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Original Investigation
December 27, 2018

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

Author Affiliations
  • 1Department of Pulmonary Medicine, Sendai Kousei Hospital, Aoba-ku, Sendai, Miyagi, Japan
JAMA Oncol. Published online December 27, 2018. doi:10.1001/jamaoncol.2018.5860
Key Points

Question  Are preexisting autoimmune markers including relevant antibodies associated with outcome or with immune-related adverse events of anti–programmed cell death 1 therapy in patients with subclinical disease with advanced non–small cell lung cancer?

Findings  In this medical record analysis of 137 patients with advanced or recurrent non–small cell lung cancer treated with the programmed cell death protein 1 inhibitors nivolumab or pembrolizumab, the presence of any preexisting antibody examined was independently and significantly associated with immune-related adverse events and with clinical benefit.

Meaning  Detecting the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with non–small cell lung cancer, maximizing therapeutic benefits while minimizing immune-related adverse events.

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 benefits while minimizing irAEs.

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