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Abstract Background Immune checkpoint inhibitors have recently become the standard of care in the first‐line treatment of extensive‐stage small cell lung cancer. Although immune‐related adverse events have been reported to influence prognosis in non‐small cell lung cancer patients, few studies have investigated the prognostic value of immune‐related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune‐related adverse events after first‐line treatment with immune checkpoint inhibitor‐based chemotherapy for extensive‐stage small cell lung cancer. Methods We enrolled 90 patients with extensive‐stage small cell lung cancer who received immune checkpoint inhibitor‐based chemotherapy as first‐line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune‐related adverse events. Results There were 23 patients with and 67 without immune‐related adverse events. Seventeen patients had grade 1–2 immune‐related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune‐related adverse event was a skin rash. The median survival time was 22 months in patients with immune‐related adverse events and 9.3 months in patients without immune‐related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19–0.83, p = 0.013). Conclusions The results of this study show that immune‐related adverse events are associated with improved survival outcomes in patients with extensive‐stage small cell lung cancer.

Summary: Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42–79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor ( EGFR ) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. Objectives: We report details of the clinical portion prior to omics analyses. Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results: A total of 103 patients (median age 70 years, range 42–88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 ( n = 27), 30 ( n = 23), and 20 mg/day ( n = 35), and 20 mg every other day ( n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did ( n = 25) and did not ( n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively ( p = 0.654). Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688

Introduction: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS). Methods: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status. Results: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p = 0.032); no such differences were observed in the nab-PC arm. Conclusions: We found that second-line ICI treatment seemed to have a little impact on OS.

Patients with EGFR‐mutated non‐small cell lung cancer (NSCLC) exhibit resistance to EGFR‐tyrosine kinase inhibitors (TKIs) within 9–14 months of therapy. Recently, EGFR‐mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression‐free and overall survival and other parameters affecting EGFR‐TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome‐focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four “OMICs” (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi‐OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment‐naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR‐TKIs using four‐OMICs analyses, focusing on both “naked or free” molecules and “capsulated” exosomal components in serially collected peripheral blood.

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

A subset of Nocardia isolates, previously belonging to N. transvalensis, has recently been given the new species designation N. blacklokiae. Here we report a case of pulmonary nocardiosis caused by N. blacklokiae in a 52-year-old immunocompetent woman presenting with low-grade fever and fatigue. The isolated Nocardia strain was resistant to sulfamethoxazole-trimethoprim and amikacin, but susceptible to amoxicillin-clavunate, ceftriaxone, clarithromycin and linezolid. With amoxicillin-clavunate treatment, the patient recovered and her condition remained stable, although recurrence occurred after cessation of the initial treatment. While infection by Nocardia is rare, clinicians should be aware of its resistance to antimicrobials including amikacin and sulfamethoxazole-trimethoprim. Keywords: Amoxicillin-clavunate, Pulmonary nocardiosis, Immunocompetent, Nocardia blacklokiae

Lung abscess has been considered to be a rare complication of pneumococcal infection, and most cases are reported to be Streptococcus pneumoniae serotype 3. A 67-year-old man presented with fever and was diagnosed to have lung abscess caused by S. pneumoniae serotype 6B. The minimal inhibitory concentration (MIC) of penicillin for the isolate was 1 μg/mL. He was treated with high-dose intravenous sulbactam/ampicillin as definitive therapy based on susceptibility testing for S. pneumoniae and recovered successfully without surgical intervention. S. pneumoniae serotype 6B can cause lung abscess. Keywords: Streptococcus pneumoniae, Lung abscess, Serotype 6B, Penicillin-resistant Streptococcus pneumoniae