br This difference was not observed in the
.007). This difference was not observed in the subgroup of patients off-trial (P ¼ .13). No significant difference in the OS rate was found between the subgroups (P ¼ .827). Our 950455-15-9 was larger and included only patients with NSCLC. Furthermore, in this study, the
Table 5 Association Between Time to Onset if IRAEs and Immunotherapy Efficacy
Abbreviations: CI ¼ Confidence interval; HR ¼ hazard ratio; IRAEs ¼ immune-related adverse events; N ¼ number; OR ¼ odds ratio; ORR ¼ overall response rate; OS ¼ overall survival.
IRAEs and Immunotherapy Efficacy in NSCLC
analysis was based only on the first evaluation scan, whereas in our study, we chose to analyze the best response reached because we know that the ICI response can be delayed (the median time to response with nivolumab in NSCLC was 2.2 months, with a large range of 1.6-11.8 months in a phase III trial9). These factors could explain why we found a statistically significant difference when comparing patients with IRAEs with patients without any IRAE, whereas this difference was inconsistently found in previous case series or case reports.
In another publication21 that reported 21% of thyroid dysfunc-tion in 59 patients treated with pembrolizumab for NSCLC, the median delay of thyroid dysfunction diagnosis was 42 days, and the OS with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (HR, 0.29; 95% CI, 0.09-0.94; P ¼ .04). A statistically significant difference was also found in our study when comparing patients with and without thyroid dysfunction. However, we could not show any difference in the OS or PFS for the other IRAE types, likely owing to the lack of patients in each group of IRAE. To our knowledge, no association between ICI outcomes and the occurrence of pneumonitis or other less frequently occurring IRAEs (eg, colitis, hepatitis, and other endo-crine dysfunctions) has been reported in the literature.
Previous studies have reported that the ORR of ICI in NSCLC is
We demonstrated a statistically significant association between IRAEs and ORR. The occurrence of IRAEs could be used to predict what the future response to treatment might be. The association between IRAEs and the efficacy of ICIs highlights the need for the better diagnosis and management of IRAEs to be able to continue ICIs as long as possible, despite the IRAEs. It could also be an additional argument in favor of pseudo-progression in doubtful sit-uations when the diagnosis between disease progression and pseudo-progression is difficult. Our study suggested a significant association between the efficacy of ICIs and the incidence of IRAEs, particularly for thyroid dysfunction. The occurrence of IRAEs may be owing to the strongest T cell activation. Further prospective studies are needed to understand the underlying mechanisms and to correlate the duration of efficacy with the duration or severity of IRAEs, as well as the effect of ICIs discontinuation on response and survival in case of severe IRAEs. We need further prospective trials with larger cohorts to assess the association between ICI efficacy and less frequent IRAEs (ie, pneumonitis, hepatitis, colitis, cutaneous adverse events). We also need longer patient follow-up periods after ICIs stop to determine whether the response duration is longer for patients with IRAEs than for those without them, even if the treatment is stopped.
Clinical Practice Points
ICIs are widely used for the treatment of advanced NSCLC. They are responsible for IRAEs, and all organs can be involved. We already have data regarding IRAE frequency, severity, and guidelines on IRAE management. However, data are missing regarding the prognostic role of IRAEs and their association with ICI outcomes.
The new finding of this study is a statistically significant association between IRAE occurrence and ICI efficacy, with a longer OS, longer PFS, better ORR, and better DCR for pa-tients with IRAEs. Furthermore, this is the largest case series on the subject.
In the foreseeable future, the appearance of IRAEs could help physicians to detect patients with good response to ICIs. The occurrence of IRAEs could also be helpful to differentiate real progression and pseudo-progression in doubtful situations.
The authors have stated that they have no conflicts of interest.
5. Brahmer JR, Kim ES, Zhang J, Smith MM, Rangwala RA, O’Brien MER. KEYNOTE-024: phase III trial of pembrolizumab (MK-3475) vs platinum-based chemotherapy as first-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) that expresses programmed cell death ligand 1 (PD-L1). J Clin Oncol 2015; 33(15 Suppl):TPS8103.