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Background: Thymic carcinoma is a very rare neoplasm for which no optimal chemotherapeutic regimen has been established to date. Hence, we performed this study to investigate the efficacy and safety of carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel as a first-line regimen for patients with advanced thymic carcinoma.Patients and methods: We conducted this multi-institutional retrospective cohort study of patients with advanced thymic carcinoma who had received carboplatin plus nab-paclitaxel as a first-line chemotherapy between August 2013 and December 2021. Results: Twelve patients were included in this study and were subjected to efficacy and safety analysis. Their median age was 62 years (range, 47–74 years), and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. After a median follow-up time of 19.7 months, the overall response rate was 50%; the median progression-free and overall survival times were 8.8 months and 23.3 months, respectively. Chemotherapy-related peripheral neuropathy was observed in 2 patients (16%; each with grade 1). Other toxicities were manageable, and there were no treatment-related deaths.Conclusion: Carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen showed good efficacy and safety in patients with advanced thymic carcinoma.

Purpose: The addition of cytotoxic chemotherapy to immune-checkpoint inhibitor (ICI) may enhance antitumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison with nivolumab monotherapy for previously treated ICI-naïve non–small cell lung cancer (NSCLC). Patients and Methods: The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. As ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued. Results: One hundred twenty-eight patients (each arm, n = 64) were included in the full analysis set. The median OS in nivolumab (arm A) and nivolumab + docetaxel (arm B) was 14.7 months (95% CI, 11.4–18.7) and 23.1 months (95% CI, 16.7–NR), respectively. The HR for OS was 0.63 (90% CI, 0.42–0.95; P = 0.0310). The median PFS in arms A and arm B was 3.1 months (95% CI, 2.0–3.9) and 6.7 months (95% CI, 3.8–9.4), respectively. The HR for progression was 0.58 (95% CI, 0.39–0.88; P = 0.0095). The ORR was 14.0% (95% CI, 6.3–25.8) in arm A and 41.8% (95% CI, 28.7–55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis and one in arm B who died of myocarditis. Conclusions: Despite a slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.

Introduction Immune checkpoint inhibitors (ICI) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated. Methods Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of the ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed for evaluation of their clinical significance. Results The Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95%CI 1.10–86.7, P = 0.009) and overall survival (OS; HR 11.4, 95%CI 1.19–52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122), but not in those treated with ICI combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95%CI 0.06–0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95%CI 1.42–21.0, P = 0.008) and OS (HR 42.6, 95%CI 6.83–226, P

Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. Methods: We evaluated 340 patients with NSCLC harboring sensitive EGFR mutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan–Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). Results: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (P=0.03, P=0.001, respectively) or 2 (P

Supplementary Data from A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non–Small Cell Lung Cancer: TORG1630

Purpose:The addition of cytotoxic chemotherapy to immune-checkpoint inhibitor (ICI) may enhance antitumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison with nivolumab monotherapy for previously treated ICI-naïve non–small cell lung cancer (NSCLC).Patients and Methods:The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. As ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued.Results:One hundred twenty-eight patients (each arm, n = 64) were included in the full analysis set. The median OS in nivolumab (arm A) and nivolumab + docetaxel (arm B) was 14.7 months (95% CI, 11.4–18.7) and 23.1 months (95% CI, 16.7–NR), respectively. The HR for OS was 0.63 (90% CI, 0.42–0.95; P = 0.0310). The median PFS in arms A and arm B was 3.1 months (95% CI, 2.0–3.9) and 6.7 months (95% CI, 3.8–9.4), respectively. The HR for progression was 0.58 (95% CI, 0.39–0.88; P = 0.0095). The ORR was 14.0% (95% CI, 6.3–25.8) in arm A and 41.8% (95% CI, 28.7–55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis and one in arm B who died of myocarditis.Conclusions:Despite a slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.

Supplementary Figure from A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non–Small Cell Lung Cancer: TORG1630

Purpose An increasing number of advanced non–small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters. Patients and methods The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and β of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs. Results The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed. Conclusions An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. Methods: We evaluated 340 patients with NSCLC harboring sensitive EGFRmutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan–Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). Results: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (P=0.03, P=0.001, respectively) or 2 (PPConclusions: The GPS predicted the survival of NSCLC patients harboring sensitive EGFRmutations who were undergoing EGFR-TKI treatment. The GPS might be ideal for routine use in clinical practice, given that it is an easily calculated parameter.

Introduction: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors. Methods: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, body mass index (BMI), and each of progression-free survival (PFS) and overall survival (OS) were assessed. Results: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI 2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, p = 0.002) and 2 (1.8 months, p = 0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, p = 0.002) and 2 (4.7 months, p = 0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1–2 (26.2% vs. 7.9%, p = 0.03). Conclusion: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy.

Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged >75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75-87) years; male/female ratio, 70/29; performance status (PS) 0-1/2-3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I-III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS Conclusion: In older adults aged >75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Citation Format: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada. Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2797.

Lung cancer is the most common cause of cancer-related death globally. In addition, its incidence increases with age, with approximately half of all cases diagnosed in patients aged ≥70. Molecular targeted therapies and immunotherapies for advanced non-small-cell lung cancer have markedly improved outcomes over the past two decades. Despite the high incidence of lung cancer in older people, most trials excluded such patients from enrollment. Therefore, the optimal treatment strategies for older patients remain unclear. The present review summarizes the published literature and provides guidance on the treatment of older patients with lung cancer within three broad stages: (i) early-stage lung cancer, (ii) locally advanced lung cancer and (iii) metastatic lung cancer. We also discuss the use of the latest evidence for older patients.

Lung cancer is the leading cause of cancer-related death worldwide, among which high-grade neuroendocrine tumors including small-cell lung cancer (SCLC) and pulmonary large-cell neuroendocrine carcinoma (LCNEC) are especially aggressive with a dismal prognosis. Although molecular subtypes of SCLC based on the expression of lineage transcription factors such as ASCL1, NEUROD1, POU2F3 and YAP1 have been identified and explored recently, LCNEC has not been well characterized so far, and in clinic, patients with LCNEC have been treated with both chemotherapy regimens for SCLC and regimens for non-small cell lung cancer. To make efficient treatment strategies for LCNEC, further advances in molecular characterization of LCNEC are warranted. Therefore, in this study, we aimed to elucidate the heterogeneity of neuroendocrine differentiation in lung cancer with LCNEC components by using epigenomic profiling. We investigated super-enhancer profiles of 24 formalin-fixed paraffin-embedded tumor tissues from patients with primary lung cancer containing LCNEC components. Unsupervised hierarchical clustering of these specimens using H3K27 acetylation signals over super-enhancer regions near transcriptional regulators identified four distinct clusters. Principal component analysis supported this classification. Immunohistochemical staining for ASCL1, NEUROD1, POU2F3 and YAP1 on these tissues was also performed and the staining results were compatible with our epigenomic profiling. Cluster 1 tissues were positive for ASCL1 and NKX2-1 while the high expression of POU2F3 or YAP1 was found in some samples among Cluster 3 and Cluster 4. None of the four transcription factors were positive in Cluster 2. Additional genomic profiling revealed no clear associations between the clusters and genetic alterations such as RB1 loss and STK11 loss. Neuroendocrine markers synaptophysin, chromogranin A and CD56 were found to be more commonly positive in tissues among Cluster 1. These findings suggest the existence of the distinct differentiation subtypes of lung cancer with LCNEC components, different from the previously reported classifications, which provides new insight into the regulation of neuroendocrine differentiation in lung cancer. Citation Format: Takashi Sato, Junko Hamamoto, Katsura Emoto, Takahiro Fukushima, Kai Sugihara, Masayuki Shirasawa, Yoshiro Nakahara, Satoshi Igawa, Yoshiki Murakumo, Takashi Kohno, Kouya Shiraishi, Hiroyuki Yasuda, Kenzo Soejima, Hideo Watanabe, Katsuhiko Naoki. Epigenomic profiling identifies distinct neuroendocrine subtypes in lung cancer with neuroendocrine differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5715.