Real-world efficacy of immune checkpoint inhibitors in PD-L1 negative non-small cell lung cancer: a multicenter retrospective study

Introduction

Background

Lung cancer remains the most common malignancy worldwide and the primary cause of cancer-related deaths (1), imposing a substantial public health burden globally. Non-small cell lung cancer (NSCLC), comprising the majority of lung cancer cases, emphasizes the urgent need for enhanced therapeutic approaches (2). Immune checkpoint inhibitors (ICIs), particularly antibodies targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have transformed the treatment landscape for metastatic NSCLC lacking targetable driver mutations.

Despite these advancements, the response to ICI therapy varies significantly among patients. PD-L1 tumor proportion score (TPS), reflecting PD-L1 expression on tumor cells, serves as a key predictor of ICI response. Clinical trials have consistently shown that higher PD-L1 expression correlates with improved outcomes. While trials such as KEYNOTE-189 and KEYNOTE-407 demonstrated overall benefits of ICI-chemotherapy combinations (3,4), long-term follow-up data indicated minimal benefit in PD-L1-negative subgroups (5). While trials including IMpower130, IMpower150, and the CheckMate series also included PD-L1-negative populations, the clinical benefit of ICIs in these patients was notably modest. The magnitude of improvement was substantially lower compared to PD-L1-positive cases, with particularly disappointing results observed in squamous cell carcinoma patients (6-9).

Rationale and knowledge gap

Clinical trial populations often differ from real-world patients, who frequently present with more comorbidities and poorer performance status. Waterhouse et al. reported that real-world outcomes of immunotherapy-based regimens tend to be inferior to those observed in pivotal trials, particularly among PD-L1-negative patients (10). This discrepancy raises critical questions about the effectiveness of ICIs in the broader, real-world population, where PD-L1-negative patients may experience diminished efficacy. Despite the increasing utilization of ICIs, real-world data specifically focusing on PD-L1-negative NSCLC patients remains limited.

Objective

Given the limited evidence in this area, this study aimed to evaluate the real-world effectiveness and safety of ICI regimens in PD-L1-negative NSCLC patients. By focusing on this specific subset of the population, we seek to provide valuable insights that can inform clinical decision-making and optimize treatment strategies for this challenging patient group. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-138/rc).

Methods

Study design

The study is a multicenter, retrospective observational study conducted across eight medical facilities situated in Kanagawa Prefecture, Japan. Ethical approval for the study was granted by the Yokohama City University Ethics Committee (approval No. B191200044). Informed consent was waived due to the retrospective nature of the study. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Study population

Patients who underwent chemotherapy against lung cancer at participating institutions between January 1, 2015 and December 31, 2022 were included. Among 1,382 patients, 987 patients had histology of NSCLC and 211 of them were PD-L1 TPS <1%. 86 patients who received molecular targeted drugs and 32 patients who received chemoradiotherapy were excluded. Seven patients with epidermal growth factor receptor (EGFR) mutation were also excluded due to potential use of molecular targeted drugs in later treatment. The entire cohort was divided into two groups based on their first-line regimen: the “IC group”, consisting of patients treated with ICI alone or ICI plus cytotoxic agents, and the “C group”, comprising patients treated with cytotoxic agents without ICI (Figure 1).

Figure 1 Flowchart of study population. EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

Data collection and assessments

Data on patient demographics, clinical characteristics, treatment details, survival outcomes, and adverse events (AEs) were retrospectively collected from electronic medical records by a reviewer at each institute. Primary endpoints were overall survival (OS) and progression-free survival (PFS). OS was defined as the time from the initiation of first-line treatment to the date of death from any cause. PFS was defined as the time from initiation of first-line treatment to date that confirmed progressive disease or of death. Patients with unknown vital status were censored at the date of last contact. Treatment response was evaluated following Response Evaluation Criteria in Solid Tumors (RECIST) guideline (11) by an attending physician. AEs were graded according to Common Terminology Criteria for Adverse Events version 5.0 (12).

Statistical analysis

Categorical variables were reported as numbers (%) and quantitative variables were reported as median and interquartile range (IQR). Kaplan-Meier method was utilized to estimate OS and PFS, with the log-ranked test for comparison. OS and PFS were reported as median with 95% confidence interval (CI). Although Cox-proportional hazard model was used for estimation of hazard ratio (HR), it was not used for statistical testing due to concerns regarding potential violation of proportional hazard assumption. For the calculation of restricted mean survival time (RMST), shorter of the maximum follow-up period in each group was used as truncation time.

Age, Eastern Cooperative Oncology Group performance status (ECOG-PS) scale (13), histology, stage, liver, bone and brain metastasis were considered potential prognostic factors. Propensity scores were estimated for each patient based on logistic regression model that included covariates with a standardized mean difference (SMD) >0.1. Inverse probability of treatment weighting (IPTW) was employed to adjust for covariates between the groups in the analysis of primary endpoints. RMST adjusted by IPTW was estimated as described elsewhere (14), with 95% CI was calculated as ±1.96 standard errors. Safety analysis utilized either Chi-squared test or Fisher’s exact test. Additional analysis focusing on each type of ICI was conducted. All statistical analysis was conducted using R version 4.3.3 (15) and its associated packages (16-20). All tests were two-tailed, with a P<0.05 considered statistically significant. Missing data on tumor stage and histology were present, highly likely to be missing completely at random because missingness could only occur during the data collection process. Since the number was very small, patients with missing tumor stage or histology were excluded from the IPTW analysis.

Results

Patient characteristics

Among 1,382 patients initially screened, 987 had confirmed NSCLC histology, of whom 211 were PD-L1-negative (TPS <1%). After excluding patients who received molecular targeted drugs (n=86), chemoradiotherapy (n=32), and those with EGFR mutations (n=7), a total of 86 eligible patients were included in this study. The cohort was divided into two groups: the IC group (n=54) receiving ICI-containing regimens and the C group (n=32) receiving chemotherapy alone. Patient characteristics are summarized in Table 1. The C group had a median age of 74 (IQR, 68–77) years compared to 68 (IQR, 62–73) years in the IC group, highlighting its older demographic. The male-to-female ratio was similar between the groups, with males accounting for 78.1% in the C group and 85.2% in the IC group. While the majority of patients exhibited ECOG-PS of 0 to 1, there were also patients with ECOG-PS 2 to 3. The C group had a higher proportion of patients with poor performance status, comprising four ECOG-PS 2 patients (12.5%) and two ECOG-PS 3 patients (6.2%), compared to the IC group which had four ECOG-PS 2 patients (7.4%). Rates of brain, liver and bone metastasis were similar between the groups. The median follow-up period was 11.3 (IQR, 5.6–30.0) months in C group and 11.6 (IQR, 6.9–23.2) months in IC group. Regarding histology, adenocarcinoma was the predominant subtype in both groups, accounting for 65.6% and 55.6% of cases in the C and IC group, respectively. Squamous cell carcinoma was the second most common, representing 28.1% and 31.5% of cases in the C and IC group, respectively. The remaining patients were presented with other histological subtypes.

Treatment regimens

In the C group, the most common regimens included platinum-based agents with pemetrexed (PEM) (50.0%) and nanoparticle albumin-bound paclitaxel (nab-PTX) (28.1%). Other regimens included combinations with bevacizumab (BEV) or S-1.

In the IC group, similar trends were observed, with 27.8% receiving carboplatin (CBDCA) plus PEM and pembrolizumab (Pembro), and another 27.8% receiving CBDCA plus nab-PTX and Pembro. Additionally, 16.7% received CBDCA plus PEM and ipilimumab (Ipi) and nivolumab (Nivo). The most frequently used ICIs were Pembro, followed by atezolizumab (Atezo). Combination immunotherapy involving Ipi and Nivo was administered in 3 cases, with 12 cases receiving this combination along with cytotoxic agents.

OS and PFS

Kaplan-Meier curves of OS and PFS are shown in Figure 2A,2B, respectively. Although the median OS was longer in the IC group, no significant difference in OS was observed between the groups (C vs. IC: median 14.3 vs. 28.4 months, P=0.53). Twenty patients in the C group and 23 patients in the IC group experienced event for OS. PFS was significantly longer in the IC group compared to the C group (C vs. IC: median 6.5 vs. 9.2 months, P=0.02). Twenty-nine patients in the C group and 37 patients in the IC group experienced event for PFS. The dynamic effects of ICI may lead to non-proportional hazard scenarios, which was suggested in our study by a “tail-plateau” feature in survival curves. However, as there is no standardized method for handling such situations, we estimated HRs following previous clinical studies and calculated RMST. The HR for OS was 0.82 (95% CI: 0.44–1.52), and for PFS was 0.56 (95% CI: 0.34–0.92). The RMST for OS was 20.2 (95% CI: 14.9–25.5) months in the C group and 23.3 (95% CI: 19.3–27.4) months in the IC group. RMST of PFS was longer in the IC group, with 15.7 (95% CI: 11.8–19.7) months compared to 9.4 (95% CI: 6.1–12.7) months in the C group.

Figure 2 OS and PFS in C vs. IC groups. (A) Kaplan-Meier curves for OS. No significant difference was observed between the groups (median 14.3 vs. 28.4 months, P=0.53). (B) Kaplan-Meier curves for PFS. PFS was significantly longer in the IC group compared to the C group (median 6.5 vs. 9.2 months, P=0.02). C group: patients treated with only cytotoxic agents; IC group: patients treated with immune checkpoint inhibitor. CI, confidence interval; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival.

IPTW analysis

Considering age, ECOG-PS ≥2, histology, stage as confounding factors with SMD >0.1, further analysis using IPTW was conducted. Covariate balance was assessed by absolute SMD (Figure 3A). Kaplan-Meier curves for OS (C vs. IC: median 14.9 vs. 23.8 months, P=0.87) and PFS (C vs. IC: median 6.6 vs. 7.8 months, P=0.20) demonstrated similar trends to those observed before weighting (Figure 3B,3C), but no significant difference was confirmed. Adjusted HRs were 1.07 (95% CI: 0.54–2.10) for OS and 0.78 (95% CI: 0.45–1.33) for PFS. Adjusted RMST were 21.6 (95% CI: 15.6–27.5) vs. 21.8 (95% CI: 17.6–26.1) months for OS, and 10.0 (95% CI: 6.4–13.6) vs. 14.1 (95% CI: 10.3–18.0) months for PFS in the C and IC groups, respectively. Survival analysis balanced by IPTW incorporating covariates including those with SMD <0.1 (age, ECOG-PS ≥2, histology, stage, liver, bone and brain metastasis) showed similar results (Figure S1).

Figure 3 OS and PFS after adjusting covariates. (A) Love plot of before and after adjusting the covariates. Empty circle: unadjusted, filled circle: adjusted. (B) Kaplan-Meier curves for balanced OS in C vs. IC groups. No significant difference was observed (median 14.9 vs. 23.8 months, P=0.87). (C) Kaplan-Meier curves for PFS in C vs. IC groups. No significant difference was observed (median 6.6 vs. 7.8 months, P=0.20). C group: patients treated with only cytotoxic agents; IC group: patients treated with immune checkpoint inhibitor. CI, confidence interval; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival.

Analysis focused on each type of ICI

Since the result of PD-L1-negative subgroup analysis diverge between pivotal clinical trials, additional analysis focusing on each type of ICI was performed (demographics shown in Tables S1,S2). Patients who received specific ICIs were extracted from the IC group and difference in OS and PFS compared to the C group were analyzed in the same way as in the IPTW section. Patients receiving Pembro had significantly better PFS (C vs. Pembro: median 6.6 vs. 8.7 months, P=0.046) compared to the C group, but not the OS (C vs. Pembro: median 14.9 vs. 30.6 months, P=0.61) (Figure 4A,4B). Ipi plus Nivo (IN) regimen did not show obvious improvement in OS (C vs. IN: median 14.9 vs. 14.0 months, P=0.36) and PFS (C vs. IN: median 6.5 vs. 7.0 months, P=0.81) (Figure 4C,4D). Results of survival analysis incorporating covariates including those with SMD <0.1 were similar (Figures S2,S3).

Figure 4 OS and PFS after adjusting covariates for each type of ICI. OS and PFS for patients treated with Pembro containing regimens compared to those of C group (A,B). PFS of Pembro treated patients was significantly longer compared to the C group (median 6.6 vs. 8.7 months, P=0.046). OS and PFS for patients treated with ipilimumab plus nivolumab containing regimens compared to those of C group (C,D). C group: patients treated with only cytotoxic agents. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; IN, ipilimumab and nivolumab; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival.

Overall response rate (ORR) and disease control rate (DCR)

The ORR was higher in the IC group (50.0%) compared to the C group (34.4%). Similarly, the DCR was higher in the IC grou p (81.5%) compared to the C group (65.6%) (Table 2).

Safety analysis

AEs of any grade occurred in 96.3% of patients in the IC group and 96.9% of patients in the C group. Grade 3 or 4 AEs were reported in 59.2% of the IC group and 56.2% of the C group. The incidence of treatment discontinuation due to AEs was similar between the groups (C vs. IC: 21.9% vs. 24.1%, P=0.71) (Table 3). Major and distinct AEs were also evaluated. Frequency of neutropenia, anemia and thrombocytopenia did not differ between the groups. Several distinct AEs were observed in the IC group (C vs. IC): aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (3.1% vs. 18.5%), pneumonitis (6.3% vs. 11.1%), diarrhea (3.1% vs. 11.1%), creatinine increased (0.0% vs. 11.1%), adrenal insufficiency (0.0% vs. 7.4%) and thyroid dysfunction (0.0% vs. 3.7%).

Discussion

This retrospective, multicenter study provides valuable insights into the real-world effectiveness of ICI-containing regimens in PD-L1-negative NSCLC patients. Our findings suggest limited benefits of ICI-containing regimens in this population, with no significant changes in PFS and OS after covariates adjustment.

Improved PFS observed in the ICI group (median 6.5 vs. 9.2 months, P=0.02) has disappeared after adjusting covariates with IPTW (median 6.6 vs. 8.4 months, P=0.18). This suggests that improved PFS in the non-adjusted data was partially due to difference in the baseline demographics. In fact, the C group tended to be older and had higher rates of ECOG-PS 2 to 3, both considered to be related to poor prognosis.

Our findings in the PD-L1-negative population extend the results observed in some pivotal clinical trials. In the KEYNOTE-189 trial, which evaluated the addition of Pembro to chemotherapy in advanced non-squamous NSCLC, the PD-L1 TPS <1% subgroup showed improved PFS (median 5.1 vs. 6.1 months; HR =0.75; 95% CI: 0.53–1.05) and OS (12-month OS rate 52.2% vs. 61.7%; HR =0.59; 95% CI: 0.38–0.92) in the Pembro group compared to the placebo group (3). Similarly, the KEYNOTE-407 trial, which focused on advanced squamous NSCLC, demonstrated a modest but significant benefit of additional Pembro in the PD-L1 TPS <1% subgroup in terms of PFS (median 5.3 vs. 6.3 months; HR =0.68; 95% CI: 0.47–0.98) and OS (median 10.2 vs. 15.9; HR =0.61; 95% CI: 0.38–0.98) (4). Although PFS in Pembro treated patients was significantly better than that of the C group, OS did not show statistical significance like the OS and PFS in the overall IC group. Several factors may contribute to this discrepancy, including our study’s smaller sample size and the real-world setting with potentially less stringent patient selection. Our study included patients with poor performance status, who are typically excluded from pivotal ICI trials. These patient groups have been reported to have a lower ICI efficacy (21,22). The possibility of subsequent treatments affecting OS could also be considered (23). Moreover, OS benefit confirmed in KEYNOTE-407 trial was not significant in the 5-year follow up data (median 11.0 vs. 15.0; HR =0.83; 95% CI: 0.61–1.13) (5). The IMpower131 trial in squamous NSCLC showed no OS improvement in the PD-L1-negative subgroup with ICI combination therapy (24) also suggesting limited efficacy of ICI in this population. Recently, CTLA-4 antibodies combined with PD-1 or PD-L1 inhibitors have emerged as hopeful treatment in PD-L1-negative NSCLC. In this study, IN containing regimens did not show improved OS or PFS compared to chemotherapy only regimens. This challenges the results of CheckMate 227 (8), and CheckMate 9LA (9) trials, but the small sample size prevents drawing definitive conclusions. Furthermore, the long-term benefits of these regimens, as exemplified by the 5-year survival rates of 19% and 22% in the PD-L1-negative population (25,26), could not be fully assessed within the follow-up period of this study. A recently introduced tremelimumab plus durvalumab plus chemotherapy treatment (27) was not included in this study. Further investigation of effectiveness of these dual immuno-oncology treatments in PD-L1-negative real-world NSCLC population is warranted. Different efficacy between ICIs is suggested from the better PFS observed in Pembro treated patients but not in IN treated patients. However, due to the smaller sample size, potential bias risk related to the selection of the treatment and inconsistency with the result of clinical trials, it would be premature to conclude.

While the additive effect of ICIs appears limited in our study population, the lack of statistical significance should be interpreted cautiously. Though not statistically significant, trends toward improved median OS, PFS, and long-term survival were observed after covariate adjustment, suggesting potential benefit in select PD-L1-negative NSCLC patients. Further investigation of predictive biomarkers is warranted to identify these responsive subgroups. Our safety analysis demonstrated comparable overall AEs rates between groups, indicating that ICI addition did not substantially increase toxicity. However, several ICI-specific AEs were noted, which may have been overshadowed by common chemotherapy-related toxicities like cytopenia in the primary analysis. These findings should inform risk-benefit assessments when considering ICI-containing regimens for this potentially vulnerable population.

This study has several limitations. First, the sample size is too small to draw definite conclusion, especially in terms of statistical power, potentially resulting in an underestimation of treatment effect of ICI. The retrospective design also limits generalizability and increases bias risk. Treatment heterogeneity complicates result interpretation, and the study’s Japanese setting may limit broader applicability. Causality cannot be established, and the impact of later treatment lines, comorbidities, stereotactic radiotherapy treatments, and non-standardized PD-L1 assays were not accounted for. The study does not validate the additional effect of ICIs with chemotherapy, nor evaluate individual regimen effectiveness. Kaplan-Meier method assumes random censoring but is not guaranteed in this study. Larger, more diverse cohort studies are needed to address these limitations and confirm our findings.

Conclusions

In real-world advanced or recurrent NSCLC with PD-L1 TPS <1%, ICI regimens did not demonstrate significantly better OS or PFS compared to chemotherapy only regimens. However, the numerical advantage of ICI regimens and the significant PFS benefit observed with Pembro, underscores the need for further study targeting diverse patient populations, including those with poor performance status.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-138/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-138/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-138/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-138/coif). The authors have no conflicts of interest to declare.

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. Ethical approval for the study was granted by the Yokohama City University Ethics Committee (approval No. B191200044). Informed consent was waived due to the retrospective nature of the study. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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