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Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

ABSTRACT: Background:Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC). Methods:A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC who were treated with PD-1/PD-L1 inhibitors between 1 September 2015 and 1 June 2019 was conducted. A total of 276 NSCLC patients with or without immune-related pneumonitis who received at least one dose of ICIs and had at least one follow-up visit were identified. Kaplan-Meier curves of the progression-free survival (PFS) of patients stratified according to immune-related pneumonitis development were evaluated with the log-rank test as a preplanned primary objective. Multivariate analysis of PFS was performed with Cox proportional hazard regression models. Results:In the cohort of 276 patients, 42 patients developed CIP attributed to PD-1/PD-L1 inhibitors. Survival analysis showed that the overall response rate was significantly higher in patients with CIP than in those without CIP (61.90% versus 29.91%, respectively, p < 0.01), and that CIP development was significantly associated with increased PFS (45.80 weeks versus 21.15 weeks, respectively, p < 0.01). Additionally, 16-week landmark analysis produced the same results. Similarly, subgroup analysis of PD-1 inhibitor-treated, nivolumab-treated, and pembrolizumab-treated groups also revealed that CIP increased survival in NSCLC patients. Additionally, grade 1-2 pneumonitis showed an association with increased ICI efficacy in NSCLC; however, grade 3-4 pneumonitis did not. In addition, only two of the four pneumonitis radiological subtypes showed associations with increased ICI efficacy in NSCLC. Conclusion:CIP is associated with enhanced PD-1/PD-L1 inhibitor efficacy in NSCLC patients. Grade 1-2 pneumonitis and the radiological features of hypersensitivity and cryptogenic organizing pneumonia (COP) may be signs of enhanced ICI efficacy. However, further studies with larger numbers of patients and longer follow-up times are needed to validate our findings.

SUBMITTER: Cui P

PROVIDER: S-EPMC7222233 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

Cui Pengfei P Huang Di D Wu Zhaozhen Z Tao Haitao H Zhang Sujie S Ma Junxun J Liu Zhefeng Z Wang Jinliang J Huang Ziwei Z Chen Shixue S Zheng Xuan X Hu Yi Y Hu Yi Y

Therapeutic advances in medical oncology 20200509

<h4>Background</h4>Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC).<h4>Methods</h4>A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC ...[more]

PMID: 32426052

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Project description:Immune checkpoint inhibitors (ICIs) are recommended as first-line treatment for late-stage non-small cell lung cancer (NSCLC), either as monotherapy or in combination with chemotherapy. However, efficacy and safety comparisons between ICIs as monotherapy and ICIs with chemotherapy are lacking. We searched PubMed, Embase, and Cochrane Library for randomized controlled trials published before February 29th, 2020, with the search terms "immunotherapy" and "chemotherapy". 10 eligible trials were identified with a total of 5,956 patients. Of these patients, 3,204 received immune therapy and 2,752 received chemotherapy. PD-1 inhibitors with chemotherapy improved OS (HR 0.84, 0.77-0.92), PFS (HR 0.80, 0.75-0.85), and objective response rate (ORR) (odds ratio (OR) 2.55, 1.20-5.28) compared to PD-1 inhibitors as monotherapy. In contrast, PD-L1 inhibitors plus chemotherapy showed no significant differences in OS, PFS, or ORR compared with PD-L1 inhibitors as monotherapy. When patients were stratified according to PD-L1 expression level, patients with high PD-L1 expression (≥ 50%) receiving PD-1 inhibitors plus chemotherapy had improved PFS, but not other outcomes, compared to PD-1 inhibitors as monotherapy. In these patients, PD-L1 inhibitors plus chemotherapy showed no significant difference in survival compared with PD-L1 inhibitors. In the low PD-L1 expression group (1%-49%), PD-1 inhibitors plus chemotherapy improved OS and PFS, but no advantage was observed in PD-L1 inhibitors plus chemotherapy in OS, PFS, or ORR compared with PD-L1 inhibitor monotherapy. When comparing PD-1/PD-L1 inhibitors plus chemotherapy with PD-1/PD-L1 inhibitors monotherapy, no significant differences were observed in the rate of immune-related adverse events (AEs). In summary, for treating patients with late-stage NSCLC, PD-1 inhibitors plus chemotherapy have improved efficacy compared with PD-1 inhibitor monotherapy, but PD-L1 inhibitors plus chemotherapy have similar efficacy as PD-L1 monotherapy. Survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy were particularly significant in patients with low PD-L1 expression levels.Systematic review registrationPROSPERO, identifier CRD42020166678 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166678).

Project description:BackgroundProgrammed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy.MethodsPubMed was searched up to 24 March 2017 for clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) in treatment of NSCLC. Besides, references of relevant articles were screened.ResultsFinally, 22 trials were included in our study, 14 with data of pneumonitis, 19 with other severe IRAEs or treatment related deaths and 5 with control groups. Incidence of all-grade pneumonitis was 2.9% (95% CI, 2.0-4.8%) and grade 3 or higher pneumonitis 2.0% (95% CI, 1.0-2.0%). Incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95% CI, 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis. Incidence of cardiorespiratory arrest (n=537) was 1.0% (95% CI, 0-2.0%), cardiac failure (n=214) 2.0% (95% CI, 1.0-5.7%), myocardial infarction (n=402) 1.0% (95% CI, 0-3.8%), stroke (n=135) 2.0% (95% CI, 0-13.0%), disease progression (n=391) 1.0% (95% CI, 0-2.9%), pancreatitis (n=700) 1.0% (95% CI, 0-2.0%) and severe skin reactions (n=836) 2.0% (95% CI, 1.0-3.8%). Incidence of treatment related deaths was 0.7%.ConclusionsImmune related adverse effects can on occasion be life-threatening even though usually rare. Incidence of pneumonitis in PD-1 and PD-L1 inhibitors was significantly higher than that in chemotherapy. More studies should be conducted to investigate the incidence of these rare but life-threatening IRAEs.

Dataset Information

Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

Publications

Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

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