Secondary sarcopenia is defined as a decrease in muscle mass due to disease or malnutrition. Several studies have reported that secondary sarcopenia is an indicator of postoperative recurrence. We hypothesized that there is a correlation between the effect of immune checkpoint inhibitors (ICIs) and sarcopenia. We retrospectively analyzed 38 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICIs between February 2016 and April 2018. Patients were divided into two groups according to the change rate of the psoas major muscle area (PMMA) at the L2–L3 position and investigated the correlation between the change rate of the PMMA and the efficacy of ICIs was investigated. The objective response and disease control rates were lower in patients with sarcopenia than in those without sarcopenia. Patients with sarcopenia exhibited a significantly shorter median progression-free survival (PFS) than non-sarcopenia patients. Moreover, focusing on good Eastern Cooperative Oncology Group performance status patients, sarcopenia patients showed a shorter PFS than non-sarcopenia patients. Patients with sarcopenia are associated with poor outcomes for immunotherapy among those with advanced NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders.

Purpose Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non–small cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression between 1% and 49%.Materials and Methods We conducted a retrospective study of patients with NSCLC who were treated with chemotherapy or chemoimmunotherapy between March 2016 and May 2023. The patients had histologically confirmed NSCLC, stage III-IV or postoperative recurrence, TTF-1 measurements, and PD-L1 expression levels between 1% and 49%. Clinical data were analyzed to evaluate the effect of TTF-1 expression on treatment efficacy.Results This study included 283 of 624 patients. TTF-1–positive patients showed longer progression-free survival (PFS) and overall survival (OS) (PFS: 6.4 months [95% confidence interval (CI), 5.0 to 9.4] vs. 4.1 months [95% CI, 2.7 to 6.1], p=0.03; OS: 17.9 months [95% CI, 15.2 to 28.1] vs. 9.4 months [95% CI, 6.3 to 17.0], p < 0.01) in the chemotherapy cohorts (n=93). In the chemoimmunotherapy cohort (n=190), there was no significant difference in PFS and OS between TTF-1–positive and –negative groups (PFS: 7.6 months [95% CI, 6.4 to 11.0] vs. 6.0 months [95% CI, 3.6 to 12.6], p=0.59; OS: 25.0 months [95% CI, 18.0 to 49.2] vs. 21.3 months [95% CI, 9.8 to 28.8], p=0.09).Conclusion In patients with NSCLC with PD-L1 expression between 1% and 49%, TTF-1 expression was a predictor of chemotherapeutic, but not chemoimmunotherapeutic, efficacy.

Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80-90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Background: Serum growth/differentiation factor 15 (GDF‐15) suppresses anti‐tumor immunity and predicts prognosis in several malignancies. Elevated GDF‐15 levels are linked to cancer cachexia, characterized by weight loss and systemic inflammation, adversely affecting patient outcomes and therapy response. However, serum GDF‐15 is not always derived from tumor tissues but also from multiple organs. Therefore, we evaluated whether intra‐tumoral GDF‐15 could be used as a biomarker for immunotherapy and its potential association with cancer cachexia.Method: We retrospectively evaluated patients with advanced non‐small cell lung cancer (NSCLC) who underwent treatment with programmed cell death‐1 (PD‐1)/programmed cell death‐ligand 1 (PD‐L1) inhibitors at the Shizuoka Cancer Center between 2017 and 2021. Patients with histologically confirmed NSCLC (stage III–IV or postoperative recurrence) who had undergone biopsy or surgery within 6 months prior to initiating immunotherapy were included. Expression of tumor‐derived GDF‐15 was evaluated using immunohistochemical staining of archival biopsy and surgical specimens. We analyzed the correlation between intra‐tumoral GDF‐15 expression and the incidence of cancer cachexia, as well as its impact on progression‐free survival (PFS) and overall survival (OS).Result: In 6 of 35 cases, tumor cells highly expressed GDF‐15. Patients with high intra‐tumoral GDF‐15 expression had a higher incidence of cancer cachexia (100% vs. 41.4%, p < 0.05), shorter PFS (3.4 vs. 13.4 months, p < 0.05), and shorter OS (9.5 vs. 26.5 months, p < 0.05) than those with low intra‐tumoral GDF‐15 expression.Conclusion: Intra‐tumoral GDF‐15 expression may predict the presence of cancer cachexia and the efficacy of PD‐1/PD‐L1 inhibitors in patients with advanced non‐small cell lung cancer.

Dual checkpoint blockade with ipilimumab plus nivolumab (I-N), with or without chemotherapy, has shown clinical efficacy for treating advanced non-small-cell lung cancer (NSCLC); however, its benefits are limited to a subset of patients. The gut microbiome influences immune responses and may impact the efficacy of immune checkpoint inhibitors, thus warranting further investigation. This prospective study enrolled 50 patients with NSCLC who were treated with I-N, with and without chemotherapy. Gut microbiota diversity and composition were assessed from fecal samples collected before treatment initiation, and tumor-infiltrating lymphocytes (TILs) were evaluated using multiplex immunofluorescence staining. Progression-free survival (PFS), overall survival (OS), and objective response rate were analyzed alongside gut microbiota characteristics and treatment regimens. High gut microbiota diversity was associated with improved outcomes in patients receiving I-N alone and with greater CD8+ TIL infiltration, particularly PD-1+CD8+ TILs. Responders receiving I-N alone showed enrichment of short-chain fatty acid (SCFA)-producing bacteria, which were linked to favorable metabolic pathways associated with antitumor immune responses. In contrast, the association between gut microbiota diversity and treatment efficacy was not observed in patients treated with I-N plus chemotherapy. Antibiotic use before treatment was independently associated with shorter PFS and OS across all treatment regimens. Gut microbiota diversity and SCFA-producing bacteria are associated with improved efficacy of I-N. Baseline gut microbiota diversity may help identify patients who are more likely to have improved outcomes with I-N plus chemotherapy than with I-N alone. These findings highlight the potential of gut microbiota as a novel biomarker for dual checkpoint blockade in NSCLC may contribute to advancing personalized medicine.

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.