PurposeTo conduct a retrospective multicenter trial to determine the significance of metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer.MethodsThis study was conducted across three medical centers in Japan. We retrospectively reviewed all patients who commenced nivolumab treatment at these centers between December 17, 2015 and July 31, 2016. Clinical data were collected, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status, and metastatic site (lymph nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant pleural effusion) at the time of commencing nivolumab treatment. Patients were followed-up until March 31, 2017.ResultsTwo hundred and one patients were enrolled. The median age at the time of commencing nivolumab treatment was 68 (range, 27–87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had a performance status of 0–1, and 42 patients had squamous cell carcinoma. The median progression-free survival of all patients was 2.5 months. In the univariate analysis, a performance status of ≥2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33–2.69; p < 0.001) and liver (HR: 2.09, 95.0% CI: 1.35–3.25; p < 0.001) and lung (HR: 1.57, 95.0% CI: 1.14–2.16; p < 0.01) metastases correlated with a significantly shorter progression-free survival in nivolumab-treated patients. In the multivariate analysis, a performance status of ≥2 (HR: 1.54, 95.0% CI: 1.05–2.25; p < 0.05) and liver (HR: 1.90, 95.0% CI: 1.21–2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI: 1.00–1.99; p < 0.05) metastases were independently correlated with a significantly shorter progression-free survival in nivolumab-treated patients.ConclusionLiver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.

Programmed death‐ligand 1 (PD‐L1) expression status is inadequate for indicating nivolumab in patients with non–small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation‐related parameters) on progression‐free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27–87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil‐to‐lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44–5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice.

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

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Abstract. The aim of the present study was to analyze the impact of metastatic status on the prognosis of epithelial growth factor receptor (EGFR) mutation-positive patients with non-small cell lung cancer (NSCLC) treated with first-generation EGFR-tyrosine kinase inhibitors (TKIs). A total of 178 EGFR mutation-positive patients with stage IIIB-IV and relapsed NSCLC who were treated with gefitinib or erlotinib as the first-line treatment were enrolled in the present study. Metastatic status, progression-free survival (PFS), overall survival (OS) and treatment-response rates were investigated. The association between the number of metastatic organ sites and patient prognosis was also investigated. The median age at the time of treatment was 72 (range, 39-91) years. A total of 168 patients had adenocarcinoma; 156 were treated with gefitinib. Patients with brain metastases, bone metastases, liver metastases and pleural effusion exhibited a significantly reduced PFS and OS time in the univariate analysis, compared with patients without each of these symptoms. In the multivariate analysis, bone metastasis was associated with a poorer PFS (hazard ratio, 2.11; 95% confidence interval, 1.44-3.09; P<0.001) and brain metastasis was associated with a poorer OS (hazard ratio, 2.41; 95% confidence interval, 1.46-3.95; P<0.001). No association was observed between metastatic status and treatment response rates. Higher numbers of different sites of organ metastases were associated with significantly poorer PFS and OS. Bone, brain metastasis and higher numbers of metastatic organ sites are negative prognostic factors for EGFR mutation-positive NSCLC patients treated with first-generation EGFR-TKIs.

PS score ≥2, steroid use at baseline and a high LDH level were predictive of poor PFS in patients with NSCLC treated with nivolumab. Careful monitoring is recommended for treating such patients with nivolumab (UMIN-ID: UMIN000025908).

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