論文No2232
Profiling Preexisting Antibodies in Patients Treated With Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer.
Toi Y, Sugawara S, Sugisaka J, Ono H, Kawashima Y, Aiba T, Kawana S, Saito R, Aso M, Tsurumi K, Suzuki K, Shimizu H, Domeki Y, Terayama K, Nakamura A, Yamanda S, Kimura Y, Honda Y.
JAMA Oncol. 2019 Mar 1;5(3):376-383. doi: 10.1001/jamaoncol.2018.5860.
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進行NSCLCにおいて抗PD-1治療は今や標準治療である。
しかし、抗PD-1をふくむ免疫チェックポイント阻害薬は進行NSCLCに伴う前臨床疾患で評価されておらず、
またその使用時に免疫関連有害事象(irAE)に関連する有用な臨床バイオマーカーは見つかっていない。
＜目的＞
進行NSCLCを伴う前臨床疾患における抗PD-1治療の安全性、有効性を、
自己免疫マーカーの有無（リウマチ因子、抗核抗体、抗サイログロブリン、抗甲状腺ペルオキシダーゼ）で評価する。
そして抗PD-1治療後の臨床的ベネフィットあるいはirAEに関連する潜在的臨床的バイオマーカーを評価した。
＜方法＞
仙台厚生病院で2016年1月から2018年1月までにニボルマブあるいはペムブロリズマブの
単剤治療をうけた137名のカルテを後ろ向きに解析した。
治療効果をirAEを、irAEに関連する候補因子の観点から評価した。
治療前の自己抗体、自己免疫マーカー、PFS、OSを評価した。
＜結果＞
進行NSCLC患者137名のうち、105名が男性で、年齢中央値は68歳（range, 36-88)であった。
99名はニボルマブ単剤を、38名はペムブロリズマブ単剤を行い、134名はECOGが0, 1であった。
PFS中央値は自己抗体がある群で6.5 (95% CI, 4.4-12.9)か月で
自己抗体がない群の3.5 (95% CI, 2.4-4.1)か月よりも有意に良好であった。
自己抗体がある場合のPDあるいは死亡のハザード比は0.53 (95% CI, 0.36-0.79; P = .002)であった。
PFSは自己抗体があるとない場合よりも有意に良好であった。
調べた自己抗体(48 patients [73%])とリウマチ因子 (26 patients [39%])はirAEを発症した群で多かった。
多変量解析では、自己抗体が存在するとirAEの独立した予測因子であった(odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001)。
皮膚障害はリウマチ因子が陽性の群で頻度が高く(47% vs 24%, P = .02)、
甲状腺機能障害は自己抗体が陽性の群で頻度が高かった(20% vs 1%, P < .001)。
＜感想＞
抗PD-1治療（ニボルマブ、ペムブロリズマブ単剤）前に自己抗体が存在すると、irAEの発症リスクが高かったようです。
一方、PFSは有意に良好だったようです。
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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.