Rate and Risk Factors of Recurrent Immune Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer

Haitao Tao; Fangfang Li; Dongxiao Wu; Shiyu Ji; Qingyan Liu; Lijie Wang; Bo Liu; Francesco Facchinetti; Tracy L. Leong; Francesco Passiglia; Yi Hu

Disclosures

Transl Lung Cancer Res. 2022;11(3):381-392.

Methods

Patient Selection

This retrospective study was conducted on patients who were diagnosed with lung cancer and received ICIs treatment in the First Medical Center of Chinese People's Liberation Army (PLA) General Hospital between January 2016 and January 2021. Patients who were ultimately diagnosed with CIP were included in analysis.

The inclusion criteria included patients who were pathologically diagnosed with locally advanced/advanced lung cancer (including NSCLC and SCLC); patients who received at least 1 cycle of PD-1/PDL-1 inhibitors and/or CTLA-4 inhibitors, whether monotherapy or combined with other drugs; and patients who developed typical clinical features and/or new typical imaging changes after ICIs treatment and were ultimately diagnosed with CIP after evaluation by a multidisciplinary team. The exclusion criteria included patients with other lung diseases with a clear alternative etiology, such as carcinomatous lymphangitis or active lung infection.

For patients who received corticosteroids for CIP treatment, a cumulative prednisolone equivalent dose was calculated. Since equivalent prednisolone 15 mg/day is the maintenance dose commonly used in rheumatic diseases,^[19] this time point is marked as a key node of corticosteroid therapy. CIP-R was defined as recurrent CIP after initial CIP improved with regard to both chest CT and clinical symptoms after proper corticosteroid treatment according to NCCN guideline and the dose of corticosteroid tapered to less than equivalent prednisolone 15 mg/day (methylprednisolone 12 mg), regardless of complete discontinuation or rechallenge with immunotherapy lung.

Data Collection

For all the patients, detailed clinical data were retrospectively collected from medical records, including demographic characteristics, histologic subtype, medical history, molecular pathology and PD-L1 expression status, previous and concurrent cancer treatments, duration of ICIs therapy, antitumor efficacy of ICIs, clinical manifestations and outcomes of CIP, rechallenge with ICIs and recurrence of CIP. A chest CT scan obtained 3 months before the initiation of ICIs treatment was recorded as baseline. Baseline chest CT scan findings, including the presence of emphysema and ILA, were also recorded.

ILA were defined by at least one of the following CT findings in no less than two lobes of the lung: ground glass appearance (GGA), reticular opacity, honeycombing or traction bronchiectasis, diffuse centrilobular nodularity, or nonemphysematous cysts on CT images.^[20,21] Patients with a history of drug-induced pneumonitis or those with radiation-related fibrotic lesions alone in the lung were excluded from the ILA group. Composite obstructive lung disease includes chronic obstructive pulmonary disease (COPD) by history, obstruction on spirometry, or emphysema on baseline CT images.^[22] CT images were evaluated by two pulmonologists who were unaware of patient outcomes by a sequential reading method. Pneumonitis grading was evaluated by the treating investigators according to the Common Toxicity Criteria for Adverse Events (CTCAE version 4.0).

Follow-up was up to August 15, 2021, allowing sufficient time to observe pneumonitis recurrence.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Chinese PLA General Hospital (No. S2021-562-01). Individual consent for this retrospective analysis was waived.

Statistical Analysis

Time to the onset of CIP was defined as the time from the first dose of an ICIs to the first occurrence of CIP-related symptoms or imaging findings in asymptomatic patients. The time to CIP-R was defined as from the time of initial CIP to the time of CIP-R. Continuous variables are described as the median [interquartile range (IQR)] and were compared using t-tests or the Mann-Whitney U test. Categorical variables were compared using the chi-square test or Fisher's exact test. Univariate and multivariate logistic regression analyses were performed on risk factors for the odds of CIP-R, including patient demographics (e.g., sex), medical histories (e.g., ILA), cancer-related factors (e.g., tumor histology), CIP-related factors (e.g., CTCAE grade). The multivariate analysis included predictors associated with CIP risk at the 0.15 significance level from the univariate analysis. Six patients who did not receive corticosteroids were excluded from the analysis of risk factors.

Kaplan-Meier estimates for median progression-free survival (PFS) and overall survival (OS) after ICIs initiation were produced for patients; log-rank and Wilcoxon tests were conducted to assess differences. The hazard ratio (HR) was estimated by a Cox regression model. All reported p values were two sided, and a significant difference was considered at the 5% level. Statistical analyses were conducted using SPSS Statistics for Windows (Version 25.0; IBM), and the figures were made by GraphPad Prism 9 (GraphPad Software Inc.).

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Table 1. Patient and treatment characteristics
Characteristics	All patients*	CIP without recurrence	CIP-R	P value
Total	80	58	20	–
Age, years				0.8
≤65	38	26	10
>65	42	32	10
Gender				0.03
Male	68	46	20
Female	12	12	0
Present/past smoker				0.22
Yes	61	47	13
No	19	11	7
ECOG PS				0.33
0–1	63	45	18
≥2	17	13	2
Tumor histology				0.016
Non-squamous NSCLC	33	28	4
Squamous NSCLC	30	17	13
SCLC	17	13	3
Stage of tumor				0.61
I–IIIA	2	2	0
IIIB–IIIC	23	16	7
IV	55	40	13
Baseline lung disease				0.43
ILA	16	13	2
Composite obstructive lung disease**	20	15	5
No	44	30	13
Thoracic radiotherapy				0.049
Concurrent chest radiotherapy	21	12	9
Previous chest radiotherapy	12	8	4
No	47	38	7
Line of ICIs treatment				0.94
First-line	53	39	13
Second-line	16	12	4
≥ Third-line	11	7	3
PD-L1 expression				0.69
0	19	15	3
1–49%	31	22	9
≥50%	20	13	6
Unknown	10	8	2
EGFR/ALK/Ros1/Ret mutation/fusion				0.7
Yes	5	3	1
No	46	35	10
Unknown	29	20	9
Regimen of immune therapy				0.69
Monotherapy	14	11	3
Combination therapy	66	47	17
PD-1/PD-L1 + chemotherapy	56	41	14
PD-1/PD-L1 + antiangiogenesis	6	4	1
PD-1 + ipilimumab	4	2	2
Best objective response of ICIs				0.81
Complete/partial response	52	48	14
Stable disease	20	14	5
Progression of disease	7	6	1
Not evaluated	1	1	0

*, includes 2 patients with grade 5 CIP; **, includes COPD by history, obstruction on spirometry, or emphysema on baseline chest CT scan. ECOG PS, Eastern Cooperative Oncology Group Performance Status; ICIs, immune checkpoint inhibitors; CIP, checkpoint inhibitor-related pneumonitis; CIP-R, recurrence of CIP; ILA, interstitial lung alterations; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; Ros1, ROS proto-oncogene 1, receptor tyrosine kinase; Ret, rearranged during transfection.

Table 2. Clinical features and management of CIP
Characteristics	CIP without recurrence	CIP-R	P value
Time to CIP, median (IQR)	3.49 (0.26–31.93)	2.78 (1.22–20.93)	0.48
Time to recurrence (month), median (IQR)	n/a	1.54 (0.98–16.7)
Radiologic features			0.96
COP	18	7
NSIP	9	3
AIP	9	3
HP	6	1
NOS	16	6
CTCAE grade			0.331
1	6	0
2	33	10
3	12	6
4	7	4
Starting dose of equivalent MP			0.053
0	6	0
0–1 mg/kg	16	2
1–2 mg/kg	23	14
>2 mg/kg	13	4
Duration of prednisolone equivalent dose>15 mg/day
Median (weeks) (IQR)	6.36 (3.12–9.86)	3.71 (2.86–6.57)	0.001
0	6	0	0
<4 weeks	7	13
4–6 weeks	18	6
6–8 weeks	17	1
>8 weeks	10	0
Other organs involved with irAEs			0.61
Yes	22	9
No	36	11
Rechallenges with ICIs			1
Yes	16	5
No	42	15

IQR, interquartile range; ICIs, immune checkpoint inhibitors; CIP, checkpoint inhibitor-related pneumonitis; CIP-R, recurrence of CIP; COP, cryptogenic organizing pneumonia; NSIP, on-specific interstitial pneumonia; AIP, acute interstitial pneumonia; HP, hypersensitivity pneumonitis; NOS, non-specified; CTCAE, Common Toxicity Criteria for Adverse Events; MP, methylprednisolone.

Table 3. Logistic regression analysis of potential risk factors for CIP-R development
Characteristics	Univariate analyses			Multivariate analyses
Characteristics	OR	95% CI	P	OR	95% CI	P
Gender (male vs. female)	0	0–∞	0.999	–	–	–
Smoker (yes vs. no)	2.301	0.774–7.114	0.148	–	–	–
ECOG PS (≥2 vs. 0–1)	0.385	0.079–1.878	0.238	–	–	–
Histologic type (non-Sq vs. Sq)	0.187	0.052–0.667	0.01	0.182	0.038–0.860	0.031
Histologic type (SCLC vs. Sq)	0.302	0.071–1.284	0.105	0.576	0.1–3.318	0.537
Stage IV vs. others	1.197	0.409–3.503	0.743	–	–	–
Driven gene mutation (yes vs. no)	1.036	0.102–10.572	0.976	–	–	–
ILA vs. no	0.769	0.231–2.562	0.669	–	–	–
Composite obstructive lung disease vs. no	0.355	0.070–1.803	0.212	–	–	–
Second-line treatment vs. first-line treatment	1.119	0.304–4.123	0.866	–	–	–
Third-line or later treatment vs. first-line treatment	1.319	0.297–5.852	0.716	–	–	–
Concurrent chest radiotherapy vs. no	4.071	1.249–13.275	0.02	3.245	0.748–14.081	0.116
Previous chest radiotherapy vs. no	2.714	0.639–11.523	0.176	2.833	0.482–16.654	2.833
PD-1/PD-L1 antibody (monotherapy vs. combination therapy)	1.349	0.330–5.514	0.677	–	–	–
Grade 3–4 vs. 1–2	2.053	0.730–5.772	0.173	–	–	–
Initial corticosteroids dose (equal methylprednisolone ≥2 vs. <2 mg/kg)	0.865	0.246–3.043	0.822	–	–	–
Duration of prednisolone equivalent dose ≥15 mg/day (>4 vs. <4 weeks)	0.084	0.025–0.283	0	0.082	0.02–0.342	0.001
Rechallenge with ICIs (yes vs. no)	0.875	0.273–2.804	0.822	–	–	–

CIP-R, recurrence of checkpoint inhibitor-related pneumonitis; ECOG PS, Eastern Cooperative Oncology Group Performance Status; SCLC, small cell lung cancer; Sq, squamous non-small cell lung cancer; non-Sq, non-squamous cell non-small cell lung cancer ILA, interstitial lung alteration; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; ICIs, immune checkpoint inhibitors; ILA, interstitial lung alterations; OS, overall survival; CI, confidence interval.