Association between the efficacy and immune-related adverse events of pembrolizumab and chemotherapy in non-small cell lung cancer patients: a retrospective study

Abstract

Background The combination of immune-checkpoint inhibitors with chemotherapy has become the standard of treatment for non-small cell lung cancer (NSCLC) patients. However, the association between therapeutic efficacy and the development of immune-related adverse events (irAEs) remains unclear in patients treated with combination therapy. We aimed to investigate the frequency of irAEs, and the association between therapeutic efficacy and the development of irAEs in patients with NSCLC. Materials and methods We retrospectively surveyed patients with chemo-naïve advanced NSCLC who received pembrolizumab plus platinum-based chemotherapy or pembrolizumab monotherapy at Juntendo University Hospital, Japan, between February 2017 and May 2021. Results Among 148 patients (median [range] age, 68 (33–85) years; 107 men [72.3%] and 41 women [27.7%]), 74 each received pembrolizumab plus chemotherapy and pembrolizumab monotherapy. IrAEs were observed in 46 (62.2%) and 41 patients (55.4%) in the combination therapy and monotherapy group, respectively. Patients with irAEs showed significantly longer progression-free survival (PFS) than those without irAEs in the combination therapy group (8.9 vs. 5.7 months; Hazard Ratio [HR], 0.53; 95% CI, 0.29–0.98; P = 0.041) and monotherapy group (11.7 vs. 5.0 months; HR, 0.40; 95% CI, 0.22–0.70; P = 0.001). In the multivariable analysis, development of irAEs was positively associated with PFS in both the groups (HR, 0.48; 95% CI, 0.26–0.89; P = 0.019 and HR, 0.38; 95% CI, 0.21–0.68; P < 0.01). In the inverse probability of treatment weighting adjusted analysis, development of irAEs was significantly associated with combination therapy (OR, 0.56; 95% CI, 0.34–0.91; P = 0.019). Conclusion Our study demonstrated that the incidence of irAEs was associated with favorable efficacy in patients treated with pembrolizumab plus chemotherapy, as well as pembrolizumab monotherapy. Also, the addition of chemotherapy to pembrolizumab significantly increased the incidence of irAEs.

Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors

“…The incidence of reported irAEs in NSCLC varies widely, ranging from 24.0% to 70.5%. This reflects heterogeneity including in study setting (observational vs randomized clinical trial), patient characteristics (cancer stage, PD-L1 status, geographical location, race and ethnicity), treatment parameters (ICI agent used either alone or combined with chemotherapy, treatment line), and irAE grading . In our cohort, the incidence of clinically meaningful irAEs was 37.0%.…”

“…31,55 The median time to developing an irAE in our study population was 3.4 months, longer than that typically cited in the NSCLC literature. 24,[36][37][38] However, we only recorded clinically meaningful irAEs per our definition, and studies have shown low-grade events develop earlier than high-grade events. 34,39 The incidence of reported irAEs in NSCLC varies widely, ranging from 24.0% to 70.5%.…”

“…It is well established that although ICIs improve clinical outcomes in NSCLC, they are complicated by immune-related adverse events (irAEs), the incidence of which varies by study setting, patient selection, treatment parameters, and irAE grading . There is growing recognition across solid malignant neoplasms that irAEs affect overall survival (OS).…”

Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

“…In addition, it has been controversial whether ICI combined with chemotherapy has an effect on irAEs. 48 , 49 However, the sample size was smaller under different ICI treatment strategies when analysed by univariate logistic regression. Conclusions related to factors influencing ICI-related pAEs need to be further validated by larger studies or clinical trials.…”

Different associations between organ-specific immune-related adverse event and survival in non-small cell lung cancer patients treated with programmed death-1 inhibitors-based combination therapy

“…Two studies reporting PD-1 inhibitors in combination with chemotherapy found that overall irAE was associated with a PFS benefit. 24,25 Nonetheless, due to their small sample sizes and short follow-up periods, these studies failed to analyze OS or investigate organ-specific irAE. In a recent meta-analysis that included 62 randomized clinical studies, the investigators concluded that irAE should not be seen as a proxy for OS of anti-PD-1 treatment, 26 which is in agreement with our findings.…”