Impact of immune-related adverse events on clinical outcomes in patients with advanced non-small cell lung cancer with low PD-L1 expression, focusing on pneumonitis: a multicenter retrospective study in Japan

Introduction

Background

Lung cancer is the leading cause of cancer-related death worldwide (1). For patients with non-small cell lung cancer (NSCLC) without genetic alterations, the treatment strategy is currently determined based on the level of programmed cell death ligand-1 (PD-L1) expression.

In driver alteration-negative advanced NSCLC with PD-L1 1–49%, the combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has been reported to improve prognosis compared to ICIs alone and platinum-based chemotherapy alone (2-7). Therefore, combined immunotherapy and chemotherapy is the first choice of treatment for driver alteration-negative advanced NSCLC with low PD-L1 expression. However, although intensifying treatment may enhance therapeutic efficacy, higher frequency of adverse effects is concerning, making patient selection a clinical challenge.

Rationale and knowledge gap

Severe immune-related adverse events (irAEs) are frequently associated with combined immunotherapy and chemotherapy, posing a significant barrier to treatment. Although the impact of these irAEs on the clinical outcomes of patients with NSCLC has been recognized, the reported findings are inconsistent (8-14). Thus, a more focused analysis of specific patients with NSCLC is needed. Current international guidelines indicate that the standard first-line treatment for advanced NSCLC without driver mutations varies based on tumor PD-L1 expression levels, and combined immunotherapy and chemotherapy is the standard first-line treatment for patients with advanced NSCLC with PD-L1 expression of 1–49%. Therefore, evaluating the efficacy and adverse events of combined immunotherapy and chemotherapy in this population is of considerable clinical significance, and we decided to focus on patients with advanced NSCLC with PD-L1 expression of 1–49%.

Objective

In this study, we investigated the clinical significance of irAEs, with particular emphasis on often fatal pneumonitis, by comparing their effects on the clinical outcomes of patients receiving combined immunotherapy and chemotherapy with those receiving chemotherapy alone. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1177/rc).

Methods

Patients

We retrospectively enrolled the patients with PD-L1 1–49% advanced NSCLC who received chemotherapy alone or combined immunotherapy and chemotherapy as first line treatment at 19 different institutions in Japan (University Hospital Kyoto Prefectural University of Medicine, Fujita Health University Hospital, Kurashiki Central Hospital, Hyogo Medical University Hospital, Niigata University Medical and Dental Hospital, St Marianna University Hospital, Saitama Red Cross Hospital, Kansai Medical University Hospital, Fukuoka University Hospital, Fukuchiyama City Hospital, Nagasaki University Hospital, Japanese Red Cross Kyoto Daini Hospital, Shonan Kamakura General Hospital, Kurume University Hospital, Saitama Medical University International Medical Center, Japanese Red Cross Kyoto Daiichi Hospital, Saiseikai Suita Hospital, Shonan Fujisawa Tokushukai Hospital, and Uji Tokushukai Medical Center) between March 2017 and June 2022. We examined the medical records of these patients and collected the following data: age, sex, smoking status, histology subtype, comorbid diseases (interstitial lung disease and autoimmune disease), concomitant medications (steroids and immunosuppressants), tumor-node-metastasis (TNM) stage (based on the TNM stage classification system version 8), metastatic sites (liver and brain), tumor expression of PD-L1 measured using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Santa Clara, CA, USA), genomic alteration [epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase], blood test data, treatment regimens, radiation therapy, Eastern Cooperative Oncology Group performance status, overall survival (OS), progression-free survival (PFS), adverse events (irAEs and other adverse drug reactions) of grade ≥3 [based on the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0] and their onset dates, and pneumonitis of all grades (based on CTCAE ver. 5.0) and their onset dates. The following adverse events were defined as irAEs: colitis, diarrhea, hepatitis, nephritis, pneumonitis, encephalitis, pituitary inflammation, adrenal dysfunction, thyroid dysfunction, myositis, skin toxicity, arthritis, fever, diabetes, and collagen disease.

The study complied with the tenets of the Declaration of Helsinki (as revised in 2013), and the protocol was approved by the Ethics Committee of Kyoto Prefectural University of Medicine through an all-center collective review (No. ERB-C-2934). The need for informed consent was waived due to the retrospective nature of the study, and the official website provided an opt-out form, which was approved by the Ethics Committee of the Kyoto Prefectural University of Medicine.

Statistical analysis

Statistical analyses were performed using EZR software (version 1.54; Saitama Medical Center, Jichi Medical University; Saitama, Japan) (15). Survival curves were calculated using the Kaplan-Meier method, and differences were compared using the log-rank test. Fisher’s exact and Kruskal-Wallis tests were used to compare background factors. Landmark analyses of OS and PFS at 14, 28, and 42 days were performed for patients who were alive or showed disease control at the respective timepoint, to account for the time-dependence of irAEs. The significance level was set at P<0.05. Missing values were excluded from the cases analyzed only for that item.

Results

Characteristics of patients

Based on the emergence of irAEs and the types of treatment received, the 850 patients were divided into three groups: those that received combined immunotherapy and chemotherapy and had no grade ≥3 irAEs (ICI-Chemo without severe irAEs), those that received combined immunotherapy and chemotherapy and had grade ≥3 irAEs (ICI-Chemo with severe irAEs), and those that received chemotherapy alone (Chemo) (Figure S1). Patient characteristics are detailed in Table 1. A total of 404 (47.5%) patients were in the ICI-Chemo without severe irAEs group, 100 (11.8%) were in the ICI-Chemo with severe irAEs group, and 346 (40.7%) were in the Chemo group. The median age was 70 years (range, 36–89 years), and the median follow-up was 15.6 months (range, 0.1–92.3 months). EGFR mutation-positive status and a history of interstitial lung diseases or autoimmune diseases were significantly more common in the Chemo group than in the other groups, and no other differences were observed between the groups.

Association between irAE incidence and survival

The major irAEs in patients who received combined immunotherapy and chemotherapy are listed in Table 2. Of the severe irAEs of grade ≥3, pneumonitis was the most common (38 cases, 38%). The differences in the incidence of irAEs in relation to the ICI used are shown in Table S1. Although the incidence of pneumonitis was similar among the kinds of ICIs, skin toxicity and adrenal insufficiency were significantly more common in patients who used nivolumab + ipilimumab than in those who were treated with other ICIs. Among the 504 patients who received combined immunotherapy and chemotherapy, 89 stopped first-line treatment due to irAEs. Moreover, 46 (51.7%) of those who stopped first-line treatment due to irAEs received second-line treatment, which was comparable to the rate of those who discontinued first-line treatment for reasons other than irAEs. However, the duration of chemotherapy suspension was significantly longer in patients who stopped for irAEs than in those who stopped for other reasons (100 vs. 21 days P<0.001). The comparison of the presence of concomitant ICIs and severe irAEs with treatment response and survival is shown in Figure S2. The median OS for the ICI-Chemo without severe irAEs, ICI-Chemo with severe irAEs, and Chemo groups were 643, 1,010, and 505 days, respectively (P=0.001; Figure S2A). The median PFS for the ICI-Chemo without severe irAEs, ICI-Chemo with severe irAEs, and Chemo groups were 210, 351, and 165 days, respectively (P<0.001; Figure S2B). Based on these findings, the ICI-Chemo with severe irAEs group exhibited the greatest prolongation in both OS and PFS compared with the other two groups. However, in the landmark analysis at 14, 28, and 42 days for patients using ICIs, neither OS nor PFS were significantly different between patients with and without severe irAEs (Figures S3,S4).

Efficacy of treatment based on the type of severe irAEs

The most common severe irAEs observed early in treatment were pneumonitis, diarrhea/colitis, and skin toxicity. Landmark analyses of OS and PFS at 42 days in patients experiencing these three severe irAEs were performed. The median OS of patients who developed severe pneumonitis within 42 days of treatment initiation was significantly shorter than those who did not (110 vs. 682 days; P<0.001; Figure 1A). The median PFS of patients who developed severe pneumonitis within 42 days was also significantly shorter than those who did not (85 vs. 225 days; P=0.02; Figure 1B). For diarrhea/colitis and skin toxicity, OS and PFS were comparable, regardless of the presence of severe irAEs (Figure 1C-1F). These results suggest that early-onset of severe pneumonitis may be a poor prognostic factor.

Figure 1 Kaplan-Meier curves at day 42 of the landmark analysis for OS and PFS for each severe irAE in patients who received combined immunotherapy and chemotherapy. Kaplan-Meier curves for OS with and without grade ≥3 pneumonitis (A), diarrhea/colitis (C), and skin toxicity (E) within 42 days, and for PFS with and without grade ≥3 pneumonitis (B), diarrhea/colitis (D), and skin toxicity (F) within 42 days. CI, confidence interval; irAEs, immune-related adverse events; NA, not available; NR, not reached; OS, overall survival; PFS, progression-free survival.

Efficacy of treatment based on the severity of checkpoint-inhibitor pneumonitis (CIP)

Next, we performed landmark analyses of OS and PFS at 14, 28, and 42 days, stratifying the patients into three groups based on the severity of CIP: absent, grades 1–2 (mild), and grades 3–5 (severe) (Figure 2). No significant differences in the OS and PFS were observed between the mild and severe groups. However, the OS and PFS of these two groups were significantly shorter than those of the absent group (P<0.001 for both OS and PFS).

Figure 2 Kaplan-Meier curves at days 14 (A), 28 (B), and 42 (C) of the landmark analysis for OS and at days 14 (D), 28 (E), and 42 (F) of the landmark analysis for PFS in patients who received combined immunotherapy and chemotherapy by grade of checkpoint-inhibitor pneumonitis. Absent: patients without pneumonitis; Mild: patients with grade 1–2 pneumonitis; Severe: patients with grade ≥3 pneumonitis. CI, confidence interval; NA, not available; OS, overall survival; PFS, progression-free survival.

Subsequently, we reanalyzed OS and PFS with the patients categorized into the following groups: patients who received combined immunotherapy and chemotherapy and did not develop CIP (ICI-Chemo without CIP), patients who received combined immunotherapy and chemotherapy and developed CIP (ICI-Chemo with CIP), and patients who received only chemotherapy (Chemo). In the landmark analysis at 42 days, the median OS of the ICI-Chemo without CIP, ICI-Chemo with CIP, and Chemo groups was 694, 160, and 505 days, respectively (P<0.001; Figure 3A), and the median PFS was 229, 85, and 165 days, respectively (P<0.001; Figure 3B).

Figure 3 Kaplan-Meier curves at day 42 of the landmark analysis for OS (A) and PFS (B) in three groups of patients: those who received combined immunotherapy and chemotherapy and had no CIP (ICI-Chemo without CIP), those who received combined immunotherapy and chemotherapy and had CIP (ICI-Chemo with CIP), and those who received chemotherapy alone (Chemo). CI, confidence interval; CIP, checkpoint-inhibitor pneumonitis; OS, overall survival; PFS, progression-free survival.

Lastly, we examined the relationship between prognosis and re-administration of ICIs in patients who received combined immunotherapy and chemotherapy and developed mild CIP within 42 days. No significant differences in OS or PFS were observed between patients with and without ICI re-administration (Figure S5). When investigating the background factors of patients who received ICIs, we found that patients who developed CIP within 42 days were significantly more likely to be aged ≥75 years, have serum lactate dehydrogenase (LDH) levels ≥245 U/L, and use steroids and immunosuppressant than those who did not (Table 3).

Discussion

Numerous clinical trials have demonstrated the benefits of combined immunotherapy and chemotherapy for advanced NSCLC, establishing this combination as first-line treatment for driver mutation-negative NSCLC with low PD-L1 expression (2-7). Similarly, in this study, patients receiving combined immunotherapy and chemotherapy had longer OS and PFS than those receiving only chemotherapy, regardless of the occurrence of severe irAEs.

Various irAEs, ranging from mild to severe, frequently occur in patients receiving combined immunotherapy and chemotherapy. Previous studies have shown an association between the occurrence of irAEs and good clinical efficacy of ICIs in NSCLC (16-18). Nonetheless, severe irAEs are a major concern in the treatment of NSCLC as they are often fatal and can hinder the continuation of ICI therapy. Both favorable and unfavorable prognoses have been documented in patients with severe irAEs, leading to a lack of consensus regarding the prognosis of these patients (8,9,11). In patients with malignant melanoma, the occurrence of immunotherapy-induced vitiligo is associated with prolonged survival, whereas no such correlation has been observed with thyroid dysfunction, diarrhea, or pneumonitis (19). In contrast, thyroid dysfunction has been reported to be associated with improved treatment response to pembrolizumab in patients with NSCLC (20). These reports suggest that the clinical significance of irAEs varies depending on their type.

In this study, irAEs, especially severe irAEs, were associated with good clinical outcomes in the analysis that did not consider the time of onset. However, no significant differences were found when landmark analyses were performed. We believe that an immortal time bias may explain these conflicting results. When investigating the prognostic correlations with early-onset CIP, diarrhea/colitis, and skin toxicity, which were major irAEs occurring within 42 days of treatment initiation, we only found significantly shorter OS and PFS in patients who experienced CIP. Interestingly, the trend was similar for all grades of CIP, and patients with early-onset CIP had a poorer prognosis than those in the chemotherapy group. The prognosis was also poor in patients with mild CIP, regardless of whether ICIs were re-administered, and the poor prognosis was suspected to be due to CIP itself, not the discontinuation of treatment.

Pre-existing pulmonary fibrosis has been reported to significantly increase the risk of CIP (21). In this study, most patients with a history of interstitial lung disease avoided ICI treatment. Nevertheless, 18% of patients receiving ICIs developed CIP, and 5% developed CIP within 42 days of treatment initiation. Patients with early-onset CIP were characterized by ages >75 years, the use of steroids or immunosuppressants, and elevated serum LDH levels. Notably, the prognosis of patients with early-onset CIP was worse than that of patients receiving chemotherapy. Based on the results of this study, careful monitoring is recommended for patients with NSCLC at high risk of early-onset CIP when considering treatment options that include ICIs.

Our study had some limitations. First, this was a non-randomized and retrospective study, with potential biases in treatment selection, information collection, and reporting of irAEs. Second, the adverse events that we considered irAEs may have been caused by drugs other than ICIs because combined immunotherapy and chemotherapy uses multiple drugs. Third, the number of cases of early-onset CIP was small, and a multivariate analysis of the risk factors for early-onset CIP was not possible. Forth, we could not compare the severity of irAEs other than CIP because we did not collect information on grade 1–2 irAEs other than CIP. Lastly, it was not possible to set a landmark longer than 42 days because the number of cases was not large.

Conclusions

Severe irAEs associated with combined immunotherapy and chemotherapy did not correlate with prognosis in patients with advanced NSCLC and low PD-L1 expression. In this study, early-onset CIP was identified as a poor prognostic factor. Further large-scale observational studies are warranted to confirm these findings.

Acknowledgments

The abstract of this article was presented at the 65th annual meeting of the Japan Lung Cancer Society held on November 1, 2024.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1177/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1177/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1177/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-2024-1177/coif). T.Y. serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. T.Y. receives research grants from Ono Pharmaceutical, Janssen, AstraZeneca, and Takeda Pharmaceutical as well as personal fees from Eli Lilly and Chugai-Roche. S.W. receives research grants from Boehringer Ingelheim and Nippon Kayaku as well as personal fees from Eli Lilly, Novartis Pharma, Chugai Pharma, Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, Merck, Takeda Pharmaceutical, Celltrion, and AstraZeneca. H.T. receives personal fees from AstraZeneca and Chugai Pharma. T.F. receives personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical and Takeda Pharmaceutical. K.K. receives personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical, Bristol-Myers Company, Boehringer Ingelheim, and AstraZeneca. T.K. receives personal fees from Chugai Pharmaceutical Co. Ltd. and MSD KK. K.T. receives research grants from Chugai Pharmaceutical Co. Ltd. and Ono Pharmaceutical as well as personal fees from AstraZeneca, Chugai Pharmaceutical Co. Ltd., MSD-Merck, Eli Lilly, Boehringer Ingelheim, and Daiichi-Sankyo. The other 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. The study complied with the tenets of the Declaration of Helsinki (as revised in 2013), and the protocol was approved by the Ethics Committee of Kyoto Prefectural University of Medicine through an all-center collective review (No. ERB-C-2934). The need for informed consent was waived due to the retrospective nature of the study, and the official website provided an opt-out form, which was approved by the Ethics Committee of the Kyoto Prefectural University of Medicine.

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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