Abstract

Background

The emergence of immune checkpoint inhibitors (ICIs) has led to major advances in cancer treatment in recent years; however, alongside the widespread use of ICIs, immune-related adverse events (irAEs) have become a growing issue [1]. Unlike classical adverse events caused by conventional anticancer drugs, irAEs develop in various organs at different times and require specific treatment [2, 3]. Immune-related pneumonitis (irP) is one of the most important irAEs in terms of frequency and severity [4–11]. Depending on the severity of irP, corticosteroids and/or immunosuppressive drugs are required for its treatment, which results in interruption of cancer therapy. In general, the prognosis of cancer patients who develop irAEs during ICI treatment is considered good; however, the opposite is reported for irP [4, 12, 13]. The management of irP is an important issue in maximising the therapeutic benefit of ICIs.

One of the key challenges in irP management is its relapse. In general, patients with irP respond relatively well to corticosteroid therapy and can resume cancer treatment after improvement. However, it has been reported that 10–40% of irP cases relapse after corticosteroid therapy [5, 6, 14–16]. Relapse of irP requires intensified treatments, such as re-treatment with corticosteroids and/or the addition of immunosuppressive agents, which hinders cancer treatment. Predicting the risk of relapse and managing irP is critical to the success of ICI therapy.

There is no established evidence regarding the risk of irP relapse. A retrospective analysis with a small number of cases reported that less than 4 weeks of treatment duration with a prednisolone equivalent dose of 15 mg/day was a risk factor for irP relapse [14]. Guidelines recommend at least 4–6 weeks of corticosteroid therapy for irP treatment, which indicates that a certain duration of corticosteroid treatment is important for relapse prevention [17, 18]. We conducted a phase II study of prednisolone, 1 mg/kg/day, tapered over 6 weeks for grade 2 or higher irP [16]. This was the first prospective clinical trial to evaluate the efficacy of corticosteroid therapy in irP. The results showed a favourable improvement rate of 91.1% after completion of the 6-week treatment, while relapse occurred in 32.1% of patients. Even after treatment with corticosteroids in sufficient doses and for sufficient duration as recommended by the guidelines, a certain amount of irP relapse was still observed. Identification of risk factors for irP relapse, other than the treatment schedule of corticosteroids, is a clinically important issue.

The purpose of this study was to identify the risk of relapse of irP after corticosteroid treatment. We followed up our previous study with additional long-term observations to accumulate data on relapse cases. In the current study, we used these follow-up data to analyse the relapse cases after corticosteroid treatment and to identify risk factors for irP relapse.

Methods

Results

Patient characteristics

Among 56 patients with irP included in the original analysis, 22 (39.3%) developed relapse of irP during the follow-up period from May 2019 and February 2024 (Fig. 1). Patient characteristics with and without the relapse of irP are presented in Table 1. The patients with irP relapse had a significantly higher proportion of radiographic pattern of OP (p=0.008). Patients with irP relapse showed a trend toward a longer duration from the start of ICI administration to the onset of irP than those without irP relapse (p=0.135). In the treatment of initial irP, 10 (17.9%) patients received 1000 mg of intravenous methylprednisolone for 3 days (one received 500 mg) before the 6-week prednisolone treatment. Patients with irP relapse tended to have a lower proportion of receiving intravenous methylprednisolone than those without irP relapse (p=0.070). There were no statistical differences in other patient characteristics between those with and without irP relapse, including smoking history, ECOG-PS, history of chronic obstructive pulmonary disease, history of radiation therapy to the chest, ICI regimen, or irP severity. There was also no difference in the number of patients who resumed anticancer agents after 6 weeks of prednisolone treatment between the patients with irP relapse (n=10, 45.5%) and those without (n=22, 64.7%) (p=0.178). There were two cases in which ICI was restarted after prednisolone therapy, neither of which had irP relapse. Median observation time was 944 days (range, 97–1638 days) at the data cut-off.

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Fig. 1

Cumulative incidence of relapse of immune-related pneumonitis. Short bars indicate censored cases

Table 1

Patient characteristics

	N=56	Relapse of irP (+), n=22	Relapse of irP (−), n=34	P-value
Age, years	72 (57–91)	73 (57–87)	72 (60–91)	0.827
Sex, men	48 (85.7)	17 (77.3)	31 (91.2)	0.241
Smoking status, ever smoker	46 (82.1)	17 (77.3)	29 (85.3)	0.491
ECOG-PS, 0/1/≥2	30 (53.6)/18 (33.3)/8 (14.8)	15 (68.2)/6 (27.3)/1 (4.6)	15 (44.1)/12 (35.3)/7 (20.6)	0.141
Severity of irP, grade 2/3/4	35 (62.5)/19 (33.9)/2 (3.6)	15 (68.2)/7 (31.8)/0	20 (58.8)/12 (35.3)/2 (5.9)	0.623
Radiographic patterns of irP,
NSIP OP EP HP	20 (35.7) 18 (32.1) 10 (17.9) 8 (14.3)	6 (27.3) 12 (54.6) 2 (9.1) 2 (9.1)	14 (41.2) 6 (17.7) 8 (23.5) 6 (17.7)	0.394 0.008 0.285 0.460
Duration to irP onset, days	100 (9-1351)	133 (19-1351)	87 (9-961)	0.135
Cancer type, non-small cell lung cancer/renal cell cancer/others	38 (67.9)/6 (10.7)/12 (21.4)	14 (66.7)/2 (9.52)/5 (23.8)	24 (68.6)/4 (11.4)/7 (20.0)	1.000
ICI therapy responsible for irP,
PD-1/L1-Ab alone/Chemo+PD-1/L1-Ab/PD-1-Ab+CTLA-4-Ab/Chemo+PD-1-Ab+CTLA-4-Ab	29 (51.8)/22 (39.3)/4 (7.1)/1 (1.8)	10 (45.5)/9 (40.9)/2 (9.1)/1 (4.6)	19 (55.9)/13 (38.2)/2 (5.9)/0 (0)	0.612
Treatment line of ICI, 1st /≥2nd	36 (64.3)/20 (35.7)	13 (61.9)/8 (38.1)	23 (65.7)/12 (34.3)	0.782
Previous history of chest radiotherapy	15 (26.8)	5 (23.8)	10 (28.6)	0.764
History of COPD	12 (21.4)	2 (9.5)	11 (31.4)	0.101
Intravenous methylprednisolone before 6-week prednisolone	10 (17.9)	1 (4.6)	9 (26.5)	0.070
Systemic chemotherapy after the improvement of irP	32 (57.1)	10 (47.6)	22 (62.9)	0.178

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Data are expressed as the median (range) or number (%)

ECOG-PS, Eastern Cooperative Oncology Group performance status; EP, eosinophilic pneumonia; HP, hypersensitivity pneumonia; ICI, immune checkpoint inhibitor; irP, immune-related pneumonitis; NSIP, non-specific interstitial pneumonia; OP, organising pneumonia; PD-1, programmed death-1; PD-L1, programmed death ligand-1; Ab, antibody; CTLA-4, cytotoxic T-lymphocyte antigen-4; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease

Risk factors for the relapse of irP

The OP pattern on chest CT had a significantly higher cumulative relapse rate of irP compared to other imaging patterns (Gray’s test, p=0.003, Fig. 2a, b). The cumulative relapse rate of irP was also significantly higher in patients with a duration to irP onset of ≥100 days from the start of ICI treatment, compared to those with <100 days to onset (Gray’s test, p=0.024, Fig. 3). Patients who received intravenous methylprednisolone before the 6-week prednisolone treatment had a lower cumulative relapse rate of irP than those without methylprednisolone (Gray’s test, p=0.046, Fig. 4). In a univariate Fine–Gray test, the OP pattern and a duration≥100 days from the start of ICI treatment to the onset of irP were significant risk factors for irP relapse (hazard ratio [HR]=3.43, 95% CI 1.51–7.79, p=0.012; and HR=2.87, 95% CI 1.10–7.52, p=0.033, respectively), while non-use of intravenous methylprednisolone was not significant (HR=5.67, 95% CI 0.87–36.83, p=0.069, Table 2).

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Fig. 2

Comparison of cumulative incidence of relapse among radiographic patterns of immune-related pneumonitis. Cumulative incidence curves of four radiographic patterns (a) and organising pneumonia (OP) pattern vs. other three (non-OP) patterns (b). Red, blue, green, yellow, and black lines indicate OP pattern, non-specific interstitial pneumonia (NSIP) pattern, hypersensitivity pneumonia (HP) pattern, eosinophilic pneumonia (EP) pattern, and non-OP pattern, respectively. Short bars indicate censored cases

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Fig. 3

Cumulative incidence of relapse according to duration to onset of immune-related pneumonitis. Cumulative incidence curves of patients with a duration from the start of immune checkpoint inhibitor treatment to onset of immune-related pneumonitis of ≥100 days (red line) and those with duration of <100 days to onset (black line). Short bars indicate censored cases

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Fig. 4

Cumulative incidence of relapse according to intravenous methylprednisolone prior to the 6-week prednisolone treatment. Cumulative incidence curves of patients who received intravenous methylprednisolone (IV mPSL) prior to the 6-week prednisolone treatment (black line) and those without (red line). Short bars indicate censored cases

Table 2

Univariate and multivariate fine–Gray test for the relapse of irP

Variables	Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age, >70yr	1.36 (0.56–3.30)	0.494
Sex, men	0.50 (0.20–1.26)	0.143
Ever smoker	0.72 (0.28–1.87)	0.509
ECOG-PS, 0 vs. ≥1	1.81 (0.73–4.47)	0.198
History of chest radiotherapy	0.99 (0.41–2.36)	0.975
Comorbidity, COPD	0.58 (0.16–2.13)	0.410
Treatment line of ICI, 1st vs. ≥2nd	0.91 (0.40–2.09)	0.820
Cancer type, lung vs. others	0.89 (0.38–2.11)	0.796
Severity of irP, grade 2 vs. ≥3	1.25 (0.50–3.13)	0.625
Radiographic patterns of irP, OP vs. others	3.43 (1.51–7.79)	0.003	3.17 (1.37–7.32)	0.007
Duration to irP onset, ≥100days	2.87 (1.10–7.52)	0.033	2.61 (1.01–6.74)	0.048
Intravenous methylprednisolone before 6-week prednisolone	0.18 (0.03–1.15)	0.069
Response to prednisolone, partial improvement vs. complete recovery	1.50 (0.57–3.97)	0.414

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ECOG-PS, Eastern Cooperative Oncology Group performance status; COPD, chronic obstructive pulmonary disease; ICI, immune checkpoint inhibitor; irP, immune-related pneumonitis; OP, organising pneumonia

In a multivariate Fine–Gray test, the OP pattern and the duration of ≥100 days from the start of ICI treatment to the onset of irP were significant risk factors for irP relapse (HR=3.17, 95% CI 1.37–7.32, p=0.007, and HR=2.61, 95% CI 1.01–6.74, p=0.048, respectively; Table 2). When alternative combinations of variables were used, intravenous methylprednisolone was not a significant risk factor for iP relapse (eTable 1 in the Supplement). Furthermore, patient characteristics (such as smoking history, ECOG-PS, history of radiation therapy to the chest, and severity of irP), as well as blood tests at the onset of irP (such as CRP, KL-6, and Sp-D) were not significantly associated with irP relapse (Table 2 and eTable 2 in the Supplement). Additionally, response after 6 weeks of prednisolone therapy (complete remission vs. partial improvement) and blood tests after 6 weeks of prednisolone therapy (such as CRP, KL-6, and Sp-D) were also not significantly associated with irP relapse (Table 2 and eTable 1 in the Supplement). When limited to irP relapses≥grade 2, the OP pattern remained a significant risk factor (p<0.001), but a duration≥100 days from the start of ICI treatment to the onset of irP and intravenous methylprednisolone were not risk factors (p=0.352 and 0.170, respectively) (eTable 3 in the Supplement). There was no significant difference in overall survival with or without intravenous methylprednisolone before the 6-week prednisolone treatment (p=0.998).

Discussion

In this study of a long-term follow-up after 6-week prednisolone tapering therapy of 1 mg/kg/day for irP, the radiographic OP pattern and the duration to irP onset≥100 days were shown to be risk factors for irP relapse. However, baseline patient characteristics, severity of irP, response to prednisolone treatment, and blood laboratory findings before and after prednisolone treatment were not risk factors for irP relapse. Given that irP relapse interferes with ICI treatment, the risk factors presented in this study will be helpful for irP management.

The OP pattern was the strongest risk factor for irP relapse. While other radiographic patterns of irP had almost the same cumulative relapse rate, only the OP pattern showed a markedly higher relapse rate. The OP is a condition of lung-tissue repair after injury, which can be cryptogenic or secondary to specific causes (e.g., infection, drug treatment, or radiation therapy) [21]. The OP pattern is relatively common among a variety of imaging patterns of irP [13, 14, 22]. While OP responds well to corticosteroids, it is well known to have a high relapse rate after corticosteroid treatment, varying from 13 to 58% [21, 23]. Considering this high relapse rate, it was reasonable to expect that irP relapse would be high in patients with the OP pattern. A retrospective analysis of 60 patients with irP showed that relapse cases tended to present the OP pattern (although no statistical analysis was available), supporting the results of this study [4].

Although evidence-based treatment for OP has not been established, it is recommended that treatment be initiated with prednisolone at 0.5–1.5 mg/kg/day and tapered over 6–12 months [21, 23]. The long-term treatment period of 6–12 months appears necessary to control OP relapse. However, in cancer patients with irP, an unnecessarily long duration of corticosteroid therapy may delay the subsequent cancer treatment and result in missed treatment opportunities. Guidelines for irP management recommend a minimum of 1–2 mg/kg/day of prednisolone, depending on the severity of the disease, with no imaging pattern as a basis for treatment selection; moreover, prednisolone should be tapered off over a minimum of 4–6 weeks depending on the severity of disease [17, 18]. However, the treatment proposed in this guideline is also not evidence based. If irP relapse occurs after an inadequate treatment period, re-treatment with a corticosteroid will be necessary, resulting in a very long treatment period. Although the optimal duration of corticosteroid treatment for irP is not clear, irP treatment strategies based on each individual patient’s risk of relapse needs to be established in the future.

The mechanism of the association between the duration to irP onset and the risk of irP relapse is unknown. There is a well-known correlation between total dose and the development of pulmonary damage in drugs with cumulative toxicity, such as amiodarone, nitrosourea and bleomycin [24–26]. However, it is difficult to explain the pathological mechanism by which treatment duration affects irP relapse in ICIs which affect immune system antibodies without cumulative toxicity. In a database study of 1,288 irP cases in which an ICI was re-administered, relapse occurred in 34%, and the median duration to irP onset was 88 days (interquartile range 58–178 days) in relapse cases, considerably longer than the 44 days (interquartile range 20–90 days) in non-relapse cases [27]. Although there may be an association between duration to irP onset and irP relapse, further evidence is needed.

The irP relapse rate of 39% in this study is relatively high compared with that found in previous studies (10–40%) [5, 6, 14–16]. There are some possible reasons for this difference in the relapse rate among studies. First, some studies included grade 1 irP (i.e., the relapse rate was estimated to be low). Second, the dose and duration of corticosteroids differed among the studies. Prolonging the duration of corticosteroids could further reduce the relapse rate but a longer treatment may also be harmful for the 60–70% of patients with irP who can be controlled with prednisolone for 6 weeks, as shown in this study. The optimal duration of corticosteroid therapy for each patient according to the relapse risk needs to be investigated in further studies.

There were three major limitations in this study. First, more than half of the irP cases were caused by programmed death (ligand)-1 monotherapy. In recent years, combination therapy with cytotoxic T-lymphocyte antigen-4 inhibitors or tyrosine kinase inhibitors and ICIs has been increasingly applied. Furthermore, new combination therapies are expected to be developed in the future. It will be necessary to verify whether the same factors as in the present study remain risk factors for irP relapse with these new ICI combination therapies. Second, in this study, the timing of chest HRCT during the follow-up period and the diagnosis of irP relapse were at the discretion of the attending physician. Therefore, asymptomatic irP relapses may have been missed or irP relapses may have been overdiagnosed. Third, this clinical study involved only a limited number of Japanese patients. There may have been some risk factors for relapse that were not evaluated in this study. Furthermore, racial differences in drug-induced lung injury have been reported, the risk factors identified in this study need to be further verified through more widespread accumulation of evidence in the future [28].

Conclusions

In patients with grade 2 or higher irP who received 6-week prednisolone tapering therapy, radiographic OP pattern and duration to irP onset≥100 days were risks for irP relapse. Because irP relapse interferes with cancer treatment, assessing the risk of irP relapse will be helpful for irP management.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Acknowledgements

Abbreviations

Author contributions

MK has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MK participated in concept and design, acquisition, analysis, and interpretation of data, statistical analyses, and drafting of the manuscript. NI participated in concept and design, interpretation of data, drafting of the manuscript, and supervision. YI, HY, HH, YS, KF, TF, and NE participated in concept and design, interpretation of data, and drafting of the manuscript. KA, KN, MF, TM, SM, DH, MT, MI, HM, NI, and YK participated in concept and design, data acquisition, and drafting of the manuscript. SF and SI carried out evaluation of chest imaging. SG participated in evaluation of chest imaging, conceptualisation, and supervision. TS participated in concept and design, drafting of the manuscript, and supervision.

Funding

This research did not receive specific grants from any funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

Individual participant data that underlie the results reported in this article, after de-identification will be shared if approved by the institutional review board of Hamamatsu University School of Medicine. Proposals should be directed to the corresponding author: [email protected].

Declarations

Footnotes

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