br BRAF br Immunotherapy type
Abbreviations: PD-1 ¼ Programmed cell death protein 1; PD-L1 ¼ programmed death-ligand 1.
to February 14, 2017 were analyzed. Patients known to have any previously controlled autoimmune disease were excluded.
Before the data collection, all patients provided signed informed consent allowing the use of data collected during standard care for research purposes. The Comité D’évaluation des Protocoles de Recherche Observationnels (reference CEPRO 2017-027) ethics committee approved this observational trial.
Data were retrieved from electronic patient records. Clinical and epidemiologic data (age, gender, tobacco status, asbestos exposure), disease data (pathology, LY 294002 status, stage), treatment data (type, treatment line, toxicity), and outcome data (response and survival) were collected.
Toxicity was assessed as in pivotal trials, and as described in the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The diagnosis and severity of IRAEs were based on clinical examinations and biological and imaging data.
Tumor response was assessed once every 2 months through computed tomography scans, according to the Response Evaluation Criteria in Solid Tumors, version 1.1.
The primary endpoint was OS. The secondary endpoints were PFS, ORR, and DCR. OS was defined as the time from the beginning of immunotherapy to death from any cause, censored at
Mathieu Grangeon et al
Figure 1 Distribution of Immune-Related Adverse Events in the Population (number of patients)
of patients being pretreated with chemotherapy prior to ICI.
the date of last follow-up. PFS was defined as the time from the beginning of immunotherapy to documented disease progression or death from any cause, censored at the date of last follow-up. Me-dians were reported with interquartile range (IQR). As per Response Evaluation Criteria in Solid Tumors, version 1.1, the ORR included patients with partial or complete responses; DCR included partial responses, complete responses, and stable disease. To describe the population, we used effectives (numbers) and percentages for qualitative variables; means with standard deviation or medians with IQR for quantitative variables. To analyze OS and PFS, the Kaplan-Meier method was used to estimate the median survival with 95% confidence interval (CI) and Cox model to estimate hazard ratios (HRs) throughout groups’ comparison with 95% CI. To assess IRAEs association with objective response rate, we used logistic regression analyses to estimate odds ratios (ORs) with 95% CIs throughout the group comparisons. Statistical analysis was per-formed using IBM SPSS Statistics for Windows, version 20.0 (IBM SPSS Inc., Chicago, IL).
Patient and Disease Characteristics
In terms of survival or response, the association between IRAE grade and ICI efficacy showed no statistically significant between-group differences for the different IRAE grades (Table 3).
The median OS and median PFS differences according to the IRAE type were assessed (Table 4). For thyroid dysfunction, a statistically significant difference was observed. The median OS rate was not determined for patients with thyroid dysfunction; the median OS rate was 18.2 months for patients without thyroid dysfunction (HR, 0.46; 95% CI, 0.25-0.86; P ¼ .01). Median PFS was 8.05 months for patients with thyroid dysfunction versus 2.59 months for patient without thyroid dysfunction (HR, 0.56; 95% CI, 0.39-0.85; P ¼ .005). No statistically significant difference was found in the median OS and median PFS among patients with pneumonitis, colitis, hepatitis, and other endocrine disorders.
Table 2 Association Between IRAE Incidence and Immunotherapy Efficacy
Median OS, mos (IQR)
Abbreviations: CI ¼ Confidence interval; DCR ¼ disease control rate; HR ¼ hazard ratio; IQR ¼ interquartile range; IRAE ¼ immune-related adverse event; OR ¼ odds ratio; ORR ¼ objective response rate; OS ¼ overall survival; PFS ¼ progression-free survival.
IRAEs and Immunotherapy Efficacy in NSCLC
Figure 2 Progression-free Survival and Overall Survival With Immune Checkpoint Inhibitors. Depending on the Incidence of IRAEs
Abbreviation: IRAE ¼ Immune-related adverse event.
To the best of our knowledge, atrioventricular (AV) valve study is the largest case series to assess the association between IRAEs and the efficacy of ICIs. Statistically significant differences were observed in the in OS, PFS, and ORR, in favor of the patients with IRAEs compared with the patients without any IRAEs. Subgroup analyses also showed better OS and PFS for patients with thyroid dysfunction.