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Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy. [ABSTRACT FROM AUTHOR]

The incidence of central nervous system metastasis is known to be high among patients with lung cancer. The frequency of brain metastasis and carcinomatous meningitis during the entire clinical course of non-small cell lung cancer is reported to be about 40% and 5%, respectively. In contrast, the incidence of cranial nerve metastasis is extremely rare, and detailed reports of its clinical course remain limited. Herein, we report 2 patients diagnosed with cranial nerve metastasis of lung adenocarcinoma and treated with radiotherapy and systemic chemotherapy. Both patients had cranial nerve symptoms, and brain magnetic resonance imaging showed cranial nerve enhancement. However, no evidence of carcinomatous meningitis was noted on magnetic resonance imaging and cerebrospinal fluid cytology. Based on these observations, these patients were diagnosed with cranial nerve metastasis of lung adenocarcinoma. Radiotherapy and chemotherapy were performed in both cases. In both cases, neurological symptoms had not worsened and imaging findings did not indicate any deteriorations. Therefore, radiotherapy and systemic chemotherapy should be considered when treating cranial nerve metastasis of lung adenocarcinoma. Early therapeutic intervention may lead to attenuation of the cranial nerve dysfunction resulting from cranial nerve metastasis. [ABSTRACT FROM AUTHOR]

Background: Anti-programmed cell death receptor (PD)-1 antibody treatment results in better prognosis than standard chemotherapy in patients with non-small cell lung cancer (NSCLC), especially those with high PD-ligand 1 (PD-L1) expression. However, several studies have reported a lack of antitumor effect of PD-1 antibody, even in patients with high PD-L1 expression. Therefore, reliable predictors of treatment response are urgently needed. The albumin–globulin ratio (AGR) is associated with prognosis in several cancers. We aimed to determine whether AGR is a predictive biomarker of anti-PD-1 antibody response in patients with NSCLC. Patients and methods: Seventy-four NSCLC patients treated with anti-PD-1 antibody were retrospectively enrolled. Patients with driver mutations were excluded. Results: The mean AGR was significantly higher in the disease control (DC) group than in the progressive disease (PD) group (p < 0.001). Receiver operating characteristic curve analysis revealed an AGR cutoff value for dividing patients into the DC or PD groups of 1.17. Multivariate logistic regression analysis showed that a high AGR (≥1.17, cutoff value) was an independent predictor of DC (p = 0.001). Progression-free survival (PFS) and overall survival (OS) were significantly longer in the high-AGR group than in the low-AGR group (p = 0.008, p = 0.002, respectively). Multivariate Cox regression analysis of PFS and OS showed that high AGR was an independent prognostic factor (p = 0.020, p < 0.001, respectively). Conclusion: Pretreatment serum AGR may be a useful predictor for DC and prognostic factor of anti-PD-1 antibody in patients with NSCLC. The clinical utility of AGR still needs to be confirmed in a prospective analysis. [ABSTRACT FROM AUTHOR]

S-1 is an oral fluoropyrimidine agent used for the treatment of non-small-cell lung cancer (NSCLC). Although S-1 monotherapy has been reported to exhibit lesser hematotoxicity compared with other third-generation chemotherapeutics, digestive toxicity was also frequently observed. Alternate-day administration of S-1 has shown a lower rate of severe digestive toxicity than the daily standard administration in patients with NSCLC. However, the safety of alternate-day S-1 therapy in elderly patients aged 75 years or older has not been investigated. The present study was a multi-center and prospective feasibility study aimed to evaluate the safety of alternate-day S-1 therapy in elderly patients with NSCLC. The patients received S-1 orally twice daily for 4 days (Monday, Wednesday, Friday, and Sunday) every week until disease progression or unacceptable toxicity. The primary endpoint was safety, which was evaluated as the number of grade ≥3 adverse events, and the secondary endpoints were progression-free survival (PFS), 1-year survival, and disease control rate (DCR). A total of 10 patients were enrolled, but 2 patients failed to initiate the treatment protocol. Finally, 8 patients were treated with the study protocol regimen. No grade 3 or higher adverse events were observed. Four (50%) and 1 (12.5%) patient had grade 2 or lower digestive symptoms such as anorexia, diarrhea, or stomatitis and grade 1 lacrimation, respectively. Moreover, 2 (25%), 1 (12.5%), and 1 (12.5%) patients had grade 2 renal dysfunction, grade 2 ileus, and elevated blood bilirubin, respectively. The median PFS was 1.5 months (95% confidence interval: 0.9–1.8), and the 1-year survival rate was 42.9%. The DCR was 12.5%. In conclusion, alternate-day S-1 administration can be a safe treatment regimen for elderly patients with NSCLC, but its therapeutic efficacy and safety for elderly patients with NSCLC should be compared against the standard S-1 administration in a large-scale study. [ABSTRACT FROM AUTHOR]

Objectives: Chemotherapy-related acute exacerbation (AE) of interstitial lung disease (ILD) is observed in certain patients with non-small cell lung cancer (NSCLC) who have ILD. Although the prognosis of AE-ILD is extremely poor, there are no established risk factors for its occurrence. Therefore, we retrospectively investigated whether high-resolution computed tomography (HRCT) findings could identify risk factors for AE-ILD.Materials and Methods: Between January 2005 and December 2016, 35 patients with NSCLC who received chemotherapy at Hiroshima University Hospital and were diagnosed with ILD on HRCT were enrolled. The extent of ground-glass attenuation (GGA), reticulation, honeycomb appearance, and emphysema, as well as the presence of micronodules, traction bronchiectasis, and consolidation were evaluated in five levels of the lung bilaterally. The HRCT scores of GGA, reticulation, honeycomb appearance, and emphysema were determined by the following formula: 100 × sum of the extent of the HRCT findings/lung area.Results: Thirty-five patients underwent various first- to fifth-line chemotherapy regimens. Nine patients (25.7%) developed AE-ILD. The median HRCT scores of GGA and reticulation were significantly higher in patients with AE-ILD than in those without. On univariate analysis, a GGA area score ≥ 24.8, reticulation area score ≥ 19.5, and KL-6 level ≥ 946 U/mL were significant risk factors. Multivariate logistic analysis revealed that only a GGA area score ≥ 24.8 was an independent risk factor of AE-ILD.Conclusions: The GGA area on HRCT is a risk factor for chemotherapy-related AE-ILD. Therefore, this parameter can be used to predict the risk of AE-ILD before administering chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non‐small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow‐on next‐generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. Methods: Patients with untreated advanced (Stage IIIB–IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single‐plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. Results: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre‐defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0–41.1, p < 0.001 [one‐sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5–17 days). Conclusion: Rapid follow‐on comprehensive testing of ctDNA should be considered prior to first‐line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single‐plex tissue testing. [ABSTRACT FROM AUTHOR]

Background: We evaluated the safety and efficacy of induction chemotherapy with bevacizumab followed by maintenance chemotherapy with bevacizumab for advanced non-small cell lung cancer (NSCLC) in this multicenter phase II study.Methods: Chemotherapy-naïve patient with stage IIIB-IV or recurrent nonsquamous NSCLC were eligible. We planned approximately four cycles of induction cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) followed by maintenance with pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) until disease progression. Progression-free survival (PFS) was the primary endpoint.Results: Forty patients received a median of four induction chemotherapy cycles. Of them, 35 (87.5%) patients received a median of nine maintenance chemotherapy cycles. The objective response was 70.6%, and the disease control rate was 97.1%. The median PFS was 10.8 (95% CI, 9.0-12.6), and overall survival was 48.0 (95% CI, 32.9-63.1) months. Median PFS of 23 patients with epidermal growth factor receptor (EGFR) mutations and of 16 patients without EGFR mutations were 12.9 (95% CI, 9.4-16.3) and 7.9 (95% CI, 1.1-14.7) months, respectively. Toxicities graded ≥3 included neutropenia (15%), anemia (15%), hypertension (7.5%), anorexia (7.5%), fatigue (7.5%), thromboembolic events (5%), jaw osteonecrosis (5%), nausea (2.5%), oral mucositis (2.5%), tumor pain (2.5%), hyponatremia (2.5%), and gastrointestinal perforation (2.5%). Treatment-related deaths were not found.Conclusions: In patients with advanced or recurrent nonsquamous NSCLC, induction chemotherapy with cisplatin, pemetrexed, and bevacizumab followed by maintenance chemotherapy with pemetrexed and bevacizumab is safe and effective regardless of their EGFR mutation status.Trial Registration: UMIN Clinical Trial Registry: UMIN000005569 . Registered date: May 8, 2011. [ABSTRACT FROM AUTHOR]

Background and Objective: Checkpoint inhibitor pneumonitis (CIP), caused by the anti‐programmed cell death‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high‐mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. Methods: Blood samples, prospectively stored before anti‐PD‐1/PD‐L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non‐small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti‐PD‐1/PD‐L1 therapy. Results: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut‐off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut‐off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. Conclusion: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients. CIP incidence in the patients with high levels of serum HMGB1 (≥ 11.24 ng/ml) was significantly and reproducibly higher than in those with its low levels (< 11.24 ng/ml) in patients with NSCLC. Our results suggest that HMGB1 may be a potential blood marker for the prediction of CIP. [ABSTRACT FROM AUTHOR]

Background: High-mobility group box 1 (HMGB1) is a pro-inflammatory protein associated with the pathophysiology of lung injury and lung tumorigenesis. Here, we investigated the predictive potential of serum HMGB1 levels for radiation pneumonitis in patients with lung cancer. Methods: This was a retrospective biomarker study of 73 patients with non-small cell lung cancer treated with definitive thoracic radiotherapy between August 2007 and January 2021. We measured HMGB1 levels in serum stored before treatment, and analyzed its association with the development of grade ≥ 2 or grade ≥ 3 radiation pneumonitis. Additionally, baseline characteristics affecting HMGB1 levels were identified. Results: Of the 73 patients, 21 (28.8%) and 6 (8.2%) patients experienced grade 2 and ≥ 3 radiation pneumonitis, respectively. Univariate and multivariate logistic regression analyses revealed that higher baseline levels of serum HMGB1 were significantly associated with a higher risk of grade ≥ 3, but not grade ≥ 2, radiation pneumonitis. The incidence of grade ≥ 3 radiation pneumonitis was higher in patients with HMGB1 levels ≥ 6.2 ng/mL than in those with levels < 6.2 ng/mL (25.0% vs. 3.5%, p = 0.019). Baseline serum levels of HMGB1 were independently and positively associated with gross tumor volume. Conclusions: Higher serum HMGB1 levels were significantly associated with the risk of grade ≥ 3 radiation pneumonitis in patients with lung cancer, and therefore, HMGB1 could be a potential blood biomarker for predicting severe radiation pneumonitis. [ABSTRACT FROM AUTHOR]

• Largest real-world study of nivolumab for Japanese NSCLC revealed treatment patterns. • Nivolumab effectiveness and safety were consistent with previous clinical trials. • Effectiveness was associated with PS, EGFR mutation, smoking status, and PD-L1. • Discontinuation of treatment was associated with types of irAEs. To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab. [ABSTRACT FROM AUTHOR]