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 (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

Background Anti‐programmed cell death 1 antibody is a standard therapy for advanced non‐small cell lung cancer (NSCLC). However, immune‐related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. Subjects, Materials, and Methods We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6‐week landmark analysis was conducted to assess the clinical benefit of early skin reactions. Results Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression‐free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6‐week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre‐existing rheumatoid factor (RF) as an independent predictor of skin reactions. Conclusion Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre‐existing RF. Further large‐scale validations studies are warranted. Implications for Practice This single‐institutional medical record review that included 155 patients with advanced non‐small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression‐free survival were significantly better in patients with skin reactions. Pre‐existing rheumatoid factor was an independent predictor of skin reactions.

CD30+ large anaplastic lymphoid cells are seen in anaplastic large cell lymphoma (ALCL), and also in lymphomatoid papulosis (LyP) and other lymphoproliferative disorders. It can be difficult precisely to categorize these disorders with CD30+ cells. We report a case of primary cutaneous CD30+ ALCL with systemic metastases in whom the clinical disease subsequently evolved into LyP. The patient was initially administered cisplatin and etoposide and made a good response. Eighteen months later, recurrent, self-healing cutaneous small nodules appeared around the original tumour site without any systemic involvement. Histopathological examination of the recurrent lesions revealed infiltration with a mixture of cells that included neutrophils, eosinophils and CD30+ large anaplastic cells cytologically identical with those in the primary lesion. The anaplastic cells in both the primary and recurrent lesions were positive for monoclonal antibodies CD30, CD25 and a monoclonal antibody directed against the chimeric protein p80(NPM-ALK). These observations suggest the possibility that the ALCL and the subsequent LyP represent different clinical manifestations of proliferation of the same clone.

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