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.

Discussion

In this study, we present CIP recurrence incidence, clinical features and survival outcomes in a real-world lung cancer cohort receiving ICIs-therapies and report important risk factors for the development of CIP-R. In this cohort, the incidence of CIP was 7.26%, which is consistent with prior real-world clinical reports.^[9,22] The recurrence rate of CIP was 25.6%, including 26.3% of patients without and 23.8% of patients with ICIs-rechallenge, highlighting the importance of risk assessment for CIP recurrence in lung cancer patients.

The results of our study suggest that, in lung cancer patients, tumor histology, concurrent chest radiotherapy, and a duration of prednisolone equivalent dose ≥15 mg/day may be risk factors associated with CIP recurrence. Prior clinical trials have shown that non-squamous NSCLC may be associated with a lower risk of CIP, reported to be around 2.4%, compared with 4.5% in squamous NSCLC.^[23,24] Similar results were reported also in retrospective real-world studies.^[9] However, tumor histology may be associated with other patient clinical or biological characteristics, such as smoking status and baseline lung disease.

Whether radiotherapy may increase the risk of CIP is still under debate. A low rate of pneumonitis (1.1%) was reported by Avrillon et al. in a French study of 591 participants receiving durvalumab after definitive chemoradiotherapy, but a higher rate of pneumonitis (61%) was reported by Miura et al. in a similar patient group.^[25,26] In clinical trials, the risk of pneumonitis was increased in patients who received prior thoracic radiation.^[27] The observed increased recurrence rate of pneumonitis might be attributed to the poor lung function induced by prior thoracic radiotherapy or NSCLC itself, rather than anti-PD-1 therapy, since CIP induced by these agents is preferentially located within lung areas involved in radiation fields.^[28]

Although the exact pathogenetic mechanisms underlying the irAEs occurrence are still unknown, CIP may be considered as a special immune-mediated interstitial lung disease based on its immunologic mechanisms of action, since checkpoint protein play a crucial role in self-tolerance, inhibition of checkpoint may lead to a degree of autoimmunity.^[6] Corticosteroids represent the first line treatment for CIP, with success in approximately 70–80% of cases.^[9] However, the starting doses, duration and timing of combination with other immunosuppressive agents have not been fully studied and are unclear according to several available guidelines about the treatment of irAEs.^[29–31] Corticosteroid doses of prednisolone equivalent dose <15 mg/day are used as maintenance doses for different rheumatic diseases. High-dose corticosteroids have significant immunosuppressive effects and have been associated with a higher risk of infection.^[19] For example, an equal duration of high dose prednisolone (≥30 mg/day) was associated with a higher risk of acquired infections in cancer patients with CIP.^[12] The initial dose of corticosteroids was recommended according to the CIP grading, but the optimal timing of a prednisolone equivalent dose ≥15 mg/day has not been clarified yet. Our data showed that the duration of prednisolone equivalent dose ≥15 mg/day was significantly shorter in the recurrence versus non recurrence groups (median, 3.73 vs. 6.36 weeks). A duration less than 4 weeks emerged as an independent risk factor for CIP recurrence, and therefore a duration of at least 4 weeks of prednisolone equivalent dose ≥15 mg/day is recommended during the tapering process of corticosteroids.

The presence of baseline lung disease has been shown in several studies to increase the risk of CIP,^[32–34] however not related to recurrence of CIP. The presence of baseline lung disease with poor lung function may lead to worse prognosis due to worsening tolerance of CIP relative to patients with normal lung function.^[35] This raises the need for pretreatment pulmonary function screening when risk factors for baseline lung disease are present.

Several limitations of this study should be addressed. First, this was a retrospective single-center study. The retrospective nature is prone to biases from missing data and the power to detect differences in risk factors for the development of CIP-R was limited by the relatively low number of cases. Second, the mechanisms of CIP were still unknown, with previous study suggesting that early-onset and late-onset CIP may be two different disease phenotypes.^[13] Unprovoked and provoked CIP-R may also have different mechanisms; however, they were analyzed together in this study. Lastly, there were six different types of PD-1 inhibitors and two different types of PD-L1 inhibitors in this study, and different drugs have distinct toxicity profiles, which may contribute to heterogeneity when analyzed together.

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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.