Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

Teraoka, Shunsuke; Fujimoto, Daichi; Morimoto, Takeshi; Kawachi, Hayato; Ito, Mitsuru; Sato, Yuki; Nagata, Kazuma; Nakagawa, Atsushi; Otsuka, Kojiro; Uehara, Keiichiro; Imai, Yukihiro; Ishida, Kaori; Fukuoka, Junya; Tomii, Keisuke

doi:10.1016/j.jtho.2017.08.022

Cited by 328 publications

(303 citation statements)

References 25 publications

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“…In concordance with our findings, several retrospective analyses have reported improved PFS and OS in patients with advanced NSCLC or melanoma that developed grade 2 or higher irAEs . A prospective cohort of 43 patients with NSCLC treated with nivolumab demonstrated a higher objective response rate in the patients that experienced irAEs (37%) compared with those without irAEs (17%), as well as longer median PFS (6.4 vs. 1.5 months) . To our knowledge, a strong relationship between irAEs and efficacy outcomes has not been reported in large prospective studies.…”

Section: Discussionsupporting

confidence: 90%

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

et al. 2019

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Background Immune‐related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti‐programmed cell death protein 1 (PD‐1) therapy. Materials and Methods All patients with metastatic melanoma and non‐small cell lung cancer (NSCLC) treated with anti‐PD‐1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan‐Meier method and log‐rank test was used for time‐to‐event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression‐free‐survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune‐related adverse events (irAEs) compared with men when treated with anti‐programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow‐up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment‐related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

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Section: Discussionsupporting

confidence: 90%

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

et al. 2019

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“…When the relationship between the occurrence of nivolumab-induced irAEs and nivolumab efficacy was analyzed by irAE category, the occurrence of rash, endocrine disorders, and gastrointestinal toxicity was correlated with the ORR to nivolumab. The occurrence of these three toxicities has previously been correlated with the efficacy of anti-PD-1 antibodies, [15][16][17][18][19] and the present data appear to support these findings.…”

Section: Discussionsupporting

confidence: 88%

Three‐year follow‐up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non‐small cell lung cancer: Pooled analysis of ONO‐4538‐05 and ONO‐4538‐06 studies

Horinouchi¹,

Nishio

Hida

et al. 2019

Cancer Medicine

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Background Nivolumab is a programmed cell death 1 (PD‐1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non‐squamous (non‐SQ) non‐small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO‐4538‐05) and non‐SQ (ONO‐4538‐06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2‐42.1) and 22.4% (14.5‐32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long‐term safety and efficacy in patients with SQ and non‐SQ NSCLC by pooling data from these two trials. Methods SQ (N = 35) and non‐SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan–Meier method. A pooled analysis of SQ and non‐SQ patients was also performed. Results In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4‐25.2), and the estimated 1‐year, 2‐year, and 3‐year survival rates were 71.4% (53.4‐83.5), 37.1% (21.6‐52.7), and 20.0% (8.8‐34.4), respectively. In non‐SQ NSCLC patients, median OS was 17.1 months (13.3‐23.0), and the estimated 1‐, 2‐, and 3‐year survival rates were 68.0% (56.2‐77.3), 37.4% (26.5‐48.1), and 31.9% (21.7‐42.5), respectively. When SQ NSCLC and non‐SQ NSCLC data were pooled, the median OS was 17.1 months (14.2‐20.6), and the estimated 1‐, 2‐, and 3‐year survival rates were 69.1% (59.6‐76.8), 37.3% (28.3‐46.2), and 28.1% (20.0‐36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. Conclusion Treatment with nivolumab improved long‐term survival and was well tolerated in patients with SQ and non‐SQ NSCLC. Trial registration JapicCTI‐132072; JapicCTI‐132073.

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“… Biomarkers associated with the efficacy of PD‐1/PD‐L1 blockade therapy. Abbreviations and sources: ctDNA, circulating tumor DNA ; dMMR, mismatch repair deficient; IL‐8, interleukin‐8 ; irAE, immune‐related adverse event ; Ki67 + PD‐1 + CD8 + T/tumor burden ; monocytes, CD14 + CD16 − HLA‐DR hi monocytes ; MSI‐H, microsatellite instability‐high; NK‐DC axis, natural killer‐dendritic cell axis ; NLR, neutrophil‐to‐lymphocyte ratio ; PD‐1, programmed cell death protein 1; PD‐1 + CD8 + T ; PD‐L1, programmed cell death ligand 1; TME, tumor microenvironment . …”

Section: Challenges For Pd‐1/pd‐l1 Blockade Therapy In Advanced Nsclcmentioning

confidence: 99%

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

2019

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This article summarizes the latest clinical applications of PD‐1/PD‐L1 blockade therapy in advanced non‐small cell lung cancer (NSCLC) worldwide and in China, reporting the bottlenecks related to the use of this therapy in clinic. An exploration of the underlying mechanism of PD‐1/PD‐L1 blockade therapy and biomarker identification will maximize the application of immune checkpoint inhibitors in advanced NSCLC and facilitate bedside‐to‐bench studies in cancer immunotherapy.

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Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

Abstract: Early irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.

Cited by 328 publications

References 25 publications

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Three‐year follow‐up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non‐small cell lung cancer: Pooled analysis of ONO‐4538‐05 and ONO‐4538‐06 studies

PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

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