Analysis of second-line therapy in patients with prior pneumonitis receiving first-line combination immunotherapy for advanced non-small cell lung cancer

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), providing durable responses and prolonged survival in a subset of patients (1-8). However, ICIs can cause immune-related adverse events (irAEs) due to enhanced immune activation. Among these, checkpoint inhibitor-related pneumonitis (CIP) is a clinically significant toxicity that can lead to treatment discontinuation and even fatal outcomes.

The reported incidence of CIP ranges from 3.3–6.6% in global clinical trials (1-8) to as high as 18–19% in real-world studies (9-11). Patients with pre-existing interstitial lung disease (ILD) are at increased risk of developing drug-induced pneumonitis, including CIP, compared with those without ILD (12-14). While prior studies have evaluated either outcomes after first-line therapy or the safety and efficacy of second-line treatments in patients with prior CIP, few have comprehensively evaluated clinical trajectory from CIP onset during first-line combination immunotherapy through subsequent treatment.

In particular, it remains uncertain whether CIP development during first-line treatment affects the likelihood of receiving second-line therapy or the outcomes of such therapy. Addressing this knowledge gap is important for informing treatment strategies and patient counseling. Moreover, while second-line therapies are often administered following CIP resolution, their safety and efficacy in this setting are not well characterized. Clarifying these issues is critical to optimizing treatment approaches for this vulnerable subgroup.

Therefore, we conducted a retrospective observational study to (I) characterize the clinical course of patients who developed CIP during first-line combination immunotherapy for advanced NSCLC; (II) compare the transition rate to second-line therapy between patients with and without prior CIP; and (III) evaluate the efficacy and incidence of drug-induced pneumonitis during second-line therapy. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-762/rc).

Methods

Study design and patients

This retrospective study included 159 consecutive patients with advanced or recurrent NSCLC who received combination chemo-immunotherapy at Fukuoka University Hospital between January 2019 and March 2024. For the purposes of this analysis, chemo-immunotherapy was considered first-line, including in patients with driver gene mutations who had previously received molecular targeted therapy. To investigate the relationship between pre-existing ILD and the development of CIP, patients were stratified by the presence or absence of baseline ILD as determined by high-resolution computed tomography (HRCT) prior to first-line immunotherapy. The incidence of CIP during first-line treatment was recorded, and compared between pre-existing ILD and non-pre-existing ILD groups. Among the 159 patients, 32 (20.1%) developed CIP. For the second-line therapy analysis, we evaluated 19 patients with prior CIP and 72 without prior CIP who experienced disease progression. The incidence of drug-induced pneumonitis during second-line therapy was assessed according to prior CIP status.

Clinical information such as age, sex, Eastern Cooperative Oncology Group performance status (PS), smoking history, histological classification, disease stage, programmed cell death ligand 1 (PD-L1) (22C3) expression levels, presence of actionable gene alterations, and pre-existing ILD status was extracted from patient charts. The ICI combination regimens and median duration of administration for first-line treatment are detailed in Table S1. Tumor staging was determined for each case based on the 8th edition of the Tumor, Node, and Metastasis Classification of Malignant Tumors (15). Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (16). The severity of irAEs were graded by attending physicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (17). Overall survival (OS) was defined as the time from the initiation of second-line therapy to the date of death, and progression-free survival (PFS) was calculated from the initiation of second-line treatment until disease progression or all-cause mortality. For reference, OS and PFS from the initiation of first-line therapy are also presented in the supplementary materials, using separate definitions. Data collection was finalized on February 28, 2025.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by Fukuoka University Medical Ethics Review Board (No. U22-02-006). As this was a retrospective study, the requirement for written informed consent was waived. Instead, an opt-out option was made available to patients via the institution’s official website (https://fukuoka.bvits.com/rinri/publish.aspx; last accessed February 28, 2025).

Statistical analysis

Comparisons of patient characteristics were performed using the Mann-Whitney U test for age and Fisher’s exact test for categorical variables. For driver gene mutations and PD-L1 tumor proportion score (TPS) analysis, some cases had missing data. These missing values were categorized as ‘UNKNOWN’ and included in the statistical analysis. All other variables had complete data. To reduce baseline imbalances between the prior CIP and non-prior CIP groups, propensity score matching was performed using logistic regression based on baseline characteristics. Histology was the only variable with a statistically significant difference between groups; therefore, matching was primarily intended to adjust for this imbalance and minimize potential confounding. Patients were matched 1:1 by the nearest-neighbor method with a caliper width of 0.2 standard deviations of the logit of the propensity score. Matching aimed to assess the impact of prior CIP on second-line therapy eligibility and outcomes, not on the effects of specific second-line regimens. Drug-induced pneumonitis incidence and objective response rate (ORR) were compared using Fisher’s exact test. PFS and OS were assessed using the Kaplan-Meier method and compared using the log-rank test. All P values were two-sided, with the threshold for statistical significance set at P<0.05. A Cox proportional hazards model was considered; however, given the small sample size and low event numbers in some strata, multivariate modeling risked overfitting. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (18).

Results

CIP and clinical outcomes in first-line immunotherapy

Of the 159 patients, 32 (20.1%) had CIP (Grade 1: 15; Grade 2: 7; Grade 3: 8; Grade 4: 2). Patient characteristics, including age, performance status, smoking history, and histological subtype, were comparable between the CIP and non-CIP groups. Among patients receiving first-line immunotherapy, the incidence of CIP was notably higher in those with pre-existing ILD, occurring in 38% (5 out of 13 patients) compared to 18% (27 out of 146 patients) in those without pre-existing ILD. Although the statistical analysis did not indicate a significant difference, a discernible trend was observed (P=0.050). No radiologically obvious usual interstitial pneumonia (UIP) pattern was observed in any of the cases, and the pre-existing ILD observed was mainly non-specific interstitial pneumonia (NSIP) pattern or UIP-indeterminate type. First-line regimens included atezolizumab plus platinum doublet with or without bevacizumab (n=74), pembrolizumab plus platinum doublet (n=53), nivolumab plus ipilimumab with or without platinum doublet (n=29), and tremelimumab plus durvalumab plus platinum doublet (n=3). The median duration of first-line therapy was 3.0 months in the CIP group and 4.4 months in the non-CIP group (Table S1). Regarding first-line treatment outcomes, the median PFS was 6.8 months in the CIP group and 6.3 months in the non-CIP group, with no statistically significant difference (P=0.69). Similarly, the median OS was 14.3 months in the CIP group and 18.0 months in the non-CIP group, with no significant difference observed (P=0.33) (Figure S1). These survival outcomes were calculated from the initiation of first-line therapy and are presented as reference data. Note that the definitions of OS and PFS in this analysis differ from those used in the subsequent second-line analysis, which forms the main focus of this study. As shown in the flow diagram (Figure 1), the transition rate to second-line therapy was 73% in the CIP group and 64% in the non-CIP group, with no statistically significant difference between the groups (Table S2), suggesting that the presence of CIP did not substantially impact the likelihood of receiving subsequent treatment.

Figure 1 Flow diagram illustrating the treatment course and outcomes of patients receiving immunotherapy (n=159). Of these, 32 patients developed CIP onset, with subsequent treatments including platinum doublets (n=1), DTX + RAM (n=9), DTX (n=5), S-1 (n=3), nabPTX (n=1), and BSC (n=7). Six patients in this group experienced no recurrence. Among the 127 patients without CIP, post-immunotherapy treatments comprised platinum doublets (n=13), targeted therapy (n=4), DTX + RAM (n=21), DTX (n=21), PEM (n=7), S-1 (n=5), ICI (n=1), and local therapies such as operation (n=2) or radiotherapy (n=2). Thirty-four patients received BSC, two were transferred for medical reasons, and 15 had no recurrence. BSC, best supportive care; CIP, checkpoint inhibitor-related pneumonitis; DTX, docetaxel; ICI, immune checkpoint inhibitor; nabPTX, nab-paclitaxel; PEM, pemetrexed; RAM, ramucirumab; S-1, tegafur, gimeracil, and oteracil potassium.

Characteristics of the study population

The clinicopathological characteristics of the 91 patients included in this study are summarized in Table 1. The median age was 68 years (range, 41–79 years). The majority of patients were male (n=64, 71%), and all had a PS of 0 or 1. A total of 76 patients (84%) were current or former smokers. Adenocarcinoma was the most common histological subtype, observed in 59% of cases. Stage IV disease was present in 85 patients (93%). Driver gene alterations were identified in 25 patients (27%). PD-L1 TPS was ≥1% in 62 patients (68%). No significant differences in patient characteristics were observed between the prior CIP and non-prior CIP groups, although histological classification differed slightly (Table 1). Specifically, the prior CIP group had a higher proportion of NSCLC not otherwise specified (n=6), three of which harbored driver gene mutations, suggesting a likely adenocarcinoma origin. This may have contributed to the apparent imbalance. Given the potential for confounding by histology and other baseline characteristics, we performed propensity score matching to minimize bias in outcome comparisons.

Efficacy based on the prior CIP

In the prior CIP group, tumor response to second-line therapy was observed in 2 of 19 patients, with an ORR of 11% [95% confidence interval (CI): 0–24%]. In contrast, in the non-prior CIP group, 10 of 72 patients responded, corresponding to an ORR of 14% (95% CI: 7–24%). The disease control rate (DCR) was 53% (95% CI: 30–75%) in the prior CIP group and 69% (95% CI: 57–80%) in the non-prior CIP group. No statistically significant differences in ORR (P>0.99) or DCR (P=0.18) were observed between the two groups (Table 2).

Of the 91 patients, 90 (99%) experienced PFS events, and 72 (79%) died during a median follow-up of 8.7 months at the time of analysis. Figure 2 illustrates the PFS and OS of patients with recurrent advanced NSCLC who received second-line therapy, stratified by the presence or absence of the prior CIP. The median PFS and OS in the prior CIP group were 2.0 and 6.4 months, respectively. Although the differences in PFS (P=0.14) and OS (P=0.07) between patients with and without prior CIP were not statistically significant, both outcomes were worse in the prior CIP group, with OS showing a trend toward shorter survival (Figure 2). After propensity score matching, baseline differences between the groups were eliminated (Table S3). The differences in PFS (P=0.09) and OS (P=0.06) remained statistically non-significant; however, a consistent trend toward shorter OS was observed in the prior CIP group (Figure 3).

Figure 2 PFS and OS in patients with recurrent advanced non-small cell lung cancer who received second-line chemotherapy, analyzed according to the presence of checkpoint inhibitor-related pneumonitis. CI, confidence interval; CIP, checkpoint inhibitor-related pneumonitis; mPFS, median PFS; mOS, median OS; OS, overall survival; PFS, progression-free survival.

Figure 3 PFS and OS in patients with recurrent advanced non-small cell lung cancer who received second-line chemotherapy, analyzed according to the presence of checkpoint inhibitor-related pneumonitis after propensity score matching. CI, confidence interval; CIP, checkpoint inhibitor-related pneumonitis; mPFS, median PFS; mOS, median OS; OS, overall survival; PFS, progression-free survival.

Drug-induced pneumonitis induced by second-line therapy

Table 3 summarizes the incidence of drug-induced pneumonitis induced by second-line therapy. In the prior CIP group, 5 of 19 patients (26%) developed drug-induced pneumonitis, with severity graded as 2 in two cases, 3 in one case, 4 in one case, and 5 in one case. Specifically, all 5 of these cases occurred among the 9 patients treated with docetaxel (DTX) plus ramucirumab (RAM), resulting in an incidence of 56% (5/9) for this regimen within the prior CIP group (Table S4). In contrast, 2 of 72 patients (3%) in the non-prior CIP group developed drug-induced pneumonitis, graded as 3 and 4 in one case each. Overall, 7 of 91 patients (8%) experienced drug-induced pneumonitis. A Fisher’s exact test revealed a significantly higher incidence in patients with prior CIP (P<0.01). We then examined the occurrence of drug-induced pneumonitis during second-line therapy according to both prior CIP and baseline pre-existing ILD status. Among the prior CIP group (n=19), drug-induced pneumonitis occurred in 1 of 3 patients with pre-existing ILD and in 4 of 16 patients without pre-existing ILD (P>0.99). In the non-prior CIP group (n=72), 3 patients had pre-existing ILD, and none of them developed drug-induced pneumonitis during second-line treatment (P>0.99). This result indicates that, in our small cohort, baseline pre-existing ILD did not show a statistically significant association with second-line drug-induced pneumonitis development. However, the “prior” development of CIP during first-line treatment itself may be a stronger predictor of increased susceptibility to subsequent treatment-induced pulmonary toxicity.

Treatment administration status and subsequent therapy

The administration of treatment and subsequent therapy is summarized in Table 4, with most regimens consisting of cytotoxic anticancer drugs. In both the prior CIP group and the non-prior CIP group, S-1—an oral fluoropyrimidine anticancer drug composed of tegafur, gimeracil, and oteracil potassium—was the most frequently administered agent. Notably, only one patient did not experience recurrence but continued to receive some form of therapy. Best supportive care (BSC) was provided to approximately half of the prior CIP group and one-third of the non-prior CIP group; however, this difference was not statistically significant. Targeted therapy was rarely used as second-line treatment because most patients with actionable mutations had already received molecular targeted agents prior to study entry.

Discussion

This study demonstrated that NSCLC patients with prior CIP had comparable transition rates to second-line therapy but showed a trend toward shorter OS and experienced a higher incidence of drug-induced pneumonitis with DTX-based regimens. Despite similar response and DCRs, the trend toward reduced survival in the prior CIP group underscores the impact of prior CIP on treatment tolerance and therapeutic options. Propensity score-matched analysis further confirmed a poorer OS trend in the prior CIP group, reinforcing the robustness of these survival findings.

Our most significant finding is the notably higher incidence of drug-induced pneumonitis during second-line treatment in the prior CIP group (26% vs. 3%, P<0.01). All such events in the prior CIP group occurred with DTX-based regimens. Specifically, among the 9 patients in the prior CIP group treated with DTX plus RAM, 5 developed drug-induced pneumonitis, representing a high incidence of 56% (5/9) for this specific regimen (Table S4). This finding suggests a possible association between DTX-based therapy and pneumonitis in patients with prior CIP; however, causality cannot be established due to potential selection bias and confounding factors.

This increased susceptibility to pulmonary toxicity may be rooted in pre-existing immunological factors, such as autoantibodies, which predispose patients to irAEs, including CIP, even prior to the initiation of ICI therapy. The early onset of CIP during first-line ICI treatment may reflect underlying immune dysregulation or heightened immune reactivity. This inflammatory response within the lung can reshape the pulmonary microenvironment, creating a “primed” state in which lung tissue becomes more vulnerable to subsequent insults, particularly from cytotoxic chemotherapy. Recent studies have demonstrated that pre-existing autoimmune conditions and immunological markers such as autoantibodies significantly increase the risk of irAEs, including pneumonitis, during ICI therapy (19,20). The initial onset of CIP may reflect a dysregulated immune baseline, which not only predisposes patients to irAEs but may also prime the lung microenvironment for heightened sensitivity to subsequent cytotoxic agents (21). These findings support the notion that prior CIP is not merely a transient adverse event but rather a clinical marker of immune hyperresponsiveness and pulmonary fragility. As such, the occurrence of CIP may serve as a predictive indicator for increased susceptibility to later pulmonary toxicity and should be carefully considered when planning subsequent treatment strategies.

Our findings align with previous reports indicating a high incidence of drug-induced pneumonia following ICI-related pneumonia. In other cohorts, the incidence has been reported to be as high as 50% in regimens containing DTX. Drug-induced pneumonia occurred in 8 out of 16 patients overall, including 1 in 4 patients receiving DTX alone and 2 in 4 patients receiving a combination of DTX plus RAM (22). However, given the small sample size, these findings should be interpreted with caution and may not be generalizable. DTX is also reported to have a high rate of treatment discontinuation due to disease progression, suggesting limitations in its efficacy. Japanese surveillance studies also show a significant incidence (e.g., 31.6%) of drug-induced pneumonitis with DTX in NSCLC patients with interstitial pneumonia (23). The relatively high incidence of treatment-associated pneumonitis observed in our single-center, real-world cohort at Fukuoka University Hospital may reflect patterns previously noted in Asian patient populations. Several retrospective analyses suggest that Asian patients could experience higher rates of pneumonitis compared to non-Asian populations, although direct comparisons are challenged by heterogeneity in treatment modalities, definitions of pneumonitis, and study settings (24,25). Factors potentially contributing to such ethnic disparities include genetic predispositions—for example, polymorphisms in the TGF-β1 gene have been associated with higher risk of radiation-induced pneumonitis in some cohorts (26)—as well as the higher prevalence of EGFR mutations among East Asian lung cancer patients, which has been suggested to modulate susceptibility to lung toxicity, though evidence remains exploratory (27). Hence, while these factors may provide biological context for our findings, causal relationships remain to be established through further large-scale, controlled studies.

In the prior CIP group, 5 of 9 patients treated with DTX plus RAM developed drug-induced pneumonitis, whereas none of the 5 patients treated with DTX alone developed drug-induced pneumonitis. Although enhanced efficacy of DTX plus RAM following immune checkpoint inhibitor therapy has been reported, there are no studies indicating an increased incidence of drug-induced pneumonitis with this combination (28). Therefore, the impact of adding RAM to DTX on drug-induced pneumonitis risk remains unclear. Possible mechanisms include residual immune priming by ICIs or cumulative pulmonary toxicity. However, further immunopathologic studies are needed.

The poorer survival trend observed in the prior CIP group may also be partly explained by limitations in subsequent treatment options. For instance, only one patient in the prior CIP group received platinum combination therapy, compared to 13 in the non-prior CIP group. While recent studies support the efficacy of platinum-based regimens post-ICI, demonstrating favorable outcomes with a median OS of 25 months and PFS of 6 months (29), their limited use in our prior CIP cohort, possibly due to clinical caution regarding pulmonary toxicity, might have impacted survival. Furthermore, the prior CIP group showed a trend toward lower rates of third-line (10/19 vs. 44/71) and very few fourth-line anticancer therapies (Table S4). This restricted access to later-line treatments highlights the significant challenges in managing patients with prior CIP and likely contributed to their shorter OS.

This study has several limitations: a small CIP cohort size, a single-center retrospective design with potential selection bias, absence of centralized radiologic review, variability in second-line treatment regimens, and lack of ILD subtype classification or fibrosis scoring, which limits insight into differential risk profiles. Specifically, there is inherent selection bias as patients eligible for second-line therapy must have survived first-line CIP and progressed sufficiently to require subsequent treatment. This implies a limitation in conducting a direct comparison between the groups when using prior CIP as the differentiating factor. While propensity score matching aimed to mitigate observed baseline differences, it cannot entirely eliminate unmeasured confounders. Furthermore, due to the small sample size, multivariate analysis using a more sophisticated Cox proportional hazards model carried a risk of overfitting, hence the choice of Kaplan-Meier methods with log-rank tests in this study. Future research should prioritize multicenter, prospective studies to enhance statistical power and generalizability. Standardized imaging assessments and ILD classification will improve risk evaluation, while uniform treatment protocols will strengthen comparability. Advancements such as radiologic analysis and biomarker-driven risk stratification hold promise for refining immunotherapy strategies and improving patient outcomes.

Conclusions

Among patients with advanced NSCLC treated with first-line combination immunotherapy, the presence of prior CIP did not affect transition to second-line therapy but was associated with poorer OS and a higher incidence of drug-induced pneumonitis during subsequent treatment. Careful therapeutic planning and close monitoring are essential when managing this vulnerable population. The implementation of multidisciplinary strategies may help improve risk stratification and therapeutic outcomes in this complex population.

Acknowledgments

We used ChatGPT, a generative artificial intelligence (AI) tool developed by OpenAI, to assist with the editing and language improvement of this manuscript. The authors reviewed and validated all AI-generated content for accuracy and appropriateness.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-762/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-762/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-762/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-2025-762/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by Fukuoka University Medical Ethics Review Board (No. U22-02-006). As this was a retrospective study, the requirement for written informed consent was waived.

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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