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.

Results

Patient Characteristics

From January 2016 to January 2021, 1,102 patients with lung cancer were enrolled in this study. After reviewing the medical records and imaging data, 102 demonstrated features of pneumonitis. Of those, 80 patients (7.26%) were included in analysis, and 22 patients were excluded because of radiotherapy-induced pneumonitis, infection pneumonitis, and heart failure (Figure 1). Seventy-eight out of 80 patients who experienced CIP clinical improvement or resolution after initial treatment were definitively included in this study (2 patients died of pneumonitis although given high-dose steroids), Among these, 20 patients (25.64%) experienced CIP-R, and 5 patients (6.4%) died during treatment of CIP.

(Enlarge Image)

Figure 1.

Screening flow chart.

Detailed patients' demographic, therapeutic, and clinical information are reported in Table 1. Demographic characteristics were similar between the CIP-R and no recurrence groups (CIP-NR) except for both sex and tumor type. Indeed all the patients with CIP-R were male, with squamous cell carcinoma as the predominant histological subtype, Conversely SCLC accounted for a larger proportion of the no recurrence group (P=0.016).

A history of composite obstructive lung disease or ILA was identified in 20 patients (25%) and 16 patients (20%), respectively. Fifty-five patients (68.8%) were stage IV, and ICIs were used predominantly administered as first-line therapy in 53 patients (66.3%). PD-L1 expression was evaluated in 70 cases (87.5%), and 51 (72.8%) showed positive expression (PD-L1 ≥1%). Three patients had EGFR mutations, 1 patient had ALK fusion and 1 patient had RET fusion. Sixty-six patients (82.5%) received PD-1/PD-L1 based combination therapy, including 56 combined with chemotherapy, 6 with antiangiogenics and 4 with CTLA-4 antibody. Thirty-three patients (41.3%) had a prior history of chest radiotherapy or concurrent chest radiotherapy (within 6 weeks of ICIs therapy). In detail the percentage of patients who received chest radiotherapy (previous or concurrent) was significantly higher among patients with CIP-R subgroup (P=0.049).

Clinical Features of CIP

The clinical features of the CIP-R patients included in the study are shown in Table 2. The median onset of pneumonitis for patients without and with recurrence was 3.49 months (IQR, 0.26–31.93 months) and 2.78 months (IQR, 1.22–20.93 months), respectively, with no significant difference in onset between the two groups (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98–16.70 months).

According to the CTCAE v4.0 criteria, 49 (62.8%) patients experienced grade 1 or 2 CIP, while 32 (41.2%) patients experienced grade 3 or 4 CIP. After recurrence, 1 patient experienced grade 5 CIP, 4 patients experienced grade 4 CIP, 13 patients experienced grade 3 CIP, and 2 patients experienced grade 2 CIP. Although there was no grade 1 in the CIP-R group, severe CIP (grade 3–4) was similar between the 2 groups. The grade of CIP was upgraded in 8 patients experiencing recurrence: 5 patients from G2 to G3, 2 patients from G3 to G4, and 1 patient from G4 to G5. The CIP grade was downgraded in 1 patient (from G4 to G3).

Concurrent irAEs occurred in 31 patients (39.7%), including hypothyroidism (10 cases), dermatitis (9 cases), hepatitis (4 cases), nephritis (2 cases), hypophysis (2 cases), myocarditis (2 case) and one case each of pancreatitis, thrombocytopenia and tuberculosis.

The baseline chest CT lesions for patients with untreated CIP included ground glass opacity (GGO) (32/78, 41.0%), consolidation (24/78, 30.8%), traction bronchiectasis (20/78, 25.6%) and reticular opacities (18/78, 23.1%). According to the classification of idiopathic interstitial pneumonia imaging patterns, 32.1% (25/78) met the pattern for cryptogenic organizing pneumonia (COP), 15.4% (12/78) met the pattern for non-specific interstitial pneumonia (NSIP), 15.4% (12/78) met the pattern for acute interstitial pneumonia (AIP), 9.0% (7/78) met the pattern for hypersensitivity pneumonitis (HP), and 28.2% (22/78) were non-specified (NOS). The radiological pattern may be changed (12/20, 60%) or not changed (8/20, 40%) in CIP-R cases (Figures 1,2).

(Enlarge Image)

Figure 2.

Representative radiological features of recurrent CIP related to ICIs rechallenge (A) and unprovoked recurrent pneumonitis (B). (A1) A 70-year-old male with squamous lung cancer. CT shows new consolidations in the left upper lobe after 3 cycles of nivolumab and ipilimumab, classified as grade 2; (A2) consolidations are nearly completely absorbed 4 weeks after glucocorticoid treatment; (A3) 3 days after rechallenge with nivolumab, CT shows diffuse ground glass opacities, suspicious for CIP recurrence, grade 3; (A4) 8 weeks after glucocorticoid treatment, resolution of the pulmonary opacities is observed. (B1) A 66-year-old male with squamous lung cancer and new flake ground glass shadows in both lungs after 1 year of pembrolizumab treatment, classified as grade 2; (B2) 3 weeks after glucocorticoid treatment, CT shows resolution of the CIP; (B3) 4 weeks later, CT shows diffuse ground glass opacities without rechallenge of ICIs; (B4) 8 weeks after steroid treatment shows resolution of the pulmonary opacities. CIP, checkpoint inhibitor-related pneumonitis; ICIs, immune checkpoint inhibitors; CT, computed tomography.

In addition to treatment discontinuation, 72 (92.3%) patients received corticosteroids and 7 patients received additional immunosuppressive treatments (including 4 infliximab and 3 tocilizumab), with 2 of them still experiencing a recurrence of pneumonitis. After recurrence, 5 patients (25%) received further immunosuppressive treatments, including 1 infliximab and 4 tocilizumab.

For the initial case of CIP, 17 patients received the dose of equivalent MP >2 mg/kg, 37 patients received a dose of 1–2 mg/kg and 18 patients received a dose of 0–1 mg/kg. The starting dose of corticosteroids was similar between the CIP-NR and the CIP-R groups, However, the duration of prednisolone equivalent dose ≥15 mg/day was significantly longer in the CIP group with 6.36 weeks (IQR, 3.12–9.86 weeks) as compared to the CIP-R group with 3.71 weeks (2.86–6.57 weeks) (Figure 3).

(Enlarge Image)

Figure 3.

Clinical course of recurrence of CIP. Individual clinical courses of patients with pneumonitis, from initiation of ICIs therapy, the first episode of CIP, the recurrence of CIP, to last follow-up or death. In most patients, there is sufficient follow-up time that minimizes the possibility of the recurrence of pneumonitis. The median onset of CIP for patients without recurrence and with recurrence was 3.49 months (IQR, 0.26–31.93 months) and 2.78 months (IQR, 1.22–20.93 months), respectively. The median interval duration between initial and recurrent CIP was 1.54 months (IQR, 0.98–20.93 months). CIP, checkpoint inhibitor-related pneumonitis; ICIs, immune checkpoint inhibitors; MP, methylprednisolone; IQR, interquartile range.

Twenty-one patients were rechallenged after recovery from initial CIP, 5 patients (23.8%) developed CIP-R, and 15 patients (26.3%) without rechallenges of ICIs experienced CIP-R. Sixteen patients accepted the same ICIs as rechallenge, including 15 patients treated with PD-1/PD-L1 inhibitors and 1 patient treated with PD-1 combined with CTLA-4 inhibitors. Four patients accepted another PD-1 inhibitor, while 1 patient who previously accepted a PD-1 inhibitor received double ICIs therapy (combined with a CTLA-4 inhibitor).

Risk Factors for CIP-R

Non-squamous NSCLC subtype (OR, 0.187; 95% CI: 0.052–0.667) and duration of prednisolone equivalent dose ≥15 mg/day (OR, 0.084; 95% CI: 0.025–0.283) were significantly associated with a decreased risk of CIP-R development, while concurrent chest radiotherapy (OR, 4.071; 95% CI: 1.249–13.275) was associated to an increased risk of CIP-R (Table 3).

Multivariate logistic regression analysis was performed on 72 (92%) patients as 6 patients who did not receive corticosteroids were excluded. The results showed that both non-squamous NSCLC histology (OR, 0.182; 95% CI: 0.038–0.860) and duration of prednisolone equivalent dose ≥15 mg/day (OR, 0.082; 95% CI: 0.02–0.342) for more than 4 weeks were independently associated with a decreased odds for the CIP-R development.

ICIs Response and Survival in Patients With CIP

Regardless of the tumor histology, stage, and ICIs regimen the objective response rate (ORR) was 47.2% (51/77), and the disease control rate (DCR) was 91.7% (70/77), with 4 cases of complete remission (CR), 47 cases of partial response (PR), 19 cases of stable disease (SD), 7 cases of progressive disease (PD) and 1 unevaluable patient. Up to August 15, 2021, 23 patients had not progressed, and 38 patients were still alive. The median follow-up time for the entire cohort is 17.40 months (range 2.92–64.85 months). The median PFS was 11.07 months (95% CI: 3.59–18.56 months) and 11.27 months (95% CI: 4.34–18.20 months) for the CIP-NR and CIP-R groups, respectively. The median OS after ICIs initiation was 25.92 months (95% CI: 13.52–38.33 months) and 19.29 months (95% CI: 11.58–26.98 months) for the CIP-NR and CIP-R groups, respectively. There was no difference in PFS or OS between the two groups (Figure S1).

(Enlarge Image)

Figure S1.

Kaplan-Meier estimates for PFS and OS after ICIs initiation stratified by CIP status. PFS, progression-free survival; OS, overall survival; ICIs, immune checkpoint inhibitors; CIP, checkpoint inhibitor-related pneumonitis.

1 2 3 4 5

Next Section

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.