Yusuke Kunimatsu’s research while affiliated with Kyoto Prefectural University of Medicine and other places

Simple Summary Sarcopenia refers to a progressive and systemic reduction in skeletal muscle mass and strength and is a primary component of cancer cachexia. This retrospective study examined the impact of the rate of muscle loss between two time points during the pretreatment period with concurrent chemoradiotherapy on the clinical outcomes during subsequent durvalumab maintenance treatment. As the results showed, patients who experienced psoas muscle loss during chemoradiotherapy had a shorter progression-free survival and experienced reduced effectiveness of durvalumab treatment. This study highlights the importance of monitoring psoas muscle changes during chemoradiotherapy to predict the success of subsequent durvalumab therapy better in non-small cell lung cancer patients. Abstract Sarcopenia assessed at a single time point is associated with the efficacy of immunotherapy, and we hypothesized that longitudinal changes in muscle mass may also be important. This retrospective study included patients with non-small cell lung cancer (NSCLC) who received durvalumab treatment after concurrent chemoradiotherapy (CCRT) between January 2017 and April 2023. Muscle loss and sarcopenia were assessed based on the lumbar skeletal muscle area. Patients with a decrease in muscle area of 10% or more during CCRT were categorized into the muscle loss group, while those with a decrease of less than 10% were categorized into the muscle maintenance group. We evaluated the relationship between muscle changes during CCRT and the efficacy of durvalumab treatment. Among the 98 patients, the muscle maintenance group had a significantly longer PFS of durvalumab treatment compared to the muscle loss group (29.2 months [95% confidence interval (CI): 17.2—not reached] versus 11.3 months [95% CI: 7.6–22.3]; p = 0.008). The multivariable analysis confirmed that muscle change was a significant predictor of a superior PFS (HR: 0.47 [95% CI: 0.25–0.90]; the p-value was less than 0.05). In contrast, the OS between the groups did not differ significantly (not reached [95% CI: 21.8 months—not reached] and 36.6 months [95% CI: 26.9—not reached]; p = 0.49). Longitudinal muscle changes during CCRT are a predictor of durvalumab’s efficacy in patients with NSCLC after CCRT.

Background: Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant NSCLC and osimertinib resistance has not yet been fully evaluated. Objective: We aimed to conduct a prospective multicenter observational study to evaluate the efficacy and safety of 1G and 2G EGFR-TKIs after the development of osimertinib resistance. Methods: Patients with EGFR-mutant NSCLC who received 1G or 2G EGFR-TKIs after developing resistance to osimertinib monotherapy were prospectively assessed at eight institutions in Japan. The primary endpoint was progression-free survival (PFS). Results: A total of 29 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. The objective response and disease control rates were 6.9% (2/29) and 58.6% (17/29), respectively. The median PFS was 1.9 months [95% confidence interval (CI): 1.3-5.3]. There was no significant difference in PFS between the 1G and 2G EGFR-TKI groups (3.7 versus 1.5 months, log-rank test p = 0.20). However, patients with normal cytokeratin 19 fragment (CYFRA 21-1) and pro-gastrin-releasing peptide (ProGRP) levels experienced longer PFS than those with elevated CYFRA 21-1 and/or ProGRP (5.5 versus 1.3 months, log-rank test p < 0.001). Conclusion: Administration of 1G or 2G EGFR-TKIs after the development of osimertinib resistance has limited efficacy in patients with EGFR-mutant NSCLC. Moreover, normal CYFRA 21-1 and ProGRP levels could be promising indicators for 1G and 2G EGFR-TKI administration after osimertinib resistance development. Trial registration number: UMIN000044049.

The incidence rate of pseudoprogression during immune checkpoint inhibitor monotherapy for non-small cell lung cancer is reportedly 3.6%-6.9%, while pseudoprogression during chemoimmunotherapy is rare. Reports on pseudoprogression during dual immunotherapy combined with chemotherapy are lacking. Herein, a 55-year-old male with invasive mucinous adenocarcinoma (cT2aN2M1c [OTH, PUL], stage IVB, and programmed death-ligand 1 expression <1%), renal dysfunction, and disseminated intravascular coagulation was treated with carboplatin, solvent-based paclitaxel, nivolumab, and ipilimumab. After treatment initiation, computed tomography (CT) on day 14 showed disease progression. The patient was diagnosed with pseudoprogression because of a lack of symptoms, improved platelet count, and decreased fibrin/fibrinogen degradation product levels. CT on day 36 showed a reduction in the primary lesion size, multiple lung metastases, and mesenteric metastases. Therefore, pseudoprogression should be considered during dual immunotherapy with chemotherapy.

Simple Summary Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials, which set the age-stratified subgroup analyses at 65 years. Considering the super-aged society of Japan, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be validated through real-world Japanese evidence. Consecutive 225 Japanese patients with SCLC were evaluated, and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The dose reduction at initiating the first cycle was significantly higher in the elderly (47.4%) than in the non-elderly (20.4%) patients (p = 0.03). The median PFS and OS in the non-elderly and the elderly were 5.1 and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate analyses revealed that age, the baseline Eastern Cooperative Oncology Group performance status, and dose reduction at initiating the first chemoimmunotherapy cycle were not correlated with PFS or OS. Abstract Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung cancer were newly diagnosed at ≥75 years in Japan. Therefore, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be evaluated through real-world Japanese evidence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated with chemoimmunotherapy were divided into the non-elderly (<75 years) and elderly (≥75 years) groups, and efficacy, including PFS, OS, and post-progression survival (PPS) were evaluated. In total, 225 patients were treated with first-line therapy, and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The median PFS and OS in non-elderly and elderly were 5.1 and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate analyses revealed that age and dose reduction at the initiation of the first chemoimmunotherapy cycle were not correlated with PFS or OS. In addition, patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) = 0 who underwent second-line therapy had significantly longer PPS than those with ECOG-PS = 1 at second-line therapy initiation (p < 0.001). First-line chemoimmunotherapy had similar efficacy in elderly and non-elderly patients. Individual ECOG-PS maintenance during first-line chemoimmunotherapy is crucial for improving the PPS of patients proceeding to second-line therapy.

Large‐cell neuroendocrine carcinomas (LCNECs), categorized as high‐grade neuroendocrine carcinomas, account for approximately 3% of resected lung cancers. LCNECs containing other components are called ‘combined LCNECs’ and have no standard treatment. A 73‐year‐old male with a metastatic brain tumour from a combined LCNEC of the lung containing adenocarcinoma and sarcomatoid components was referred to our department. The patient was treated with chemotherapy consisting of carboplatin and nanoparticle albumin‐bound (nab)‐paclitaxel in combination with atezolizumab, which was decided in accordance with the histological evaluation of the components. This treatment resulted in partial response and remained durable for 12 months with an ongoing regimen. The current case suggests that the constituents of chemoimmunotherapy should be selected in accordance with the reported efficacy of relevant regimens for each component of the combined LCNEC. This study reports the case of a patient with combined large‐cell neuroendocrine carcinoma (LCNEC) whose symptoms were due to brain metastasis. Because the histological findings of the resected brain tumour and transbronchial biopsy specimen suggested combined LCNEC with a mixture of adenocarcinoma and sarcomatoid components, atezolizumab in combination with carboplatin and nanoparticle albumin‐bound (nab)‐paclitaxel was selected as the first‐line treatment regimen. This treatment resulted in partial response and remained durable for 12 months with an ongoing regimen.

Introduction: Cancer patients have been prioritized for vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there are limited data regarding the safety, efficacy, and risk of developing immune-related adverse events (irAEs) associated with mRNA vaccines in patients with lung cancer, especially those being actively treated with immune checkpoint inhibitors (ICIs). Methods: This multicenter prospective cohort study was conducted at nine hospitals in Japan. Patients with lung cancer (≥20 years) actively treated with ICIs between 4 weeks pre-first vaccination and 4 weeks post-second vaccination were enrolled. The primary endpoint was the incidence of irAEs of any grade based on an assumed incidence without vaccination rate of 35%. Immunogenicity was assessed by measuring anti-spike (S)-IgG antibody levels against SARS-CoV-2. Results: A total of 126 patients with lung cancer (median age, 71 years; interquartile range, 65-74) were enrolled from May to November 2021 and followed up until December 2021. Twenty-six patients (20.6%, 95% CI: 13.9-28.8%) and seven patients (5.6%, 95% CI: 2.3-11.1%) developed irAEs of any grade pre- and post-vaccination, respectively, which was lower than the predicted incidence without vaccination. None of the patients experienced exacerbation of pre-existing irAEs post-vaccination. S-IgG antibodies were seroconverted in 96.7% and 100% of the patients with lung cancer and controls, respectively, but antibody levels were significantly lower in lung cancer patients (P<0.001). Conclusions: Patients with lung cancer who were actively treated with ICIs were safely vaccinated without an increased incidence of irAEs; however, their vaccine immunogenicity was lower. This requires further evaluation.

Pulmonary pleomorphic carcinoma (PPC) is well-known for its aggressive nature that is usually resistant to platinum-based chemotherapy. On the other hand, the efficacy of an immune checkpoint inhibitor-based regimen in PPC has been elucidated. PPCs harboring epidermal growth factor receptor (EGFR) mutations are extremely rare, and the efficacy of EGFR-tyrosine kinase inhibitors in PPC is limited compared to their efficacy in EGFR-mutated adenocarcinoma. A 43-year-old female patient presenting with a lung mass with multiple brain metastases, carcinomatous pericarditis, and multiple bone metastases was referred to our department. Transbronchial biopsy confirmed the diagnosis of PPC harboring an EGFR mutation with exon 19 deletion. Subsequently, she was treated with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, which resulted in partial response with shrinkage of the primary lesion and brain metastases. This partial response remained durable for 11 months with an ongoing regimen. The current case suggests that osimertinib would show promising effects as a first-line treatment for PPCs harboring EGFR mutations, as well as a reasonable sequence of therapy followed by immune checkpoint inhibitor-based regimens.

Chromosomal rearrangements involving the c‐ros oncogene 1 (ROS1) are identified in approximately 1% of non‐small cell lung cancer (NSCLC) patients. Crizotinib is the first tyrosine kinase inhibitor (TKI) against ROS1‐rearranged NSCLC. G2032R, a secondary resistant mutation, is observed in 41% of patients treated with crizotinib. Entrectinib, a TKI against neurotrophic tropomyosin receptor kinase, is reportedly efficacious against ROS1‐rearranged NSCLC. However, ROS1‐G2032R is resistant to entrectinib both in vitro and in vivo. We report an 85‐year‐old female patient with ROS1‐rearranged NSCLC, who developed drug‐induced interstitial lung disease (DI‐ILD) 2 months after crizotinib treatment, and was treated with prednisolone followed by entrectinib. Entrectinib treatment resulted in stable disease with a marginal response after a partial response to crizotinib. Entrectinib treatment following crizotinib cessation due to DI‐ILD was efficacious, which suggested that ROS1‐G2032R gatekeeper mutation, frequently observed in crizotinib‐resistant disease, was absent. We report a patient with c‐ros oncogene 1 (ROS1)‐rearranged non‐small cell lung cancer, who developed drug‐induced interstitial lung disease 2 months after crizotinib treatment, and was sequentially treated with entrectinib, resulting in a stable disease with a marginal response.

An esophageal stricture is an abnormal esophageal narrowing, usually caused by esophageal diseases and rarely by lung cancer. They cause malnutrition, performance status (PS) deterioration, and difficulty in the oral administration of antitumor drug tablets. A 78-year-old female patient with lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation, experienced dysphagia due to an esophageal stricture caused by retrotracheal lymph node metastases. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor that is efficacious against EGFR-sensitizing mutations. The esophageal stricture hampered food intake and oral administration of osimertinib, causing severe malnutrition and deterioration to PS 3. Esophagogastroduodenoscopy (EGD) revealed severe and entire circumferential stenosis (7 cm in length) of the upper esophagus without mucosal abnormality. A nasogastric tube was inserted under EGD guidance, and an osimertinib suspension was administered accordingly: a tablet containing 80 mg of osimertinib was suspended in 50 mL of sterile hot water (55 ℃) for ten minutes, and the suspension was administered through a nasogastric tube once daily. Dysphagia improved 15 days after the introduction of osimertinib. After 21 days, the patient could take foods and drugs orally, and her PS improved to 1. Administering an osimertinib suspension via a nasogastric tube was a viable option in managing esophageal strictures in patients with EGFR-sensitizing mutations.