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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.

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

Background Osimertinib monotherapy is currently the standard of care as a first-line treatment for patients harboring epidermal growth factor receptor (EGFR) mutations; however, some EGFR-mutated non-small cell lung cancer (NSCLC) patients exhibit primary resistance and an insufficient response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Elevated programmed death-ligand 1 (PD-L1) expression in tumors was reported as a negative predictive factor for outcomes of first- or second-generation EGFR-TKIs. Methods We prospectively assessed advanced NSCLC patients with EGFR mutations who were treated with osimertinib at 14 institutions in Japan between September 2019 and December 2020. Relationships between outcomes of osimertinib monotherapy and patients' characteristics were reviewed. Results Seventy-one patients who underwent the tumor PD-L1 test were enrolled. Multivariate analysis identified tumor PD-L1 expression as an independent predictor for progression-free survival (PFS) with osimertinib treatment (P=0.029). The objective-response and disease-control rates for osimertinib treatment were significantly lower in patients demonstrating elevated PD-L1 levels relative to those with low or negative PD-L1 level (P=0.043 and P=0.007, respectively). Furthermore, among patients treated with osimertinib, those with high PD-L1 levels exhibited shorter PFS relative to those with low plus negative PD-L1 level (median PFS: 5.0 vs. 17.4 months; P Conclusions Elevated tumor PD-L1 expression is associated with poor outcomes of osimertinib monotherapy in previously untreated advanced NSCLC patients with EGFR mutation. Further clinical trials are warranted to accumulate evidence demonstrating the effectiveness of combination therapy with osimertinib for EGFR-mutated advanced NSCLC patients with elevated tumor PD-L1 expression. Trial registration UMIN000043942.

Background Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next‐generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM. Methods Eligible patients with MPM having adequate organ function and a performance status of 0–2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m2 AMR on days 1–3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression‐free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints. Results This trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2–11.2) months, and the median OS was 9.1 (range, 6.2–22.0) months. The median number of treatment cycles was three (range, 2–11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia. Conclusions Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM., Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM.

IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum‐based chemotherapy as first‐line treatment for advanced non‐small‐cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open‐label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non‐squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co‐primary study endpoints were overall survival (OS) and investigator‐assessed progression‐free survival (PFS) per RECIST 1.1 in the intention‐to‐treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7‐30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36‐1.14]). PFS was 12.8 (95% CI, 8.6‐16.6) mo in the APP arm vs 4.5 (95% CI, 4.1‐6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21‐0.58]). Grade 3/4 treatment‐related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum‐based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs., The global phase 3 IMpower132 study evaluated atezolizumab plus pemetrexed and platinum‐based chemotherapy vs chemotherapy alone for first‐line treatment of advanced non‐squamous NSCLC. A subgroup analysis of 101 Japanese patients showed that atezolizumab plus chemotherapy was well tolerated in these patients and provided overall treatment benefit vs chemotherapy alone. These results are consistent with the global study.

Background A history of radiotherapy and chemoradiotherapy (CRT) reportedly increases the efficacy of the PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC). We investigated the efficacy of anti-PD-(L)1 therapy after CRT failure and how CRT changes the status of PD-L1 expression on tumours and on tumour-infiltrated lymphocytes (TILs). Methods We retrospectively reviewed patients with unresectable locally advanced NSCLC (LA-NSCLC) who were treated with CRT between 2007 and 2018 and evaluated the efficacy of the PD-(L)1 blockade after CRT failure. We also compared the PD-L1 (clone: 22C3) expression levels and the tumoral and stromal distributions of CD8-positive TILs using paired formalin-fixed, paraffin-embedded specimens obtained before and after CRT. Results We identified 422 patients and 65 patients who had relapsed after CRT received anti-PD-(L)1 therapy. The objective response rate (ORR) and the progression-free survival (PFS) after anti-PD-(L)1 therapy were 48% and 8.7 months (95% CI, 4.5–13), respectively. The RR and PFS did not differ according to the pre-CRT PD-L1 expression levels. PD-L1 expression changed in 16 of the 18 patients between before and after CRT, but a specific trend was not seen (increased, 9 patients; decreased, 7 patients; no change, 2 patients). In contrast, the density of tumoral CD8-positive TILs increased after CRT treatment (pre-CRT median, 110/mm2 versus post-CRT median, 470/mm2; p = 0.025). Conclusions Anti-PD-(L)1 therapy was effective in patients with LA-NSCLC who had progressed after CRT regardless of their pre-CRT PD-L1 expression. The efficacy of anti-PD-(L)1 therapy for patients with NSCLC with CRT failure was superior to that of standard second-line treatment for patients with advanced NSCLC.

Background Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database. Patients and Methods Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival. Results Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P = 0.047), and hypoalbuminemia (P = 0.0021) were identified as prognostic factors in a multivariate analysis. Conclusion The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.

Objectives Immune checkpoint inhibitors (ICIs) have shown antitumor activity against a wide variety of malignancies. ICI-induced immune-related thrombocytopenia is a rare immune-related adverse event (irAE). Little is known about the treatment of refractory immune-related thrombocytopenia in non-small cell lung cancer (NSCLC) patients treated with pembrolizumab. Results We report the case of a patient with advanced NSCLC complicated by pembrolizumab-induced refractory immune-related thrombocytopenia who showed remarkable improvement in the thrombocytopenia in response to eltrombopag olamine treatment. Conclusion Eltrombopag olamine can be a viable treatment option for refractory pembrolizumab-induced immune-related thrombocytopenia in an NSCLC patient.

Due to antiretroviral therapy, human immunodeficiency virus (HIV) patients and non-HIV patients have a similar life expectancy. The leading cause of death among HIV patients is lung cancer. However, clinical toxicities with immune checkpoint inhibitors, including durvalumab, in HIV-positive patients with non-small cell lung cancer (NSCLC) remain unknown. We report a 45-year-old Japanese HIV patient, who was safely treated with durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) for locally advanced NSCLC without significant toxicities until his disease progressed. This case demonstrates the safety of durvalu­mab consolidation therapy for HIV-positive patients after CCRT for locally advanced NSCLC.

The development of PD-1 pathway inhibitors has dramatically altered the treatment of advanced/recurrent non-small-cell lung cancer patients. However, the prognostic significance of their ongoing usage is controversial, especially for patients who have not progressed for a period of time. If discontinuation has no negative impact on survival, suspension may reduce side effects from toxicity and help alleviate the economic burdens on health insurance systems and patients. This randomized controlled trial enrolls patients who have responded well to PD-1 pathway inhibitors for >12 months. The aim is to confirm the non-inferiority of discontinuation of PD-1 pathway inhibitors, relative to continuation, in terms of overall survival. A total of 216 patients will be enrolled over 3 years. This trial has been registered in the Japan Registry for Clinical Trials as jRCT1031190032 (https://jrct.niph.go.jp/). An ancillary study examining the prognostic and predictive role of circulating tumor DNA using Guardant360® is planned.

Simple Summary Thymic carcinoma is a rare cancer, and its biology remains largely unknown. Although complete surgical resection is a standard treatment for thymic carcinoma, systemic chemotherapy is frequently administered in metastatic or recurrent cases. Given the rarity, therapeutic agents are often confirmed on the basis of the results of phase II trials or retrospective studies. Platinum-based combination chemotherapy has long been employed for treating thymic carcinoma. Recently, biomarkers have been explored, and molecular profiles and major oncogenic pathways have gradually been revealed by next-generation sequencing, resulting in the development of targeted therapies. Moreover, clinical trials assessing combination therapy with immune checkpoint inhibitors are ongoing and are expected to be efficacious for treating thymic epithelial tumors. We reviewed the current role of systemic chemotherapy, including targeted therapies and immune checkpoint inhibitors, considering recent findings regarding its biology. Abstract Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National Comprehensive Cancer Network Guidelines. Metastatic and refractory thymic carcinomas require systemic pharmacotherapy. Combined carboplatin and paclitaxel, and cisplatin and anthracycline-based regimens have been shown a fair response rate and survival to provide a de facto standard of care when compared with other drugs employed as first-line chemotherapy. Cytotoxic agents have been pivotal for treating thymic carcinoma, as little is known regarding its tumorigenesis. In addition, genetic alterations, including driver mutations, which play an important role in treatments, have not yet been discovered. However, molecular pathways and biomarker studies assessing thymic epithelial tumors have been reported recently, resulting in the development of new agents, such as molecular targeted agents and immune checkpoint inhibitors. As treatment options are currently limited and the prognosis remains poor in metastases and recurrent thymic carcinoma, genetic alterations need to be assessed. In the present review, we focused on the current role of targeted therapies and immune checkpoint inhibitors in treating thymic carcinoma.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4–12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27–88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.

Introduction There are two treatment strategies for non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (tumor proportion score ≥ 50%): pembrolizumab plus chemotherapy and monotherapy. We retrospectively compared their efficacy and safety. Materials and methods We reviewed the efficacy and safety of first-line pembrolizumab-containing regimens administered between 2017 and 2020 to consecutive patients. The patients were divided into a pembrolizumab plus chemotherapy group (Combo group) or monotherapy group (Mono group). To compare the efficacy, we monitored the time to failure of strategy (TFS) defined as the time from the start of treatment to the occurrence of one of the following events: the addition of any drug not included in the primary strategy, progression of cancer after complete therapy, progression and no subsequent therapy, or death, whichever occurred first. We used the propensity score matching (PSM) to reduce the bias. Results A total of 126 patients were identified (89 in the Mono group and 37 in the Combo group). PSM matched 36 individuals from each of the two groups. The overall response rate and median progression-free survival of the Combo group were better than those of the Mono group. However, the median TFS was almost the same (11.3 months vs. 14.9 months; hazard ratio 1.40 [95% confidence interval 0.62–3.15]). The frequency of all serious adverse effects was higher in the Combo group than in the Mono group. Discussion Due to similar efficacy in TFS, both pembrolizumab plus chemotherapy and monotherapy are valid options for NSCLC.

BACKGROUND: Osimertinib exhibits good efficacy in patients with T790M-positive non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Compared with the clinical trials, in real-world clinical practice, osimertinib must be administered to older patients and those with poor Eastern Cooperative Oncology Group performance status (ECOG-PS). Therefore, we investigated the association between osimertinib efficacy/safety and PS score, age, and other clinical features in patients with T790M-positive NSCLC. METHODS: We reviewed all patients with T790M-positive NSCLC and acquired resistance to initial EGFR-TKIs who were administered osimertinib between March 2016 and January 2018 at the Tokyo Metropolitan Cancer and Infectious Diseases Center in Komagome Hospital, Japan. RESULTS: In total, 31 patients, including 8 young (

Background Few studies have investigated the clinical efficacy of third- and later-line of chemotherapy after standard chemotherapy for previously treated advanced non-small cell lung cancer (NSCLC). We prospectively evaluated the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) following standard chemotherapies for previously treated advanced NSCLC. Methods The eligible patients having adequate organ functions with performance status 0–2 were enrolled after completing standard chemotherapy. They received weekly nab-paclitaxel 100 mg/m2 intravenously on days 1, 8, and 15 every 3 weeks. The primary end point was objective response rate (ORR). Median progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated as secondary end points. Results This trial was discontinued because of late accrual. Twenty two patients were enrolled from April 2013 and February 2019. The total ORR was 22.7% [95% CI 7.8–45.4] and disease control rate (DCR) was 81.8% [95% CI 59.7–94.8]. Median PFS was 3.4 months [95% CI 2.3–4.1] and median OS was 7.4 months [95% CI 4.2–10.7]. Median follow-up interval was 6.7 months hematological AEs of Grade 3/4 included anemia (18%), leukopenia (18%), and neutropenia (32%), while the most frequent nonhematological AEs were fatigue (50%) and peripheral neuropathy (36.4%). Severe AEs related to treatment were observed in only one patient. Conclusion Nab-paclitaxel may be a safe and effective later-line chemotherapeutic option for previously treated advanced NSCLC after standard of chemotherapies based on other trials.

Objectives Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. Materials and Methods DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test. Results We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. Conclusion Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.

Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome. Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6 months, or (2) a body weight loss > 2% in patients with a body mass index

Background The efficacy of anti–programmed death receptor 1 (PD-1) therapy in patients with large cell neuroendocrine carcinoma (LCNEC) remains unclear. We investigated the outcome of anti–PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment. Patients We retrospectively reviewed patients with advanced LCNEC treated with systemic chemotherapy. We also evaluated PD ligand 1 (PD-L1) expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles. Results Seventy patients were enrolled, and 13 of 70 patients received anti–PD-1 therapy. The progression-free survival (PFS) and objective response rate (ORR) of the anti–PD-1 therapy were 4.2 months and 39%, respectively. The overall survival of patients treated with anti–PD-1 therapy (n = 13) was significantly better than those treated without anti–PD-1 therapy (n = 57) (25.2 months vs 10.9 months; P = .02). Among the 13 patients treated with anti–PD-1 therapy, 10 patients (90%) had PD-L1–negative tumors. Patients with a high density of tumoral CD8-positive TILs (≥38/mm2) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: P = .02; PFS: P = .003). Additionally, all 3 patients with TP53 mutation co-occurring with PIK3CA mutation (2 of 8 patients) or RB1 mutation (1 of 8 patients) responded to anti–PD-1 therapy. Conclusions Anti–PD-1 therapy was effective regardless of PD-L1 positivity in patients with advanced LCNEC. Our investigation might suggest that the density of tumoral CD8-positive TILs and the presence of co-occurring mutations are predictors of the efficacy of anti–PD-1 therapy in patients with advanced LCNEC.

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

Introduction Several studies have demonstrated that non-small cell lung cancer patients (NSCLCs) harboring epidermal growth factor receptor (EGFR) mutations have poor clinical outcomes in response to treatment with programmed death-1 (PD-1) inhibitors. However, it remains unclear whether EGFR-mutated NSCLCs with a high programmed death-ligand-1 (PD-L1) expression (tumor proportion score ≥ 50%) respond to PD-1 inhibitors. Methods We retrospectively investigated the NSCLCs who had received PD-1 inhibitors between January 2016 and December 2018 to assess the efficacy of PD-1 inhibitors in patients with an EGFR mutation and high PD-L1 expression. Results There were 153 patients with a high PD-L1 expression level, and the median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 1.3–12.4 months] in the patients with EGFR mutations (n = 17) and 8.3 months (95% CI 6.0–11.7 months) in those with wild-type EGFR (n = 136; hazard ratio (HR) 1.62; 95% CI 0.83–2.87). Among the 110 patients in the low PD-L1 expression group, the mPFS was 1.6 months (95% CI 1.3–5.9 months) in the patients with EGFR mutations (n = 18) and 3.8 months (95% CI 2.5–5.9 months) in those with wild-type EGFR (n = 92; HR 2.59; 95% CI 1.48–4.31). The HR for PFS in the group with EGFR mutations and high PD-L1 expression was 0.97 (95% CI 0.56–1.59) compared to the group with wild-type EGFR and low PD-L1 expression. Conclusions PD-1 inhibitors can serve as one of the treatment options for NSCLCs with an EGFR mutation and high PD-L1 expression.

Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative‐intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum‐based chemotherapy were enrolled. The patients received S‐1 orally twice daily at a dose of 40‐60 mg/m2 for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one‐sided). Twenty‐six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3‐46.9) and an 80.8% disease control rate (90% CI, 65.4‐90.3). The median PFS was 4.3 months (95% CI, 2.3‐10.3 months) and median OS was 27.4 months (95% CI, 16.6‐34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment‐related death was observed. S‐1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736)., Not a few patients of TC can be treated with S‐1 in a longer period. The toxicity of S‐1 was also acceptable. S‐1 is a promising drug for TC with easy accessibility and low cost.

Baseline tumor size (BTS) and the presence of massive lesions are important for predicting the clinical course of cancer. However, their impact on survival and clinical response in patients with advanced NSCLC undergoing immune checkpoint inhibitor (ICI) treatment has been scarcely investigated. We retrospectively reviewed 294 patients who underwent ICI therapy for advanced or recurrent non-small-cell lung cancer (NSCLC) between January 2016 and July 2019. Of these 294 patients, 284 (96.6%) had at least one measurable lesion. Of these, 263 patients treated with ICI monotherapy were included in the analysis. The median total and maximum target lesion diameters were 96.5 mm and 49.1 mm, respectively. Median progression-free survival (PFS) with massive lesions (max BTS > 50 mm, group A) and without massive lesions (max BTS ≤ 50 mm, group B) was 2.5 months (95% CI 1.8–3.7) and 6.7 months (95% CI 5.1–9.7), respectively. Median overall survival (OS) for groups A and B was 9.5 months (95% CI 5.5–12.3) and 20.0 months (95% CI 13.3–32.0), respectively. The multivariate analysis revealed marked associations between the presence of massive lesions and both PFS and OS. The presence of massive lesions (max diameters > 50 mm) is an independent prognostic factor in advanced NSCLC treated with ICI monotherapy. Although overall response rates were similar between groups A and B, the disease control rate was significantly poorer for group A. Max BTS might be useful for predicting clinical outcomes for patients undergoing immunotherapy as a parameter reflecting their tumor burden.

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

Polypharmacy is a common problem among older adults. However, its prevalence and impact on the clinical outcomes of anticancer treatment, such as survival and adverse events, in older patients with advanced cancer have not been well investigated. We retrospectively reviewed data from Japanese patients treated with an immune checkpoint inhibitor (ICI) for advanced or recurrent non-small-cell lung cancer (NSCLC) between 2016 and 2019. Among 157 older (aged ≥ 65 years) patients, the prevalence of polypharmacy, defined as ≥ 5 medications, was 59.9% (94/157). The prevalence of potentially inappropriate medication use, according to the screening tool of older people’s prescription (STOPP) criteria version 2, was 38.2% (60/157). The median progression-free survival (PFS) in patients with and without polypharmacy was 3.7 and 5.5 months, respectively (P = 0.0017). The median overall survival (OS) in patients with and without polypharmacy was 9.5 and 28.1 months, respectively (P

Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma.This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777.Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events.The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma.Center for Clinical Trials, Japan Medical Association.

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMIN000026777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

Metastasis of non-small cell lung cancer (NSCLC), indicating hematogenous dissemination, is more frequent in patients harboring epidermal growth factor receptor (EGFR) mutations, who respond dramatically to EGFR–tyrosine kinase inhibitors (TKIs). Based on the proposed association of miliary pulmonary metastasis and EGFR mutations in the previous studies, we conducted a retrospective study to assess survival of NSCLC with miliary pulmonary metastases in 223 patients harboring EGFR mutations who were treated with single agent EGFR–TKIs. Progression-free survival (PFS) and overall survival (OS) with single agent EGFR–TKIs were 11.7 months [95% confidence interval (CI) 9.6–13.7] and 23.7 months (95% CI 20.3–26.9), respectively. Patients with and without miliary pulmonary metastases were matched using propensity scores (n = 29 per group) based on clinical characteristics. After matching, the PFS were 8.2 months (95% CI 5.2–15.0) and 14.3 months (95% CI 9.6–30.0) (p = 0.02) in patients with and without miliary pulmonary metastases, respectively. Conversely, the OS were 15.3 months (95% CI 10.6–19.4) and 27.9 months (95% CI 22.0–33.0) (p = 0.003) in patients with and without miliary pulmonary metastases, respectively. By multivariate analysis, miliary pulmonary metastasis was associated with poor prognosis (p = 0.0035). The prognosis of patients with advanced NSCLC harboring EGFR mutations with miliary pulmonary metastasis demonstrated significantly worse outcomes compared to those without miliary pulmonary metastasis.

BACKGROUND The Oncomine™ Dx Target Test based on next-generation sequencing has been approved for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients. METHODS We assessed the tissue sample factors that affect the success rate of Oncomine™ Dx Target Test companion diagnostics and the feasibility of using biopsy specimens for Oncomine™ Dx Target Test companion diagnostics in advanced non-small-cell lung cancer patients. RESULTS Ninety-nine biopsy samples were subjected to genetic testing using the Oncomine™ Dx Target Test companion diagnostics to detect v-raf murine sarcoma viral oncogene homologue B1 mutations (Cohort 1), and 136 biopsy samples were examined using Oncomine™ Dx Target Test companion diagnostics for the detection of multiple oncogenic mutations (Cohort 2) between July 2018 and April 2020. We retrospectively collected clinical and pathological data, including tissue size and tumour cell content. The success rate was 77% (76/99) in Cohort 1 and 93% (127/136) in Cohort 2. In Cohort 1, the success rate was significantly associated with the tumour cell content: the success rate was 63% for samples with a tumour cell content of

Immune checkpoint inhibitors (ICIs) are becoming a standard therapy for non-small-cell lung cancer in the advanced stage. As these ICIs become widely available in clinical practice, immune-related adverse effects will become more common. Here we report a patient with lung adenocarcinoma who was treated with nivolumab and developed obstruction because of biliary inflammation. A 63-year-old Japanese man having lung adenocarcinoma with pleural dissemination complained of epigastric pain on the fifth cycle of nivolumab. Computed tomography showed wall thickening at the lower part of the bile duct and cholecystitis. Endoscopic retrograde cholangiopancreatography was repeatedly performed for drainage and stenting of the bile duct. Biopsies did not show obvious malignancy. Laboratory data on day 85 demonstrated grade 3 elevation of serum alkaline phosphatase, transaminase, and amylase levels. We initiated high-dose oral prednisone, resulting in gradual improvement of symptoms and laboratory data. Follow-up magnetic resonance cholangiopancreatography demonstrated no progression of duct obstruction, which confirmed the absence of biliary malignancy. Combined with results from previous reports, nivolumab may cause extrahepatic cholangitis.

Pazopanib, a multitargeting tyrosine kinase inhibitor, has single-agent activity in patients with advanced soft-tissue sarcoma. Herein, we describe 2 cases of pneumothorax that occurred during pazopanib treatment in patients with soft-tissue sarcoma. These 2 patients had multiple lung metastases. According to previous reports and our past experience, the risk of pneumothorax may be higher in patients with multiple lung metastases. Although a causal relationship is uncertain, the risk of pneumothorax when prescribing pazopanib for these patients should be considered.

The advent of antiretroviral therapy has changed the disease spectrum constitution among patients living with human immunodeficiency virus (HIV), while the incidence of death due to non-AIDS-defining cancers, particularly lung cancer, continues to increase in the USA and Europe. However, the availability of detailed reports of the clinical characteristics of lung cancer among Asian populations is limited. The present study retrospectively analyzed the clinical characteristics, treatment regimens and outcomes of lung cancer patients with HIV who were treated in a single institution between 1988 and 2013. Of the 20 lung cancer patients living with HIV included in this study, 90% were diagnosed since 1996 in the post-antiretroviral era. The median CD4+ cell count was 373.5/µl, whereas 65% of the patients were diagnosed with adenocarcinoma and 30% with squamous cell carcinoma. Epidermal growth factor receptor mutations were detected in 3 (27%) of the 11 specimens for which data were available, of which 65% had advanced-stage disease. Of the 20 patients, 9 underwent surgery, 6 received radiotherapy and 5 received chemotherapy as a first-line treatment. Treatment was generally well-tolerated. The median survival period was 35.8 months for all stages and 14.0 months for advanced stages. The treatment outcomes in our institution were favorable in comparison with previous studies from the USA and Europe, although these findings may be due to ethnic differences or the efficacy of treatment for HIV and lung cancer.

Although liver metastasis has been known to be associated with poor prognosis, only a few studies have shown an association between liver metastasis and treatment outcomes with immune checkpoint inhibitors (ICI). Furthermore, factors associated with prognosis have remained unclear. The present study therefore evaluates the efficacy of nivolumab, pembrolizumab, and atezolizumab among patients with non-small cell lung cancer (NSCLC) who had liver metastasis and identifies factors correlated with prognosis. A total of 215 patients with advanced and recurrent NSCLC who received ICI therapy at a single center were retrospectively reviewed. A total of 41 patients (19.1%) had liver metastasis upon initiation of ICI therapy. Overall, 125, 64, and 26 patients were treated with nivolumab, pembrolizumab, and atezolizumab, respectively. Among the included patients, those with liver metastasis had shorter overall survival (OS) [hazard ratio (HR), 2.04; 95% CI 1.33–3.13] and progression-free survival (PFS) (HR, 1.89; 95% CI 1.29–1.71) compared to those without the same. Patients with liver metastasis had a response rate (RR) of 22.5%. Among patients with liver metastasis, inferior OS was associated with low albumin, poor Eastern Cooperative Oncology Group performance status, driver mutation, and number of liver metastasis (≥ 5). Moreover, patients with liver metastasis who had good Royal Marsden Hospital (0–1) and Gustave Roussy Immune (0–1) scores showed significantly longer OS and PFS. Despite the poor outcomes with ICI treatment in patients with advanced and recurrent NSCLC who had liver metastasis, some characteristics among patients with liver metastasis may be associated with prognosis.

Background Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. Material and Methods We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. Results In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). Conclusion The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study.

Introduction: Soluble CD27 (sCD27) is associated with somatic immune reaction status. Moreover, sCD27 level is associated with the prognosis of patients with prostate cancer who receive immunotherapy. Objective: In this study, we assessed sCD27 levels in patients with advanced lung cancer and determined their correlation with survival and clinicopathologic parameters. Methods: Serum samples were collected from patients with advanced lung cancer, and sCD27 was quantified via enzyme-linked immunosorbent assay. The association between sCD27 levels and clinicopathologic status and patient survival was retrospectively analyzed. Results: Of 96 patients analyzed, 73 had adenocarcinoma, 7 had squamous cell carcinoma, and 15 had small cell carcinoma. Median serum sCD27 level was 36.54 U/mL (range, undetectable–104.47); this is lower than that previously reported for patients with lung cancer, including those with localized stages. Patients with squamous cell carcinoma had higher sCD27 levels (p = 0.010). Age, performance status, and serum albumin levels were significantly correlated with serum sCD27 level. Patients with high serum sCD27 levels (≥32.52 U/mL; n = 58) had poorer prognosis than those with low serum sCD27 levels (n = 38; median survival, 7.3 vs. 21.8 months, respectively, p< 0.0001). Conclusions: High sCD27 level is associated with poor prognosis and may reflect the immune-exhausted status of patients with advanced lung cancer.

Nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1), is the standard second-line therapy for advanced non-small cell lung cancer (NSCLC). In the current immunotherapy era, it is often difficult to evaluate the therapeutic effect, disease progression, and pseudo-enlargement of the tumor or the emergence of another etiology. In the present report, we describe a 79-year-old patient with hepatocellular carcinoma (HCC) newly detected during nivolumab treatment for recurrent NSCLC. When the patient was 73 years old, he had suffered from NSCLC and received concurrent chemoradiotherapy comprising cisplatin and docetaxel, achieving a complete response. Six years after the chemoradiotherapy, the patient had multiple lung and hepatic lesions. We thus started the treatment with nivolumab for recurrent NSCLC. All those lesions responded to nivolumab over nine cycles. By contrast, a lesion was newly detected in the medial segment of left hepatic lobe, liver segment 4 (S4), and was gradually getting larger, as judged by computed tomographic scan. Liver biopsy revealed the growing lesion to be a well-differentiated HCC. Consequently, the patient was treated with radiofrequency ablation to HCC, while nivolumab treatment was continued for NSCLC. Immunohistochemical analysis of the HCC specimens revealed nuclear accumulation of β-catenin compared with normal liver cells and undetectable expression of program death ligand 1 (PD-L1). Such expression profiles of β-catenin and PD-L1 in HCC may be responsible for the resistance against nivolumab treatment. Immunohistochemical features of the biopsy specimens may be predictive of the effectiveness of the immunotherapy in HCC.

Previously, the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab (BEV) was investigated. A subgroup analysis of the IMpower150 trial, which investigated the combination of atezolizumab, carboplatin, paclitaxel, and bevacizumab (ABCP), demonstrated the benefit of ABCP in patients harboring EGFR mutations. This study aims to assess the prognostic significance of the qualification for BEV use and the proportion of patients who potentially benefit from BEV-containing combination therapy before and after initial EGFR-TKI treatment. We retrospectively analyzed the data of 297 patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations who had received EGFR-TKIs. We performed statistical analyses using the Kaplan–Meier method and the Cox regression adjusted for risk factors. Of the 297 patients, 203 (68%) were eligible to receive BEV (“BEV fit”) at the time of EGFR-TKI initiation. Among the “BEV unfit” patients at baseline (n = 70), 14 (20%) became eligible to receive ABCP (“ABCP fit”) at the time of EGFR-TKI failure. The median overall survival (OS) of the “BEV fit” and “BEV unfit” patients was 26.2 [95% confidence interval (CI) 23.7–31.2] and 19.1 (95% CI 15.0–25.1) months, respectively (P

The pathological diagnosis of lung cancer has largely been based on the morphological features observed microscopically. Recent innovations in molecular and genetic technology enable us to compare conventional histological classifications, protein expression status, and gene abnormalities. The introduction of The Cancer Genome Atlas (TCGA) project along with the widespread use of the next-generation sequencer (NGS) have facilitated access to enormous data regarding the molecular profiles of lung cancer. The World Health Organization classification of lung cancer, which was revised in 2015, is based on this progress in molecular pathology; moreover, immunohistochemistry has come to play a larger role in diagnosis. In this article, we focused on genetic and epigenetic abnormalities in non-small cell carcinoma (adenocarcinoma and squamous cell carcinoma), neuroendocrine tumor (including carcinoids, small cell carcinoma, and large cell neuroendocrine carcinoma), and carcinoma with rare histological subtypes. In addition, we summarize the therapeutic targeted reagents that are currently available and undergoing clinical trials. A good understanding of the morphological and molecular profiles will be necessary in routine practice when the NGS platform is widely used.

Background S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. Methods Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1–14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4–6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). Results From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9–8.7), 21.4 months (95% CI: 14.7—not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. Conclusions S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.

9061 Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.[Table: see text]

Background: Biomarkers that enable objective evaluation of the clinical effects of immunotherapy for allergic rhinitis have yet to be identified. Methods: This study included 40 patients who were enrolled in a large randomized, double-blind, placebo-controlled, multicenter study examining the efficacy of sublingual immunotherapy (SLIT) using Japanese cedar (JC) pollen extract during two consecutive pollen seasons from 2010 to 2012. Based on changes in total nasal symptom medication score, patients in the SLIT and placebo groups were subdivided into two subgroups: good responders and poor responders. The levels of JC pollen-specific IL-10+Foxp3+ cells and specific Th2 cytokine-producing cells were measured and the association with the efficacy of SLIT was analysed. Results: The total nasal symptom medication score was significantly lower in the SLIT group compared with the placebo group. The number of JC pollen-specific Th2 cytokine-producing cells increased during the pollen season in the placebo group and in poor responders in the SLIT group; however, the increases were inhibited in the good responders in the SLIT group. The number of JC pollen-specific IL-10+Foxp3+ cells increased only in these good responders. Conclusions: Changes in levels of allergen-specific Th2 cytokine-producing cells and IL-10+Foxp3+ cells could be objective biomarkers for SLIT.

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy. Folic acid and vitamin B12 were given orally for ˃1 week before pemetrexed administration. The primary end-point was onset of a grade ≥3 neutropenia ratio (50 % of threshold expression ratios; an expectation expression ratio of 21 %; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180). A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥3 neutropenia was 36 % (95 % CI 22–52 %). Grade ≥3 non-hematologic toxicity and hematologic toxicity were seen in 20 % (5 cases) and 44 % (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2–3 cycle. This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

Thymic epithelial tumors are rare malignancies, and their pathological classification has been refined for many times. In 1961, Bernatz et al . have subtyped thymic malignancies according to lymphocytes and epithelial component; however, the concept of thymic carcinoma was not introduced (1).

BACKGROUND: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. METHODS: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. RESULTS: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). CONCLUSIONS: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients. Citation Format: Rui Kitadai, Akihiro Yoshimura, Tadaaki Yamada, Yusuke Okuma, Takayuki Takeda, Takanori Kanematsu, Junji Uchino, Yasuhiko Nishioka, Koichi Takayama. Retrospective analysis of docetaxel in combination with ramucirumab for previously treated non-small cell lung cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4306.

e21719 Background: Chemoradiotherapy (CRT) followed by durvalumab as maintenance therapy prolonged progression-free survival (PFS) and overall survival (OS) in unresectable locally advanced NSCLC (LA-NSCLC). Additionally, the history of radiotherapy and CRT has been reported to increase the efficacy of PD-1 blockade in advanced NSCLC patients. We evaluated the efficacy of anti-PD-(L)1 antibody therapy after CRT failure, and how CRT changes the status of PD-L1 expression on tumors and tumor infiltrated lymphocytes (TILs) in tumor microenvironment (TME) in unresectable LA-NSCLC patients. Methods: We retrospectively reviewed unresectable LA-NSCLC patients treated with CRT between December 2007 and December 2018, and evaluated the efficacy of PD-1 blockade after CRT failure. We also analyzed PD-L1 (clone: 22C3) expression on tumor cells, and CD8 positive TILs using the paired specimens that had been obtained pre-CRT and post-CRT failure. Results: We identified 422 patients who received CRT. Median follow-up was 36.1 months (range 2.7–138.1 months). Among these patients, sixty-five patients who had progressed post-CRT received anti-PD- (L)1 therapy (PD-1 therapy: 61 patients, PD-L1 therapy: 4 patients). Response rate (RR) and PFS of anti-PD-(L)1 therapy were 48% (95% CI, 35–60) and 8.7 (95% CI, 4.5–13.0) months. The RR and PFS did not differ according to PD-L1 expression levels (Table). Of the 18 patients, 9, 7, and 2 showed upregulation in PD-L1 expression or down- or no change, respectively, post-CRT. In contrast, the density of CD8 positive TILs in TME increased by CRT treatment ([pre-CRT]: median, 110 ± 239 /mm2 vs. [post-CRT]: median, 470 ± 533 /mm2, p = 0.025). Conclusions: The clinical outcome of anti-PD-(L)1 therapy after CRT failure in LA-NSCLC patients could be better than advanced NSCLC patients, but did not differ according to PD-L1 expression levels. The efficacy of PD-(L)1 therapy enhanced by CRT treatment could be due to the infiltration of CD8 T-cells into TME. [Table: see text]

44 Background: Cancer cachexia is known to a multifactorial catabolic syndrome and is observed 15-40% in general cancer population with worse prognosis. A recent study suggested a shorter survival period in non-small cell lung cancer (NSCLC) patients with a higher pembrolizumab clearance associated with cachexia. We here conducted analyses for the clinical impact of cachexia in advanced NSCLC treated with pembrolizumab. Methods: We evaluated consecutive advanced NSCLC patients who received pembrolizumab between March 2017 and December 2018 at the National Cancer Center Hospital. Cachexia was defined as a body weight loss >5% over the past 6 months or >2% in patients with a BMI