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For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

Summary: Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates “C-CAT Findings” reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries.

The dosing pattern of pembrolizumab is based on population pharmacokinetic (Pop-PK) analysis of clinical trials. Data for Japanese patients or patient populations with poor conditions such as cachexia are scarce. In this study, we performed a Pop-PK analysis of Japanese non-small cell lung cancer patients and analyzed the relationship between exposure, treatment effect, and survival.A total of 270 blood samples from 76 patients who received 200 mg pembrolizumab every 3 weeks between March 2017 and December 2018 were included. Blood concentrations of pembrolizumab were measured using mass spectrometry, and Pop-PK analysis was conducted using the Phoenix NLME software with a one-compartment model.The estimated median of clearance (CL) in this analysis population was 0.104 L/day, about half of the historical data for Western data. Overall, pembrolizumab CL decreased over time, with some populations showing increased CL early in the treatment and others showing decreased CL over time. When the time-varying CL was stratified by quartile, the group with decreasing CL showed significantly better treatment response and survival than the group with increasing CL, even though the group included more patients with cachexia. Detailed analysis suggested that the patient population that responded to pembrolizumab treatment had an improved general condition and reduced protein catabolism, further decreasing CL.In populations that benefit from pembrolizumab treatment, CL may be reduced early in their treatment, which may be a predictive and prognostic factor. However, further prospective validation of our findings is needed.

Treatment for small cell lung cancer (SCLC) has not changed significantly compared to the overwhelming development of targeted therapies for non-small cell lung cancer. However, recent epigenetic and expressional analyses have revealed that SCLC can be divided into four distinct subtypes, which may lead to precision treatments. The situation appears slightly similar to the "four-color problem," a classic mathematical problem stating that no more than four colors are required to color the regions so that no two adjacent areas have the same color. This review introduces the framework for subtyping SCLC into four molecular subtypes and the promising targeted treatment for each subtype.

Administration of 400 mg pembrolizumab every 6 weeks (400 mg Q6W) has been approved on the basis of the results of simulated pharmacokinetic modeling and exposure-response analyses. Nevertheless, the safety of switching dosage from 200 mg every 3 weeks (Q3W) to 400 mg Q6W during treatment remains unclear.This study involved patients (N = 45) with advanced NSCLC, in whom the pembrolizumab dosage was switched from 200 mg Q3W to 400 mg Q6W between August 2020 and November 2021 in our institute.At the time of switching, the median age of the patients was 71 (range: 32-84) years, and 32 patients (71.1 %) were males. The median number of cycles of 200 mg Q3W before switching was six (range: 1-31). After switching, new or worsening immune-related adverse events (irAEs) occurred in 17 of the 45 patients (37.8%) within three cycles. The irAEs were pneumonitis in 11 patients (24.4%), diarrhea in three patients (6.7%), renal dysfunction in two patients (4.4%), adrenal dysfunction in two patients (4.4%), a skin rash in one patient (2.2%), fulminant type 1 diabetes mellitus in one patient (2.2%).The switching of pembrolizumab dosage from 200 mg Q3W to 400 mg Q6W resulted in the occurrence of new or worsening irAEs, in particular, pneumonitis, in the early cycles even in patients who had received stable treatment with 200 mg Q3W.

SMARCA4-deficient thoracic tumor is a novel disease entity characterized by mutations in SMARCA4 resulting in loss of its expression. They could be divided according to their phenotypes; carcinoma or sarcomatoid. It remains unclear how many patients with these SMARCA4-deficient tumors could benefit from inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1).SMARCA4-deficient thoracic tumor cases were retrospectively identified from pathology and gene expression databases at the National Cancer Center Hospital in Japan. Clinical outcomes of patients treated with PD-1/PD-L1 inhibitors were reviewed.Eighteen patients with SMARCA4-deficient thoracic tumor [carcinoma (n = 10), sarcomatoid (n = 7), and ambiguous type (n = 1)] were identified. Of the twelve [carcinoma (n = 7), sarcomatoid (n = 5)] who had received immune checkpoint inhibitors (ICIs), 5 [carcinoma (n = 3), sarcomatoid (n = 2)] showed a partial response, all of whom had received an ICI as the first-line therapy. The overall response rate was The PD-L1 tumor proportion scores of the 5 responding patients were 100%, 80%, 5% (n = 2), and less than 1%. The median progression-free survival (PFS) of all the patients was 2.4 months [95% confidence interval (CI), 1.1 months-not achieved (NA)], while the median PFS of the 3 patients who received first-line ICIs was not reached (95% CI, 1.1 months-NA).PD-1/PD-L1 inhibitors showed promising results in the treatment of SMARCA4-deficient tumor. Further studies, especially on patient selection and combination therapy, are needed.

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Supplementary Data from C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan

Summary:Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates “C-CAT Findings” reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries.

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Supplementary Figure from C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan

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The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI.See articles by Tomita et al., p. 1236, and Peng et al., p. 1251

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Figure S6. Differential abundance analysis of antibiotic resistance genes and virulence factors between R and NR for WGS datasets.

Figure S5. Limited gut microbiome compositional changes are observed during treatment with checkpoint inhibitors.

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Table S1

Figure S4: Sensitivity and specificity analysis of the Integrated Microbiome Prediction Index for response prediction in responder (R) vs nonresponder (NR), further stratified by inclusion (+) or exclusion (-) of stable disease (SD) if available.

Figure S7. 16S rRNA amplicon data processing for predicted functional elements using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) based on taxonomic composition.

Figure S3. Complete species list for each index identified through re-analysis of raw sequencing data or as reported by the authors.

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Purpose:While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.Experimental Design:We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach.Results:Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105).Conclusions:Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

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Figure S2. Alpha diversity analysis across all cohorts using Chao1, observed species, Shannon, and Simpson Reciprocal measures.

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Figure S1. Correlation analysis between 16S rRNA amplicon and metagenomic taxonomic relative abundance estimates.

Table S2

Curative-intent surgery is the best therapeutic option for thymic malignancies. However, patients with advanced or recurrent thymic malignancies often require palliative-intent chemotherapy or radiotherapy. Since thymic malignancies are rare cancers, the efficacy and safety of treatments have been verified based on small Phase 2 trials or retrospective studies.We comprehensively reviewed the treatment strategies for thymic malignancies, including surgery, radiotherapy, and pharmacotherapy, including cytotoxic chemotherapy, molecular-targeted therapy, and immunotherapy. Additionally, we reviewed specific situations, such as pleural dissemination, central nervous system metastasis, and paraneoplastic syndrome.Cytotoxic chemotherapy remains the standard option in pharmacotherapy. However, multikinase inhibitors, such as sunitinib and lenvatinib, and immune checkpoint inhibitors including pembrolizumab have been developed to treat thymic carcinomas. Now, a Phase 2 study is evaluating whether lenvatinib plus pembrolizumab benefits patients with type B3 thymoma or thymic carcinoma. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin inhibitors may contribute to disease control and octreotide scan is only applicable to somatostatin analogues. Although the genomic characteristics of thymic malignancies have been analyzed, few actionable mutations have been detected in general. The development of a treatment strategy using combination pharmacotherapy is anticipated.

Background Combination therapy based on radiotherapy and immune checkpoint inhibitors (ICIs) was recently reported as effective for various cancers. The radiation-induced immune response (RIIR) is an essential feature in ICI-combined radiotherapy; however, the effects of drugs used concomitantly with RIIR remain unclear. We screened for drugs that can modify RIIR to understand the mutual relationship between radiotherapy and combined drugs in ICI-combined radiotherapy. Methods We established a high-throughput system with reporter gene assays for evaluating RIIR, focusing on factors acting downstream of the STING-IRF pathway, which can stimulate cancer cells, T cells, and dendritic cells. We further quantified the effects of 2595 drugs, including those approved by the Food and Drug Administration, on RIIR in vitro. Results The reporter assay results correlated well with the expression of immune response proteins such as programmed death-ligand 1. This high-throughput system enabled the identification of drugs including cytotoxic agents, molecular-targeted agents, and other agents that activate or suppress RIIR. Conclusions Our study provides an encyclopedic catalogue of clinically approved drugs based on their effect on RIIR. In ICIs combined radiotherapy, activation of STING-IFN may improve the therapeutic effect and our result could form a biological basis for further clinical trials combining radiotherapy with ICIs.

Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety.Clinical trial registration: jRCTs071200002

Aprepitant is used with dexamethasone and 5-HTUrinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers.The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy.CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

Background: The efficacy of osimertinib as a first-line treatment for patients with poor performance status (PS) remains unclear. Patients & methods: This multicenter retrospective study evaluated patients treated with osimertinib between 2018 and 2020, with PS 2–4. Results: Among 36 patients with PS 2, the median progression-free survival (PFS), 1-year PFS, median overall survival (OS) and 1-year OS were 14.5 months, 65.4%, 18.1 months and 72.7%, respectively. Among 20 patients with PS 3–4, the median PFS, 1-year PFS, median OS and 1-year OS were 3.0 months, 27.1%, 5.0 months and 46.1%, respectively. Conclusion: Osimertinib was not as efficacious as other EGFR-tyrosine kinase inhibitors.

Introduction Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti–programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression. Methods We retrospectively reviewed patients with advanced NSCLC treated with anti–PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti–PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing. Results Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score Conclusions Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti–PD-1/PD-L1 therapy.

Introduction The accelerated development of lung cancer treatments has resulted in a single global study that is sufficient for a new agent and indication to be approved. Not all new treatments predominate globally, and differences in standards of care may influence the efficacy of treatments in the real world. Methods The results from Japanese domestic trials and global trials that included a subset population of Japanese patients were evaluated for 18 genomic targeted agents and immune therapies approved after 2000. The results were collected from drug applications that were reviewed for treatment approval in Japan. Results Japan is one of the first countries to approve and fully reimburse new agents around the world. Alectinib and nivolumab, which were first developed by Japanese pharmaceutical companies, were evaluated in an independent domestic trial, which resulted in their early approval. For most other indications, 1.1–15.8% of the patients who participated in pivotal registration studies were Japanese, and their treatment results were comparable to those of the overall population. Overall survival was less likely to be improved by four agents for which the post-protocol therapy might have been different in Japan than in other countries. Conclusions Overall, a positive result in a global trial was emulated in Japanese patients and led to the approval of a new standard treatment in Japan. Early approvals were attained by either participating in the global registrational study or conducting a domestic phase II study. The higher efficacy of new agents may be an issue in the future, as Japanese patients had early access to the new agent and may receive better treatment after the trial.

BACKGROUND/AIM Programmed death-ligand 1 (PD-L1) expression on tumor cells is a predictive biomarker of programmed cell death 1 (PD-1) blockade therapy. This study sought to clarify predictors of the efficacy of nivolumab in non-small cell lung cancer (NSCLC) patients with PD-L1 expression-negative tumors. PATIENTS AND METHODS We retrospectively reviewed the records of advanced NSCLC patients between January 2016 and April 2019, and investigated the predictive marker of nivolumab including the status of CD8+ tumor infiltrating lymphocytes (TILs). RESULTS A total of 70 NSCLC patients were included. Overall response rate (ORR) and progression-free survival (PFS) were better in patients with a heavy smoking history (smoking index: SI≥600) than in those without (SI

The severity and asscociated mortality of coronavirus disease 2019 (COVID-19) are higher in patients with thoracic cancer than in healthy populations and those with other cancer types. Here, we investigated real-world data on the incidence of COVID-19 and false-negative cases using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing in patients with thoracic cancer. We retrospectively reviewed patients with advanced thoracic cancer at the National Cancer Center Hospital between March 2020–May 2021. Blood samples were collected and evaluated for IgM and IgG antibodies specific for nucleocapsid (N) and spike (S) protein SARS-CoV-2 before and after rRT-PCR testing. False-negative cases were assessed based on anti-SARS-CoV-2 antibody levels before and after rRT-PCR testing. A total of 2,107 patients with thoracic cancer were identified between March 2020 and May 2021, 7 (0.3%) of whom developed COVID-19. Among the 218 patients who underwent at least one rRT-PCR test because of suspected COVID-19 symptoms or as a screening test at our institute, the most common diagnosis was non-COVID-19 pneumonia (34.4%), followed by tumor fever (30.7%). Furthermore, of the 218 patients, 120 paired serum samples before and after rRT-PCR testing were available. Seroconversion was identified in all three patients with positive SARS-CoV-2 rRT-PCR results but was only observed in 1 out of the 117 patients who tested negative; the rate of false-negative cases was low (0.9%). COVID-19 incidence among patients with advanced thoracic cancer was low during the early phase of the pandemic in Japan.