Purpose: Although the efficacy of programmed cell death–1 (PD-1) blockade is generally poor for non–small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. Patients and Methods: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin–pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). Results: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin–pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61–2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53–1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin–pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell–inflamed gene expression profile score (0.11 vs. −0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. Conclusions: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.

Elderly patient with advanced cancer is one of the most vulnerable populations. Skeletal muscle depletion during chemotherapy may have substantial impact on their physical function. However, there is little information about a direct relationship between quantity of muscle and physical function. We sought to explore the quantitative association between skeletal muscle depletion, and muscle strength and walking capacity in elderly patients with advanced non–small cell lung cancer (NSCLC). Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to initiate first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. Lumbar skeletal muscle index (LSMI, cm2/m2), incremental shuttle walking distance (ISWD, m), and hand-grip strength (HGS, kg) were assessed at baseline, and 6 ± 2 weeks (T2) and 12 ± 4 weeks (T3) after study enrollment. Associations were analyzed using linear regression. Altogether, 11 women and 19 men with a median age of 74 (range, 70–82) years were included in the study; 24 received cytotoxic chemotherapy and 6, gefitinib. Mean ± standard deviation of LSMI, ISWD and HGS were 41.2 ± 7.8 cm2/m2, 326.0 ± 127.9 m, and 29.3 ± 8.5 kg, respectively. LSMI and ISWD significantly declined from baseline to T2 and T3. HGS significantly declined from baseline to T2 and T3 only in men. Change in LSMI was significantly associated with change in HGS (β = 0.3 ± 0.1, p = 0.0127) and ISWD (β = 8.8 ± 2.4, p = 0.0005). Skeletal muscle depletion accompanied with physical functional decline started in the early phase of the chemotherapy in elderly patients with advanced NSCLC. Our results suggest that there may be a need for early supportive care in these patients to prevent functional decline during chemotherapy. Trial registration number: UMIN000009768 Name of registry: UMIN (University hospital Medical Information Network). URL of registry: Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.

Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of hospital stay, and inpatient medical costs among elderly patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy. Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to receive first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. ADL was assessed using the Barthel index. The disability-free survival time (DFS) was calculated as the time between the date of study entry and the date of onset of a disabling event, which was defined as a 10-point decrease in the Barthel index from that at baseline. The mean cumulative function of the length of hospital stay and inpatient medical costs (¥, Japanese yen) was calculated. The study patients comprised 11 women and 19 men, with a median age of 74 (range, 70–82) years. Cachexia was diagnosed in 19 (63%) patients. Cachectic patients had a shorter DFS (7.5 vs. 17.1 months, p < 0.05). During the first year from study entry, cachectic patients had longer cumulative lengths of hospital stay (80.7 vs. 38.5 days/person, p < 0.05), more frequent unplanned hospital visits or hospitalizations (4.2 vs. 1.7 times/person, p < 0.05), and higher inpatient medical costs (¥3.5 vs. ¥2.1 million/person, p < 0.05) than non-cachectic patients. Elderly NSCLC patients with cachexia showed higher risks for disability, prolonged hospitalizations, and higher inpatient medical costs while receiving chemotherapy than patients without cachexia. Our results might indicate that there is a potential need for an early intervention to minimize progression to or development of cachexia, improve functional prognosis, and reduce healthcare resource burden in this population. Trial registration number: UMIN000009768 . Name of registry: UMIN (University hospital Medical Information Network). Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.

Background: Quantitative skeletal muscle mass loss has the potential to predict the therapeutic effects of immune checkpoint inhibitors. This study aimed to assess the impact of muscular quality on the abovementioned outcomes.Methods: This study retrospectively reviewed the medical records of patients with advanced non‐small cell lung cancer (NSCLC) who had received PD‐1/PD‐L1 inhibitor monotherapy between March 2016 and February 2018. High muscle quality was stipulated as a skeletal muscle density ≥41 and ≥33 Hounsfield units in patients with a body mass index (BMI) <25 kg/m² and ≥25 kg/m², respectively, as assessed using lumbar computed tomography images. High muscle quantity was stipulated as a lumbar skeletal muscle index ≥41 cm²/m² in women, ≥43 cm²/m² in men with a BMI <25 kg/m², and ≥53 cm²/m² in men with a BMI ≥25 kg/m². We evaluated the associations of these muscular parameters with the overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS).Results: Out of 156 patients, 80 (51.3%) and 47 (30.1%) showed low muscle quality and quantity, respectively. Patients with high muscle quality showed higher ORR (35.0 vs. 15.8 %, p<0.05) and longer PFS durations (median, 4.5 vs. 2.0 months, p<0.05) than those with low muscle quality. There were no noted differences in the ORR or PFS between patients with high and those with low muscle quantities. On the contrary, regardless of muscle quality and quantity, there were no differences in OS between patients with high and those with low muscle status.Conclusions: Lumbar skeletal muscle quality has the potential to predict the therapeutic effect of anti‐programed cell death 1/programed cell death ligand 1 inhibitor monotherapy in patients with advanced NSCLC.

Venous thromboembolism (VTE) is frequently observed in patients with advanced cancer. The objective of this prospective observational study was to estimate, based on intensive screening, using computed tomography, lower‐extremity ultrasonography, and D‐dimer testing, the prevalence of VTE in patients with advanced cancer.Patients with metastatic or locally advanced cancer without anticoagulant therapy, who were planning to receive chemotherapy during 4 weeks, were eligible. Evaluations of VTE were performed at pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy. Primary endpoint was cumulative incidence of VTE for 24 weeks. Secondary endpoints included incidence of VTE (pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy), VTE according to primary cancer site, symptomatic VTE, pulmonary thromboembolism (PE), and treatment of VTE.We enrolled 860 patients with a median age of 68 years, including 34% female and 71% lung cancer. Cumulative incidence of VTE for 24 weeks was 22.6% (95% confidence interval: 19.8%–25.5%) (194 of 860 patients). Incidence of VTE was 11.3% pretreatment, 16.8% 12 weeks, and 14.1% 24 weeks. Symptomatic VTE was observed in 4.0% and PE in 1.0% of patients. By multivariate analysis, sex, D‐dimer level, and platelet count were independent risk factors of VTE for 24 weeks.This large prospective observational study showed that cumulative incidence of VTE was high in advanced cancer patients, mainly lung cancer. Although most patients showed asymptomatic VTE, intensive screening of VTE may be considered in advanced cancer patients, especially in women with high level of D‐dimer and decreased platelet count (UMIN000015243).