched analysis confirmed that the OS of the patients improved significantly between periods 1 and 2 [hazard ratio (HR) =0.55; 95% confidence interval (CI): 0.43–0.69; P<0.001] (Figure 3A). and between periods 1 and 3 (HR =0.57; 95% CI: 0.46–0.71; P<0.001) (Figure 3B). However, the OS did not significantly differ between periods 2 and 3 (HR =0.96; 95% CI: 0.74–1.25; P=0.79) (Figure 3C).
Figure 3.
Comparison of OS of propensity score-matched patients with NSCLC in each period. Matching for baseline characteristics: (A) patients in period 1 vs. period 2; (B) patients in period 1 vs. period 3; (C) patients in period 2 vs. period 3. CI, confidence interval; m, months; No., number; NSCLC, non-small-cell lung cancer; OS, overall survival.
Multivariate Cox proportional hazards regression analysis
A Cox proportional hazards regression analysis was performed to identify the independent prognostic factors of OS. Across all periods, factors such as ECOG PS score and the use of ICIs were the significant predictors of survival. The use of ICIs was associated with improved OS in all three periods. Specifically, in period 1, the HR was 0.59 (95% CI: 0.38–0.90; P=0.02). In period 2, the association became more pronounced, with an HR of 0.45 (95% CI: 0.30–0.68; P<0.001). Similarly, in period 3, the use of ICIs remained a strong predictor of improved OS, with an HR of 0.53 (95% CI: 0.34–0.80; P=0.003). Furthermore, treatment period (categorized as periods 1, 2, and 3) was included as a variable in the multivariate Cox model to assess potential temporal trends. However, neither period 2 (HR =0.86; 95% CI: 0.68–1.14; P=0.34) nor period 3 (HR =0.86; 95% CI: 0.68–1.12; P=0.29) showed a statistically significant association with OS when compared to period 1. These findings indicate that the improvement in survival over time was primarily driven by ICI use rather than by other temporal advancements in clinical management (Table 3). In addition, PD-L1 expression levels ≥1% were not identified as independent prognostic factors for OS in period 2 and period 3, despite the increasing proportion of patients undergoing PD-L1 testing during these periods.
Table 3. Cox proportional hazards model analysis of OS in NSCLC patients without identified driver mutations.
| Characteristics | Total | Period 1 [2007–2015] | Period 2 [2016–2018] | Period 3 [2019–2024] | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | HR | 95% CI | P | No. | HR | 95% CI | P | No. | HR | 95% CI | P | No. | HR | 95% CI | P | ||||
| Age (years) | |||||||||||||||||||
| <75 | 503 | 0.99 | 0.83–1.19 | 0.95 | 94 | 0.80 | 0.62–1.04 | 0.10 | 52 | 1.65 | 1.06–2.55 | 0.03 | 113 | 0.82 | 0.59–1.15 | 0.26 | |||
| ≥75 | 259 | 196 | 138 | 169 | |||||||||||||||
| Sex | |||||||||||||||||||
| Female | 139 | 0.95 | 0.74–1.23 | 0.72 | 236 | 0.95 | 0.65–1.39 | 0.80 | 152 | 1.04 | 0.62–1.72 | 0.89 | 235 | 0.91 | 0.56–1.47 | 0.69 | |||
| Male | 623 | 54 | 38 | 47 | |||||||||||||||
| Smoking status | |||||||||||||||||||
| Never smoker | 76 | 0.93 | 0.67–1.30 | 0.67 | 35 | 0.93 | 0.58–1.48 | 0.75 | 19 | 0.68 | 0.31–1.49 | 0.34 | 22 | 1.50 | 0.79–2.86 | 0.22 | |||
| Former or current smoker | 686 | 255 | 171 | 260 | |||||||||||||||
| Histology | |||||||||||||||||||
| Non-Sq | 484 | 0.84 | 0.70–1.00 | 0.054 | 190 | 0.88 | 0.68–1.15 | 0.35 | 127 | 0.61 | 0.42–0.88 | 0.008 | 167 | 1.03 | 0.74–1.44 | 0.87 | |||
| Sq | 278 | 100 | 63 | 115 | |||||||||||||||
| ECOG PS | |||||||||||||||||||
| 0 or 1 | 658 | 0.36 | 0.29–0.46 | <0.001 | 261 | 0.49 | 0.33–0.75 | <0.001 | 158 | 0.36 | 0.22–0.60 | <0.001 | 239 | 0.24 | 0.16–0.36 | <0.001 | |||
| ≥2 | 104 | 29 | 32 | 43 | |||||||||||||||
| Stage | |||||||||||||||||||
| Recurrence after surgery or radiotherapy | 255 | 0.71 | 0.59–0.85 | <0.001 | 87 | 0.77 | 0.59–1.01 | 0.06 | 68 | 0.54 | 0.37–0.80 | 0.008 | 100 | 0.73 | 0.52–1.03 | 0.07 | |||
| IIIB–IV | 507 | 203 | 122 | 182 | |||||||||||||||
| PD-L1 expression | |||||||||||||||||||
| ≥1% | 283 | 0.87 | 0.69–1.09 | 0.22 | 8 | 0.32 | 0.14–0.74 | 0.008 | 110 | 1.01 | 0.70–1.47 | 0.94 | 165 | 1.08 | 0.76–1.52 | 0.67 | |||
| <1% or unknown | 479 | 282 | 80 | 117 | |||||||||||||||
| Use of ICI up to the date of confirmation of survival | |||||||||||||||||||
| Yes | 383 | 0.52 | 0.43–0.64 | <0.001 | 27 | 0.59 | 0.38–0.90 | 0.02 | 132 | 0.45 | 0.30–0.68 | <0.001 | 224 | 0.53 | 0.34–0.80 | 0.003 | |||
| No | 379 | 263 | 58 | 58 | |||||||||||||||
| Treatment period | |||||||||||||||||||
| Period 2 vs. 1 | 190 vs. 290 | 0.86 | 0.68–1.14 | 0.34 | |||||||||||||||
| Period 3 vs. 1 | 282 vs. 290 | 0.86 | 0.68–1.12 | 0.29 | |||||||||||||||
CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ICI, immune checkpoint inhibitor; NSCLC, non-small-cell lung cancer; OS, overall survival; PD-L1, programmed death-ligand 1; Sq, squamous cell carcinoma.
Discussion
This study investigated a historically underrepresented subgroup of patients with advanced-stage NSCLC who had either driver mutation-negative or unknown mutation status. Our findings provide new insights by demonstrating that the incorporation of ICIs into chemotherapy regimens has contributed significantly to improved survival outcomes over the past two decades in patients lacking actionable driver mutations.
In all treatment periods, ICI use consistently emerged as a significant prognostic factor for OS in multivariate analysis. The marked increase in ICI utilization during periods 2 and 3 appears to have driven the observed improvements in OS. Together, these results emphasize the critical role of ICI integration in this patient population. To assess whether factors other than ICI use contributed to improved survival, we included treatment period as a covariate in the multivariate analysis. However, neither period 2 (HR =0.86; 95% CI: 0.68–1.14) nor period 3 (HR =0.86; 95% CI: 0.68–1.12) showed a statistically significant association with OS, suggesting that increased ICI use—not other systemic factors—was the key driver of improved outcomes. These findings align with major clinical trials demonstrating the efficacy of ICIs, such as KEYNOTE-042, KEYNOTE-407, and KEYNOTE-189 for pembrolizumab, and CheckMate 9LA for combination therapy with nivolumab and ipilimumab (8,11-13). However, these trials have strict inclusion criteria. Our real-world data support the generalizability of ICI benefits to mutation-negative or unknown-status patients.
In real-world settings, several studies have reported improved prognoses among patients with advanced-stage lung cancer. Howlader et al. analyzed mortality trends in NSCLC and SCLC from 2001 to 2016 in the United States, finding that advances in targeted and immune therapies after 2013 contributed to notable survival gains (14). Similarly, our study found that ICI use was associated with improved outcomes in patients with driver mutation-negative or unknown mutation status in recent years. Notably, the 2-year survival in men rose from 26% in 2001 to 35% in 2014, with similar trends observed in women, indicating mortality reductions outpaced incidence declines. In contrast, in small-cell lung cancer (SCLC), the reduction in mortality rate was significantly attributed to a decreased incidence, without remarkable improvement in survival. These data strongly suggest that advancements in targeted therapy and immunotherapy, as shown by Howlader et al. (14), have played an essential role in enhancing NSCLC prognosis. Takano et al. further examined the survival trends among patients with stage IV NSCLC treated at Nippon Foundation Cancer Institute Hospital between 1995 and 2017. After assessing patients according to five distinct periods, continuous improvements in median survival were reported. Similar to ours, the findings of the previous study emphasized the increasing role of ICIs in improving survival outcomes in recent years, particularly in patients without EGFR or ALK mutations (15). Ariyasu et al. expanded these findings by analyzing the clinical data collected from 2,078 patients with stage IV NSCLC over six diagnostic periods from 1995 to 2022. Their results revealed a gradual improvement in the mOS across all periods, from 8.9 months in 1995–1999 to 13 months in 2005–2009. Based on the most recent data [2020–2022], a median value has not yet been identified. However, prolonged survival from 17.9 months in 2010–2014 to 25.2 months in 2015–2019 was particularly significant (P<0.005). In addition, in patients without EGFR or ALK mutations, the usage of ICIs increased significantly—from 8.3% in 2010–2014 to 67.0% in 2015–2019—corresponding to a significant improvement in mOS. These findings suggest that ICIs, especially in mutation-negative populations, may serve as an effective alternative to conventional platinum-based chemotherapy (16). As described in a previous study, ICIs have remarkably improved the prognosis of patients with advanced-stage lung cancer. Nevertheless, prior reports focusing specifically on the mutation-negative or unknown subgroup remain limited. Our study thus contributes important real-world evidence in this area.
The use of combined ICIs and chemotherapy as first-line treatment increased notably during period 3 compared to period 2. The lack of a statistically significant OS difference between periods 2 and 3 may be explained by the shorter follow-up duration in period 3 (11.2 vs. 18.2 months). Furthermore, baseline patient characteristics in period 3—such as a higher proportion of older adults and lower PD-L1 testing coverage—may have masked survival gains from increased ICI use. Although no prospective data are available, retrospective studies—such as those by Pelicon et al., Yu et al., and Tao et al.—have supported our findings regarding the benefit of combination ICI strategies, even in mutation-negative patients. Supporting our findings, Pelicon et al. reported that chemo-ICI resulted in better mOS than ICI monotherapy (21.3 vs. 19.4 months) (17). Likewise, Yu et al. demonstrated that the combination of PD-1 inhibitors and anlotinib yielded superior PFS (6.0 vs. 3.4 months) and OS (16.1 vs. 11.9 months) compared with nivolumab alone in driver-negative adenocarcinoma (18). Furthermore, Tao et al. showed that combining ICIs with iodine-125 seed implantation led to significantly longer PFS and fewer grade ≥3 adverse events than standard external beam radiotherapy in driver-negative NSCLC (19). These results collectively reinforce the value of multimodal combination strategies in mutation-negative populations.
Qiu et al. analyzed 832 patients with advanced-stage NSCLC who received either ICI monotherapy or combination therapy following platinum-based chemotherapy (20). After PSM and Cox regression analysis, the combination group showed longer OS (16.0 vs. 13.1 months; HR =0.64; P=0.002), a shorter time to treatment discontinuation (HR =0.72; P=0.002), and a significant survival advantage (HR =0.50; P<0.001). Their findings align with our results, highlighting the benefit of chemo-ICI even in later-line settings. Combination therapy with ICIs may be associated with a better OS compared with ICI monotherapy after the initial platinum-based chemotherapy in patients with advanced-stage NSCLC. Despite the higher proportion of patients receiving ICI and platinum combination therapy in period 3, our study did not detect a significant difference in OS. In period 2, ICI monotherapy was used more frequently, and differences in patient characteristics—such as a higher proportion of women, non-squamous histology, stage III disease, and PD-L1 expression ≥50%—may have contributed to the differences in OS. In addition, the follow-up period in period 3 was shorter than that in period 2 (Table 2), and this might have affected the results.
This study had several limitations that should be acknowledged. First, a higher proportion of patients in period 1 lacked genetic testing, which may have led to underrecognized driver mutations and misclassification. In addition, multiplex testing has recently been introduced for identifying various genetic mutations in advanced-stage lung cancer. However, several genetic tests were not performed during period 2. Consequently, some cases classified as driver mutation-negative in period 2 might not truly be driver mutation-negative.
In a study conducted by Kris et al. in 2014, the survival rate of 318 patients with driver mutations who did not receive molecular-targeted therapy was 2.38 years. Meanwhile, the median survival of 360 patients with driver mutation-negative lung cancer was 2.08 years (21).
The KEYNOTE-789 trial was recently published. This study assessed the efficacy of pembrolizumab combined with pemetrexed and platinum-based chemotherapy in patients with NSCLC who presented with EGFR mutations (22). The trial showed that the median PFSs of the pembrolizumab and placebo groups did not significantly differ (5.6 vs. 5.5 months; HR =0.80; P=0.01). Similarly, the mOS did not significantly differ between the pembrolizumab and placebo groups (15.9 vs. 14.7 months; HR =0.84; P=0.04). As shown in a previous study, patients with driver mutations were more likely to respond less favorably to ICIs. Further, in this patient group, there were minimal differences in terms of efficacy between ICIs and standard platinum-based chemotherapy. Older patients in this study might have been underdiagnosed with driver mutations due to less comprehensive testing. This may have also contributed to the observed outcomes. Moreover, the lower rate of ICI use in these patients could have a minimal impact on the overall results. While survival improved from period 1 to 3, likely due to expanded ICI use, our subgroup analysis of patients not treated with targeted therapies suggests that the presence or underdiagnosis of driver mutations may not have significantly influenced these trends.
Finally, as this was a single-center, retrospective study, potential biases, such as selection bias, might have existed. However, the analysis of data from a single institution can be consistent in both data collection and treatment approaches. In addition, PSM and multivariate analysis were conducted to decrease these biases. Notably, our institution is a general hospital, not a specialized oncology facility. Thus, the patients commonly had a poorer PS and multiple comorbidities compared with those in specialized centers. Our findings are more likely to reflect real-world clinical practice.
Conclusions
Over the past two decades, survival in patients with advanced-stage NSCLC lacking actionable mutations has improved significantly, largely due to the integration of ICIs into standard chemotherapy regimens. However, no significant difference in OS was observed between ICI monotherapy and combination therapy with chemotherapy. These findings underscore the need to refine treatment selection and explore optimal ICI-based strategies. Further prospective and real-world studies are warranted to evaluate long-term outcomes, particularly in diverse clinical populations.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Japanese Red Cross Wakayama Medical Center (approval No. 1314). The need for informed consent was waived because of the retrospective nature of the study, with an opt-out option provided to the patients.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2202/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2202/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2202/dss
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