Research ArticleClinical Studies

Association Between the Severity of Immune-related Adverse Events and the Prognosis in Patients With Non-small Cell Lung Cancer Receiving Treatment With Immune Checkpoint Inhibitors

MINEHIKO INOMATA, MASAHIRO MATSUMOTO, KANA HAYASHI, ZENTA SETO, TAKAHIRO HIRAI, KOTARO TOKUI, CHIHIRO TAKA, SEISUKE OKAZAWA, KENTA KAMBARA, SHINGO IMANISHI, TOSHIRO MIWA, RYUJI HAYASHI, SHOKO MATSUI and KAZUYUKI TOBE
Anticancer Research July 2023, 43 (7) 3241-3246; DOI: https://doi.org/10.21873/anticanres.16498

Abstract

Background/Aim: Among patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI), survival is reported to be longer in those experiencing immune-related adverse events (irAEs). We evaluated the progression-free survival (PFS) in the absence of further treatment after ICI therapy was discontinued because of the emergence of irAEs in patients with NSCLC. Patients and Methods: Data from patients with NSCLC in whom ICI therapy was discontinued because of the development of irAEs were retrospectively analyzed. The primary endpoint was the PFS from the last day of administration of ICIs, in the absence of any further treatment. Results: A total of 162 patients with NSCLC received treatment with ICIs between January 2016 and December 2021. Among them, ICI therapy was discontinued in 33 patients because of the appearance of irAEs. The median (95% confidence interval) PFS in the absence of any treatment after the last administration of ICIs was 7.2 (4.2-12.3) months. According to the Common Terminology Criteria for Adverse Events, the Cox proportional hazards model was used to identify the severity of irAEs, which were determined to be significantly associated with the PFS in the absence of any further treatment after the last administration of ICI therapy. Conclusion: Although the present study showed that the PFS in patients with NSCLC was relatively long in the absence of any further treatment after the last administration of ICIs, the PFS was associated with the severity of the irAEs, and some patients showed early disease progression or death.

Key Words:

Systemic drug therapy is the standard for patients with advanced non-small cell lung cancer (NSCLC). Recently, it was demonstrated that monotherapy with immune checkpoint inhibitors (ICI) confers longer survival compared with treatment using cytotoxic agents in patients with previously untreated NSCLC showing positive tumor expression of programmed death 1-ligand (PD-L1) (1), and ICI combined with platinum doublet was associated with higher survival rates, irrespective of the tumor PD-L1 expression level (2-4).

During the treatment with ICIs, careful monitoring and prompt treatment of immune-related adverse events (irAE) are required, although it has also been reported that the survival rate is higher in patients who experience irAEs than in those who do not (5-9). Notably, there is a lack of information on progression-free survival (PFS) in the absence of further treatment after discontinuing ICI therapy because of the appearance of irAEs. Analysis of PFS is necessary to provide useful information for the management of patients whose ICIs have been discontinued in clinical practice. Therefore, we conducted the present study to evaluate PFS in patients with NSCLC who discontinued ICI therapy because of irAEs and did not receive any further treatment.

Patients and Methods

Study design and patient selection. We retrospectively analyzed the data of patients diagnosed with NSCLC. The inclusion criteria were as follows: 1) patients cytologically or histologically diagnosed with advanced NSCLC; 2) patients who received ICI treatment between January 2016 and December 2021; 3) patients who discontinued ICI treatment because of the onset of irAEs. The exclusion criteria were as follows: 1) patients who resumed ICI treatment within 3 months of discontinuing ICI therapy; 2) patients who displayed disease progression at the time of discontinuing ICI therapy; 3) patients who died of irAEs. The performance status (PS) of the subjects was evaluated when the ICI treatment was initiated. The neutrophil/lymphocyte ratio was calculated by dividing the neutrophil count by the lymphocyte count on the last day of ICI therapy. IrAEs were distinguished from non-irAEs based on the attending physician’s judgment. The severity of the irAEs was classified according to the Common Terminology Criteria for Adverse Events version 5. The tumor PD-L1 expression level was evaluated at a commercial laboratory (BML Inc., Tokyo, Japan), and the tumor proportion score was calculated using the 22C3 antibody (Agilent Technologies Inc., Santa Clara, CA, USA).

The present study was conducted following the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects (Ministry of Health, Labour and Welfare, Japan). The need to obtain informed consent from the study subjects was waived under the approval of the Ethics Committee, University of Toyama (approval number: R2021078), and we disclosed information about the study to the subjects.

Statistical analysis. The primary endpoint was the PFS from the last day of ICI administration, in the absence of any further treatment, and the secondary endpoint was the OS from the last day of ICI administration. The PFS was calculated from the last day of ICI administration to the date of detecting disease progression. Progression was defined as clinical progression according to the physician’s judgment or radiological progression of the disease defined according to the Response Evaluation Criteria in Solid Tumors version 1.1. PFS was censored at the last visit without disease progression or the day on which the subsequent treatment was initiated. OS was calculated from the last day of ICI administration to the date of death and censored on the last known survival date.

The association of each of the clinical variables with the PFS in the absence of further treatment after the last day of ICI therapy and the OS were evaluated using the log-rank test and analyzed by multivariate analysis using the Cox proportional hazards model. All the statistical analyses were performed using JMP ver. 15.0.0 (SAS, Cary, NC, USA). p<0.05 was considered statistically significant.

Results

Patient characteristics. A total of 163 patients with NSCLC received ICI therapy between January 2016 and December 2021. In 46 of the patients, ICI treatment was discontinued because of the appearance of AEs. In nine of the patients, ICI treatment was discontinued because of the appearance of non-irAEs, including rash caused by other drugs, infection, pulmonary embolism, appetite loss, hyponatremia, fatigue, and deterioration of PS. In three of the patients, disease progression was observed at the time of discontinuing ICI treatment. One patient died of irAEs. After excluding these patients, the data of the remaining 33 patients were analyzed. Table I shows the patient characteristics. PD-L1 expression had not been evaluated in two patients. ICI treatment was discontinued because of the appearance of grade 1, 2, and 3 irAEs in seven, 13, and 13 patients, respectively. The irAEs included interstitial lung disease (ILD) in 11 patients, colitis in five patients, elevated serum aspartate aminotransferase/alanine aminotransferase in three patients, and myocarditis in 2 patients. Steroid treatment was administered in 24 patients to help control the irAEs.

View this table:
Table I.

Patient characteristics.

Outcome. Figure 1 shows the Kaplan–Meier curve for PFS from the last day of ICI administration in the 33 patients. PFS was censored because of the absence of disease progression during the observation period in six patients, initiation of subsequent treatment in five patients, and death due to reasons other than lung cancer in one patient. The median (95% confidence interval, CI) was 7.2 (4.2-12.3) months.

Figure 1.
Figure 1.

Kaplan–Meier curve of progression-free survival (PFS) and overall survival (OS) in 33 patients with non-small cell lung cancer, in the absence of further treatment after the last day of administration of immune checkpoint inhibitors.

Table II shows the associations between the patient characteristics and the PFS after discontinuation of ICI therapy in the absence of further treatment. The log-rank test revealed that the PFS was significantly shorter in patients with irAEs of greater severity. Figure 2 shows the Kaplan–Meier curve constructed to compare the PFS in the absence of further treatment after ICI therapy and the OS between patients experiencing grade 1 and grade 2-3 irAEs. Patients with grade 1 irAEs showed a significantly longer PFS in the absence of further treatment after ICI therapy (median, 16.2 vs. 4.7 months, p=0.001, log-rank test) and OS (median, not reached vs. 20.2 months, p=0.039, log-rank test) than patients with grade 2-3 irAEs. Table III shows a comparison of patient characteristics between patients with grade 1 and grade 2-3 irAEs. There was imbalance in proportion of steroid use for controlling the irAEs and frequency of ILD between the two groups. Thus, history of steroid use, incidence of ILD, and the severity grade of the irAEs were selected as independent variables for adjustment in the Cox proportional hazards model.

View this table:
Table II.

Univariate analysis using the log-rank test to assess the association between clinical parameters and progression-free survival in the absence of any treatment after the onset of the immune-related adverse events.

Figure 2.
Figure 2.

Kaplan–Meier curve to compare the progression-free survival (PFS) in the absence of further treatment and the overall survival (OS) between non-small cell lung cancer patients with grade 1 and grade 2-3 immune-related adverse events.

View this table:
Table III.

Comparison of the characteristics between patients with grade 1 and grade 2-3 immune-related adverse events.

Table IV shows the results of the multivariate analysis performed using the Cox proportional hazards model, which revealed that the severity of the irAEs is significantly associated with the risk of disease progression after adjusting for steroid use and type of irAEs (ILD or non-ILD).

View this table:
Table IV.

Multivariate analysis using the Cox proportional hazards model to assess the association between clinical parameters and progression-free survival in the absence of any treatment after the onset of the immune-related adverse events.

Discussion

In the present study, the median (95%CI) PFS in patients after ICI treatment was discontinued because of irAEs was 7.2 (4.2-12.3) months. This was consistent with the reported association between irAEs and favorable prognosis in patients with NSCLC treated with ICIs. However, the survival of each individual varied, and the PFS and OS were shorter in patients with more severe irAEs.

Favorable outcomes have been reported in patients experiencing irAEs. Haratani et al. reported that the occurrence of irAEs was associated with favorable survival outcomes. In their study population, 12 (17.4%) of the 69 patients who developed irAEs exhibited a grade of ≥3, and 24 (34.8%) needed steroid treatment for the irAEs (5). Hosoya et al. reported that early development of irAEs (within 3 weeks of the initiation of ICI treatment) might be predictive of a longer PFS (8). In that study, 34 (85%) of the 40 patients who developed early irAEs were grade 1-2 in severity. Furthermore, clinical trials that evaluated the efficacy of combined nivolumab plus ipilimumab therapy with or without cytotoxic agents reported that a substantial number of patients exhibited long PFS in the absence of any further treatment after discontinuing ICI therapy because of irAEs (3, 10). However, Suresh et al. reported that the development of ILD worsens survival in patients receiving ICI treatment (11).

A pooled analysis of the IMpower trials showed that low-grade irAEs were associated with improved outcomes in the patients receiving atezolizumab-containing therapy (12). It has also been reported that the relationship between the irAEs and the efficacy of ICIs in cancer patients is observed in patients experiencing low-grade irAEs (13) and that irAEs of ≥3 do not correlate with increased OS or PFS (14). Severe irAEs are life-threatening and may require treatment discontinuation and systemic immunosuppression, which can decrease the efficacy of ICIs (12). Steroids exert immunosuppressive effects, including induction of T cell apoptosis and maturation impairment of dendritic cells. However, it has also been shown that transient steroid use for the treatment of irAEs does not affect the OS (15). Suresh et al. proposed that the hypoxia from the ILD, especially when it is severe, can result in failure of other organs, resulting in a poor prognosis (11). Organ impairment caused by severe irAEs might adversely affect tumor immunity, leading to an unfavorable outcome.

There are several limitations of our present study. Because of its retrospective nature, the exclusion of bias is difficult. In addition, because the sample size was small, comprising only 33 patients, entirely reliable adjustment for confounding factors might not have been possible, even though multivariate analysis was performed.

In summary, a favorable prognosis was observed in patients with ICI treatment that was discontinued because of the appearance of irAEs. However, our analysis also revealed that the PFS was shorter in patients with severe irAEs. For these patients, strict follow-up, and early resumption of treatment, if possible, is necessary.

Footnotes

  • Authors’ Contributions

    Minehiko Inomata contributed to the study’s conception and design. Data collection was performed by Minehiko Inomata, Masahiro Matsumoto, Kana Hayashi, Zenta Seto, Takahiro Hirai, Kotaro Tokui, Chihiro Taka, Seisuke Okazawa, Kenta Kambara, Shingo Imanishi, Toshiro Miwa, Shoko Matsui, and Ryuji Hayashi. The first draft of the manuscript was written by Minehiko Inomata. Kazuyuki Tobe supervised the study. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.

  • Received April 13, 2023.
  • Revision received May 8, 2023.
  • Accepted May 9, 2023.

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Association Between the Severity of Immune-related Adverse Events and the Prognosis in Patients With Non-small Cell Lung Cancer Receiving Treatment With Immune Checkpoint Inhibitors
MINEHIKO INOMATA, MASAHIRO MATSUMOTO, KANA HAYASHI, ZENTA SETO, TAKAHIRO HIRAI, KOTARO TOKUI, CHIHIRO TAKA, SEISUKE OKAZAWA, KENTA KAMBARA, SHINGO IMANISHI, TOSHIRO MIWA, RYUJI HAYASHI, SHOKO MATSUI, KAZUYUKI TOBE
Anticancer Research Jul 2023, 43 (7) 3241-3246; DOI: 10.21873/anticanres.16498
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