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.

Abstract and Introduction

Abstract

Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence.

Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence.

Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26–31.93 months] and 2.78 months (IQR, 1.22–20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98–16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86–6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12–9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038–0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02–0.342; P=0.001) were independently associated with a decreased odds of CIP-R development.

Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.

Introduction

Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer, including the first- and second-line therapy of advanced non-small cell lung cancer (NSCLC) without driver mutations, the first-line therapy of extensive-stage small cell lung cancer (SCLC) and the consolidative therapy of unresectable stage III NSCLC after concurrent chemoradiotherapy.^[1–5] However, despite clinical benefits characterized by a significant increase of long-term survival, ICIs use is associated with a wide spectrum of immune-related adverse events (irAEs) whose pathogenetic mechanisms are still largely unknown.^[6]

Although clinical trials suggest a rare incidence of immune checkpoint inhibitor-related pneumonitis (CIP) (approximately 4–6%), restrictive enrollment criteria may underestimate the true incidence in clinical practice.^[7,8] Indeed, the incidence of CIP reported in real-world lung cancer cohorts ranges from 5% to 19%.^[9,10] CIP is a serious adverse event in ICIs treated patients, and is the leading cause of death among the different irAEs, with an overall mortality rate of approximately 0.45%.^[11,12] However, the inflammatory characteristics of CIP that result in morbidity and mortality are also associated with enhanced programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitor efficacy in NSCLC.^[13]

Although irAE is generally reversible after appropriately corticosteroids treatment, several retrospective studies have reported recurrence of CIP (CIP-R).^[14–18] Nishino et al. first reported that a patient with lung cancer receiving anti-PD-1 treatment experienced recurrent pneumonitis in absence of ICIs-rechallenge after a documented resolution, named a "pneumonitis flare".^[14] Asher et al. reported three patients with melanoma who experienced unprovoked CIP-R after complete resolution without ICIs-rechallenge, named a "unprovoked recurrent pneumonitis".^[16] Dolladille et al. reported a 28.8% recurrence rate of the same irAEs after a rechallenge with the same ICIs, and pneumonitis was associated with a higher recurrence rate compared with other irAEs.^[17] Recurrent CIP seem to be not uncommon, CIP-R occurred without rechallenge of ICIs maybe a unique feature of CIP, which was similar to the durable and persisted response after ICIs discontinuation.^[14] However, there is limited information on patients of CIP-R in recent research, especially regarding unprovoked recurrent pneumonitis.

The aim of this study was to characterize the clinical and radiological features, cancer-related and CIP-related factors of lung cancer patients experiencing CIP-R, in order to identify potential risk factors to CIP-R either related or not to ICIs rechallenge. We present the following article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-168/rc).

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

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.