Profiling Preexisting Antibodies in Patients Treated With Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer

Abstract

IMPORTANCE Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. OBJECTIVE To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. DESIGN, SETTING, AND PARTICIPANTS This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. EXPOSURES Absence or presence of specific autoimmune markers and antibodies before treatment. MAIN OUTCOMES AND MEASURES Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. RESULTS Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). CONCLUSIONS AND RELEVANCE The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic b...

Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment

“…The development of irAEs after anti-PD-1/PD-L1 treatment has been proposed to be positive prognostic factors. 6,[30][31][32] In our study, we also found that NSCLC patients with grade 1/2 irAEs had significantly higher ORR and PFS. The occurrence of irAEs may be a sign of more robust immune response after PD-1 blockade which may lead to better treatment outcome.…”

“…Second, although we focused on T cells, recent reports have claimed the role of B cells, autoantibodies, and serum cytokines. 5,6,9 Analysis of all peripheral blood components will be required to comprehensively understand the pathophysiology of irAEs. Third, some lateonset irAEs were observed and further investigation is required to explain the long latent period between the immunological change and clinical manifestation.…”

Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

“…Peiro et al also reported similar ndings 17 . Although Toi et al 18,19 and Maekura et al 20 reported that thyroid peroxidase (TPO) antibody and thyroglobulin antibody (TgAb) levels before ICI therapy were predictive factors for the development of hypothyroidism, whereas our study showed no association with TPO antibody levels but suggested an association with TgAb levels (P = 0.05). Meanwhile, a high TSH level before treatment appeared to be a possible predictive factor for the development of hypothyroidism.…”

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti-Programmed Cell Death 1 Monotherapy for Advanced Non-Small Cell Lung Cancer

“…Previous studies have suggested a few predictive biomarkers of irAEs in patients treated with immune‐checkpoint inhibitor. We previously reported that any pre‐existing antibodies are independent predictors of irAEs in patients with advanced NSCLC . Osorio et al found that thyroid dysfunction during pembrolizumab treatment of NSCLC is associated with antithyroid antibodies.…”