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


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

In This Article


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.

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).

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).

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).

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.