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.

Lung cancer has the highest mortality rate among all cancers in most developed countries. The number of elderly patients with lung cancer has been increasing, reflecting the global increase in aging population. Therefore, standard chemotherapeutic regimens for elderly patients with lung cancer need to be established. However, the effectiveness of chemotherapy in elderly patients with advanced non-small-cell lung cancer remains controversial because they are often excluded from clinical trials. Some clinical trials have shown that the therapeutic benefit of a third-generation anticancer drug alone was superior to best supportive care. In contrast, platinum-doublet was superior only in terms of overall survival and progression-free survival, and other trials reported an increased rate of treatment-related death in the elderly patients. In recent years, some novel treatment modalities for lung cancer have been developed and shown to significantly improve the therapeutic outcomes, including targeted therapy for lung cancer harboring driver mutation, combination therapy of angiogenesis inhibitor and cytotoxic agents, and immune checkpoint inhibitor. Although several clinical trials with these agents have shown favorable outcome regardless of age, their safety in the elderly patients has not been established. Herein, we discuss the current clinical status and future prospects in elderly patients with lung cancer.

Background: Durvalumab consolidation after chemoradiotherapy (CRT) is a standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, studies on immunological and nutritional markers to predict progression-free survival (PFS) and overall survival (OS) are inadequate. Systemic inflammation causes cancer cachexia and negatively affects immunotherapy efficacy, which also reflects survival outcomes. Patients and Methods: We retrospectively investigated 126 patients from seven institutes in Japan. Results: The modified Glasgow Prognostic Score (mGPS) values, before and after CRT, were the essential predictors among the evaluated indices. A systemic inflammation-based prognostic risk classification was created by combining mGPS values before CRT, and C-reactive protein (CRP) levels after CRT, to distinguish tumor-derived inflammation from CRT-induced inflammation. Patients were classified into high-risk (n = 31) and low-risk (n = 95) groups, and the high-risk group had a significantly shorter median PFS of 7.2 months and an OS of 19.6 months compared with the low-risk group. The hazard ratios for PFS and OS were 2.47 (95% confidence interval [CI]: 1.46–4.19, p < 0.001) and 3.62 (95% CI: 1.79–7.33, p < 0.001), respectively. This association was also observed in the subgroup with programmed cell death ligand 1 expression of ≥50%, but not in the <50% subgroup. Furthermore, durvalumab discontinuation was observed more frequently in the high-risk group than in the low-risk group. Conclusion: Combining pre-CRT mGPS values with post-CRT CRP levels in patients with locally advanced NSCLC helps to predict the PFS and OS of durvalumab consolidation after CRT.

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.

Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells. Experimental Design: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho–receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion–positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes. Results: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion–positive lung cancer was associated with poor RET-TKI treatment outcomes. Conclusions: The YAP–HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment. See related commentary by Ortiz-Cuaran and Leonce, p. 958

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Meanwhile, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associated with baseline PLR (hazard ratio (HR): 2.49, p = 0.0473), systemic immune-inflammation index (SII; HR: 2.65, p = 0.0337), prognostic nutrition index (PNI; HR: 4.15, p = 0.00185), and the 3-week values for SII (HR: 2.85, p = 0.0473) and PNI (HR: 3.04, p = 0.0125). Immunological and nutritional markers could be useful in predicting the outcomes of first-line treatment with alectinib. Since PLR and SII consist of platelet counts, platelet count could be an important constituent of these markers.