goto yasuhiro

This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

There is limited evidence regarding the second-line treatment for patients with unresectable, advanced, or metastatic pleural mesothelioma receiving first-line nivolumab plus ipilimumab combination immunotherapy. Although chemotherapy with pemetrexed and a platinum-based agent is empirically administered as the second-line treatment in clinical practice, its effect in patients after nivolumab plus ipilimumab remains unclear. Therefore, this retrospective observational study aimed to elucidate the efficacy of pemetrexed plus platinum therapy as a second-line treatment for pleural mesothelioma after first-line nivolumab-ipilimumab immunotherapy. Forty-three patients with unresectable or advanced pleural mesothelioma were enrolled in this study. Median overall survival was 17.1 months (95 % confidence interval [CI]: 9.3- not estimable), and median progression-free survival was 5.7 months (95 % CI: 3.9-11.9). The one-year overall survival rate was 62.8 % (95 % CI: 45.0-76.3) and one-year progression-free survival rate was 26.2 % (95 % CI: 10.4-45.2). In patients with measurable lesions, the overall response rate was 30.3 % and disease control rate was 69.7 %. These results are similar to those of previous studies on pemetrexed-platinum for pleural mesothelioma in first-line settings, suggesting that pemetrexed-platinum therapy can be considered an appropriate choice for the second-line treatment of mesothelioma after immunotherapy.

OBJECTIVES: To develop a comprehensive machine learning model incorporating various clinical factors, including frailty and comorbidities, to predict 30-day readmission and mortality risk in patients with chronic obstructive pulmonary disease (COPD). METHODS: This retrospective cohort study used electronic health records (EHR) from Fujita Health University Hospital (2004-2019) for 1294 patients with COPD and 3499 hospitalization or death events. The EHR contained longitudinal patient data (demographics, diagnoses, test results, clinical records). We developed two eXtreme Gradient Boosting models, the comprehensive Top64 and practical 11-feature models. We compared these with the Comorbidity, Obstruction, Dyspnea, and Previous Exacerbations index (CODEX) model, a widely used tool for predicting hospital readmission or death in patients with COPD. The area under the receiver operating characteristic curve (AUC) with 95% confidence interval (CI), sensitivity, and specificity were used to evaluate the model performance. RESULTS: The Top64 (AUC: 0.769, 95% CI: 0.747-0.791) and practical 11-feature (AUC: 0.746, 95% CI: 0.730-0.762) models performed better than the CODEX model (AUC: 0.587, 95% CI: 0.563-0.611). The Top64 model showed 0.978 sensitivity and 0.341 specificity, and the practical 11-feature model achieved 0.955 sensitivity and 0.361 specificity. The calibration curves showed good agreement between the observed and predicted results for both models. CONCLUSIONS: A machine learning approach based on clinical data readily available from the EHR performed better than existing models in predicting 30-day readmission and mortality risks in patients with COPD. A comprehensive risk prediction tool may enhance individualized care strategies and improve patient outcomes in COPD management.

BACKGROUND: In Japan, chemoimmunotherapy was approved as treatment for advanced or recurrent non-small-cell lung cancer (NSCLC), including for patients with epidermal growth factor receptor (EGFR) mutations, in December 2018. However, the impact of its approval on real-world clinical outcomes among patients with EGFR-mutant NSCLC remains unclear. The aim of our study was to assess that impact. METHODS: We retrospectively assessed consecutive patients with advanced or recurrent EGFR-mutant NSCLC who received platinum-based cancer therapy after EGFR-tyrosine kinase inhibitors (TKIs) at 20 institutions in Japan from January 2017 to July 2022. RESULTS: We evaluated 120 (27.2%) patients before the chemoimmunotherapy approval and 321 (72.8%) after. Overall, no significant differences in progression-free survival (PFS) or overall survival (OS) were observed between the pre- and post-approval groups (p = 0.72 and p = 0.89, respectively). In the subgroup with programmed cell death-ligand 1 (PD-L1) expression ≥ 50%, the post-approval group had a significantly longer PFS (p = 0.007) and OS (p = 0.048) than the pre-approval group. In contrast, in the PD-L1 < 50% cohort, no significant differences in the PFS (p = 0.54) or OS (p = 0.75) were noted between the groups. CONCLUSIONS: The approval of chemoimmunotherapy did not affect treatment outcomes among patients with EGFR-mutant NSCLC who received platinum-based therapy after EGFR-TKIs. However, patients with high levels of PD-L1 expression had improved outcomes post-approval, suggesting potential benefits in this subgroup.

BACKGROUND: The aim of this study was to identify poor prognostic factors and explore optimal second-line treatment strategies for patients with epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) who developed resistance to EGFR tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: We retrospectively evaluated patients with advanced or recurrent EGFR-mutant NSCLC who received platinum-based systemic therapy after EGFR-TKI failure from January 2017 to July 2022 at 20 institutions. Logistic regression analysis was used to identify factors associated with 1-year mortality after the start of systemic therapy. RESULTS: We included 393 patients in the final analysis (101 received atezolizumab, bevacizumab, carboplatin, and paclitaxel [ABCP], 292 received chemotherapy); 143 (36.3%) had an overall survival (OS) <1 year. Compared to the group with OS ≥1 year, the group with OS <1 year had significantly higher rates of performance status (PS) 2-4 and brain, liver, and bone metastases. Multivariable analysis revealed that PS ≥2, bone metastasis, and failure to respond to pretreatment EGFR-TKI were associated with poor OS. ABCP had numerical, but not statistically significant, OS improvement versus chemotherapy in patients with at least 1 poor prognostic factor (P = .079). Among patients with bone metastases (48.3%, n = 190), those treated with ABCP had a significantly longer median OS than those treated with chemotherapy (P = .032). CONCLUSION: EGFR-mutant NSCLC with PS ≥2 or bone metastases was associated with a poor prognosis after EGFR-TKI failure. Patients with poor prognostic factors, especially bone metastases, may benefit more from ABCP than from chemotherapy.

Duchenne muscular dystrophy (DMD) is a progressive myopathy caused by a mutation in the dystrophin gene. Cardiac disease is currently the leading cause of death in patients with DMD; thus, early diagnosis and management of cardiomyopathy are essential. Intra-voxel incoherent motion (IVIM) analysis provides quantitative values from diffusion-weighted imaging (DWI) and may serve as a novel index for evaluating myocardial properties in DMD. We conducted IVIM analysis in patients with DMD and compared their results with those of healthy volunteers to confirm that IVIM analysis can detect myocardial damage more effectively than conventional imaging methods. Patients with DMD who underwent cardiac magnetic resonance IVIM were enrolled. D and F values were measured using DWI of the left ventricle. Six healthy volunteers served as the control group. Twelve male patients with DMD were enrolled (median age, 14 years). Creatinine kinase levels were elevated, brain natriuretic peptide values remained within the normal range, and troponin T levels were only mildly elevated. The D value in patients with DMD was significantly higher than that in healthy volunteers, indicating increased diffusion in the myocardium (2.59 vs. 1.85, p = 0.0057); however, the F value was comparable between the two groups (0.62 vs. 0.61, p = 0.60). The D and F values from IVIM analysis provided a more detailed reflection of myocardial properties. Myocardial diffusion in patients with DMD was elevated compared with that in healthy volunteers.

UNLABELLED: Chemoimmunotherapy is recommended for patients with non-small cell lung cancer (NSCLC) with low PD-L1 expression, but the effect of additional immunotherapy is heterogeneous in this population. To identify patients who do not benefit from the addition of immune checkpoint inhibitors (ICI) to chemotherapy, we conducted a retrospective study at 19 institutions in Japan. We analyzed 851 patients with advanced NSCLC with a PD-L1 tumor proportion score of 1% to 49% who received chemoimmunotherapy (n = 504) or chemotherapy (n = 347) between March 2017 and June 2022. After adjustment by propensity score matching, the median overall survival (OS) was 22.3 months in the chemoimmunotherapy group and 17.0 months in the chemotherapy-alone group (P = 0.01). Multivariate analysis showed that among 12 clinical factors, liver metastases (P = 0.001) and history of antibiotic use (P = 0.02) were independently associated with shorter OS in the chemoimmunotherapy group. Patients with liver metastases (OS, P = 0.4; progression-free survival, P = 0.06) or history of antimicrobial use (OS, P = 0.24; progression-free survival, P = 0.09) did not benefit from the addition of ICI to chemotherapy. Patients with a history of antimicrobial use experienced more severe pneumonitis with chemoimmunotherapy than all patients (P = 0.04). This cohort study showed that liver metastases and prior antimicrobial therapy are the most important clinical factors that attenuate the efficacy of chemoimmunotherapy in patients with low PD-L1 expression. SIGNIFICANCE: This study shows that liver metastases and prior antibiotic use are key factors for chemoimmunotherapy in advanced NSCLC cases with low PD-L1 expression. They reduce the benefit of adding ICIs to chemotherapy, underscoring the need for new strategies to improve ICI efficacy in patients.

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) represents 3-7% of all cases and causes oncogene addiction. Although ALK tyrosine kinase inhibitors (ALK-TKIs) are effective for treating ALK-positive NSCLC, some patients still show suboptimal responses and poor outcomes. Clinically simple and detectable biomarkers for this group are limited. Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1 and CYFRA) are widely used tumor markers in NSCLC. Elevated CEA levels are linked to tumor progression and resistance to cell death, while CYFRA is widely expressed in poorly differentiated squamous cell carcinomas. CYFRA has been identified as a prognostic factor in epidermal growth factor receptor (EGFR)-positive NSCLC, but its role in ALK-positive NSCLC remains unclear. Therefore, we retrospectively assessed the value of CEA and CYFRA as predictive biomarkers in patients with ALK-positive NSCLC treated with ALK-TKIs. METHODS: This retrospective study analyzed 197 patients with advanced or recurrent ALK-positive NSCLC, who were diagnosed across 13 institutions in Japan and received their first ALK-TKI between July 1, 2014 and December 31, 2022. Eligible patients had measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were stratified based on normal (≤5.0 and ≤3.5 ng/mL) or high (>5.0 and >3.5 ng/mL) baseline serum CEA and CYFRA levels. Serum CYFRA and CEA levels, which were measured using commercially available immunoassays per standard institutional protocols. The primary endpoint was progression-free survival (PFS) with initial ALK-TKI therapy, and secondary endpoints included overall survival (OS) and objective response rate (ORR). Multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 152 patients with available CYFRA data, 91 (59.9%) had normal CYFRA levels and 61 (40.1%) had elevated levels. In this analysis, patients in the high CYFRA group had significantly shorter median PFS and OS (9.27 and 28.8 months, respectively) than those in the normal CYFRA group (42.0 and 143.3 months, respectively). Multivariate analysis confirmed that high CYFRA levels were independent predictors of poor PFS (HR: 2.35, 95% CI: 1.50-3.68, P<0.001) and OS (HR: 3.28, 95% CI: 1.89-5.70, P<0.001). Furthermore, the high CYFRA group had lower ORR and complete response (CR) rates, compared with the normal CYFRA group. In contrast, no significant differences in PFS or OS were observed between patients with normal and elevated CEA levels. CONCLUSIONS: Elevated CYFRA levels correlate with reduced PFS and OS in ALK-positive NSCLC, indicating potential as a prognostic biomarker. Given CYFRA's association with tumor heterogeneity, which reduces ALK-TKI efficacy, its assessment could aid in risk stratification and treatment planning. Additional research is needed to verify the predictive value of CYFRA for ALK-TKI efficacy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) in combination with chemotherapy have demonstrated efficacy in the treatment of non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1-49%. However, older patients remain underrepresented in clinical trials, and optimal treatment strategies for this population remain unclear. This study sought to evaluate the efficacy and safety of first-line treatment with either platinum-based chemotherapy alone (Chemo) or in combination with ICIs (ICI/Chemo) in older patients with NSCLC who have low PD-L1 expression. METHODS: This retrospective multicenter study included patients diagnosed with advanced NSCLC (stage IIIB-IV) with a PD-L1 TPS of 1-49% from 19 Japanese institutions. We examined the relationship between baseline patient characteristics and treatment outcomes within each group. Propensity score matching (PSM) was used to balance patient characteristics between the ICI/Chemo and Chemo groups. RESULTS: We evaluated data from 613 patients, finding that the ICI/Chemo group (n=370) exhibited significantly longer median progression-free survival (PFS) and overall survival (OS) compared to the Chemo group (n=243). Among the 613 patients, 152 were aged ≥75 years. Of these, 63 received Chemo, while 89 underwent ICI/Chemo as first-line treatment. In this older cohort, ICI/Chemo significantly improved median PFS; however, no significant difference was observed in OS. Nonetheless, the incidence of grade ≥3 adverse events and pneumonitis of any grade was higher in the ICI/Chemo group compared to the Chemo group among older patients. Multivariate analysis using Cox proportional hazards models indicated that Eastern Cooperative Oncology Group performance status (ECOG PS) was significantly associated with PFS and OS. In older patients with ECOG PS 0, ICI/Chemo showed significant PFS benefits; in those with ECOG PS 1, both the PFS and OS were similar between the two groups. CONCLUSIONS: ICI combined with chemotherapy may be a potentially effective treatment strategy for older patients with NSCLC and low PD-L1 expression. However, compared with the overall population, the benefits of adding ICI to chemotherapy were decreased, while the risk of toxicity may increase, making appropriate patient selection crucial for this population. Particularly, in patients with ECOG PS 1, the additional benefit of ICI over chemotherapy was minimal in terms of efficacy, suggesting that the introduction of ICI combined with chemotherapy should be carefully considered for this patient population.

BACKGROUND: The efficacy of immune checkpoint inhibitor (ICI) monotherapy on non-small-cell lung cancer (NSCLC) varies by epidermal growth factor receptor (EGFR) mutation subtypes. However, the impact of these subtypes on the clinical outcomes of chemoimmunotherapy (Chemo+ICI) or platinum-based chemotherapy (Chemo) in real-world practice remains unclear. OBJECTIVE: This study evaluated the impact of EGFR mutation subtypes on NSCLC treatment outcomes of Chemo and Chemo+ICI. PATIENTS AND METHODS: We retrospectively analyzed patients with advanced or recurrent EGFR-mutant NSCLC from 20 institutions between January 2017 and July 2022. Patients received Chemo with or without ICI after failure of EGFR-tyrosine kinase inhibitors. Common EGFR mutations were categorized as exon 19 deletions and exon 21 L858R mutations. RESULTS: Among the 403 patients, 205 (50.9%) had exon 19 deletions, and 198 (49.1%) had L858R mutations. For patients with L858R mutations, Chemo+ICI significantly improved progression-free survival (PFS) compared with Chemo (7.0 vs 5.3 months; p = 0.04). However, no significant difference in PFS was observed between treatments for patients with exon 19 deletions (6.7 vs 6.0 months; p = 0.96). Multivariate analysis identified Chemo+ICI as an independent predictor of PFS in patients with L858R mutations (hazard ratio 0.63; 95% confidence interval 0.43-0.92; p = 0.02). CONCLUSIONS: Among patients with common EGFR mutation subtypes, those with L858R mutations demonstrated significantly improved PFS with Chemo+ICI than with Chemo. These findings suggest that Chemo+ICI may offer a more effective treatment option for patients with L858R-mutant NSCLC, warranting further investigation in prospective studies.

Bronchoscopic lung volume reduction (BLVR) with endobronchial valves is an established treatment for selected patients with advanced emphysema. A 74-year-old male patient with chronic obstructive pulmonary disease and severe dyspnea was scheduled to undergo BLVR targeting the right middle lobe bronchus based on high-resolution CT findings, which showed severe emphysematous changes with hyperinflation and fissure completeness of 98% in the right middle lobe. The physician conducted preoperative virtual reality (VR)-assisted planning using the patient's imaging data, enabling comprehensive visualisation of the bronchial tree, airway measurements, and procedural simulation. The Chartis system confirmed a 'no flow' pattern, supporting the absence of collateral ventilation. During the procedure, a size 5.5 valve was placed in the right B4/5 bronchus following VR and intraoperative assessments. The patient remained stable postoperatively without complications. VR enhanced procedural planning by improving airway assessment, optimising valve sizing, and reducing cognitive load, leading to increased efficiency and operator confidence. Further research is warranted to validate the utility of VR in bronchoscopic interventions.

BACKGROUND: Severe immune-related adverse events (irAEs) are often associated with combined immunotherapy and chemotherapy in patients with non-small cell lung cancer (NSCLC). However, their effect on clinical outcomes has yet to be fully elucidated. In this study, we investigated the impact of irAEs, particularly pneumonitis, on clinical outcomes in patients receiving combined immunotherapy and chemotherapy for NSCLC. METHODS: We retrospectively enrolled 850 patients with programmed cell death ligand-1 (PD-L1) 1-49% advanced NSCLC who were treated with chemotherapy alone or with combined immunotherapy and chemotherapy as first-line treatment at 19 different institutions in Japan between March 2017 and June 2022. Using data from their medical records, we examined the type and severity of irAEs and their association with clinical outcomes, including overall survival (OS) and progression-free survival (PFS). RESULTS: OS and PFS were not significantly different between patients with and without severe irAEs. However, in the group receiving combined immunotherapy and chemotherapy, those who developed pneumonitis within 42 days of treatment initiation had shorter OS and PFS, irrespective of the pneumonitis grade, and a worse prognosis than those who received chemotherapy alone. Additionally, early-onset pneumonitis was more likely in patients aged >75 years, those with high lactate dehydrogenase levels, and those receiving steroids or immunosuppressants, suggesting that these factors may contribute to the risk of early-onset pneumonitis. CONCLUSIONS: Early-onset pneumonitis is a poor prognostic factor in patients with PD-L1 1-49% advanced NSCLC receiving combined immunotherapy and chemotherapy. Further large-scale observational studies are warranted to confirm these findings. KEYWORDS: Non-small cell lung cancer (NSCLC); severe immune-related adverse events (irAEs); pneumonitis.

PURPOSE: To our knowledge, the ACHILLES/TORG1834 trial is the first randomized study comparing afatinib and chemotherapy in patients with non-small cell lung cancer (NSCLC) harboring sensitizing uncommon epidermal growth factor receptor (EGFR) mutations. METHODS: This randomized, open-label study was performed at 51 Japanese institutions and recruited treatment-naïve patients with nonsquamous NSCLC with uncommon EGFR mutations, excluding exon 20 insertions and T790M mutations. Patients were randomly assigned 2:1 to receive afatinib (30 or 40 mg orally, at the treating physician's discretion) or a combination of platinum (cisplatin or carboplatin) and pemetrexed, followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, and safety. A prespecified interim analysis was planned to provide clinically meaningful information promptly, along with a crossover recommendation if necessary. RESULTS: A total of 109 patients were enrolled between March 2019 and February 2023. In the interim analysis, the Data and Safety Monitoring Committee recommended early study termination. The median PFS was significantly longer in patients receiving afatinib than in those undergoing chemotherapy (10.6 v 5.7 months; hazard ratio, 0.421 [95% CI, 0.251 to 0.706]; P = .0010). ORRs to afatinib were similar across the overall population and among participants with major uncommon (G719X, L861Q, and S768I), compound, and other mutations (61.7%, 55.8%, 72.7%, and 60.0%, respectively). The most common grade 3 or higher adverse events were diarrhea, paronychia, and rash for afatinib, and appetite loss and nausea for chemotherapy. CONCLUSION: Afatinib should be considered the standard initial therapy for patients with NSCLC with sensitizing uncommon EGFR mutations.

OBJECTIVES: In patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, a chemoimmunotherapy regimen of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) has shown promising outcomes following treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, evidence on whether ABCP provides a survival advantage over platinum-based chemotherapy in real-world clinical settings remains limited. This study aimed to investigate the efficacy and safety of ABCP versus platinum-based chemotherapy in patients with EGFR-mutant NSCLC who underwent EGFR-TKI treatment. MATERIALS AND METHODS: We retrospectively assessed consecutive patients with EGFR-mutant-NSCLC who received platinum-based chemotherapy or ABCP after EGFR-TKI treatment at 20 institutions in Japan between January 2017 and July 2022. RESULTS: Overall, 408 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. A total of 306 patients (75.0 %) received chemotherapy (Chemo) or chemotherapy plus bevacizumab (Chemo + BEV), and 102 patients (25.0 %) received ABCP. After propensity score matching, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between the Chemo or Chemo + BEV and ABCP groups (6.0 months versus 7.2 months, log-rank test; p = 0.44 and 22.5 months versus 21.3 months, p = 0.84, respectively). Limiting to the programmed cell death-ligand 1 (PD-L1) ≥ 50 % cohort, the ABCP group had a significantly longer PFS than did the Chemo or Chemo + BEV group (7.9 months versus 4.8 months, log-rank test; p = 0.02). CONCLUSION: In patients with EGFR-mutant NSCLC previously treated with EGFR-TKI, ABCP achieved comparable outcomes to those of platinum-based chemotherapy. Among patients with high PD-L1 expression, ABCP may be a superior treatment option.

BACKGROUND: Clinical trial eligible patients with advanced non-small cell lung cancer (aNSCLC) and low programmed cell death ligand 1 (PD-L1) expression achieve greater benefit from immune checkpoint inhibitor (ICI) combination chemotherapy (ICI-Chemo) compared with Chemo alone. We examined whether patients ineligible for clinical trials may benefit from ICI-Chemo. METHODS: This multicenter retrospective cohort study enrolled patients with aNSCLC, including unresectable Stage III (IIIB/IIIC) and IV disease with a PD-L1 tumor proportion score of 1-49% treated with ICI-Chemo or Chemo as first-line therapy from 2018 to 2023 in Japan. Treatment outcome and safety of ICI-Chemo versus Chemo groups in trial-eligible and trial-ineligible patients was compared based on criteria from previous phase III clinical trials. RESULTS: Overall, 728 patients were analyzed: 333 trial-eligible and 395 ineligible patients. The median overall survival was 25.1 months in the ICI-Chemo group and 18.5 months in the Chemo group for eligible patients (HR 0.73, 95 %CI: 0.54-0.97) and was 18.2 months in the ICI-Chemo group and 14.9 months in the Chemo group for ineligible patients (HR 0.75, 95 %CI: 0.59-0.95). Median progression-free survival was longer with ICI-Chemo in both groups. For ineligible patients, performance status (PS) ≥ 2 and squamous cell carcinoma (SqCC) were clinical factors associated with worse survival prognosis, and survival outcomes with ICI-Chemo and Chemo were comparable. The ineligible group had no increase in severe adverse events compared to the eligible group. CONCLUSIONS: This study suggests a possible clinical benefit of receiving ICI-Chemo for trial-ineligible patients with low PD-L1 expression, excluding those with PS ≥ 2 or SqCC.

BACKGROUND: Although chemoimmunotherapy is recommended for advanced nonsquamous non-small cell lung cancer (NSCLC) with low programmed cell death ligand 1 (PD-L1) expression, no head-to-head comparisons of immune checkpoint inhibitors (ICIs) have been performed. Therefore, we compared the effect and safety of regimens in these patients to guide evidence-based treatment. METHODS: This retrospective study included patients with advanced nonsquamous NSCLC with a PD-L1 tumor proportion score of 1% to 49% administered ICI combination platinum-based chemotherapy between May 2018 and May 2023 at 19 institutions in Japan. The main analysis compared survival outcomes and the incidence of grade ≥3 adverse events among regimens. RESULTS: Among 316 included patients (median [range] age, 69 [36-89] years; 242 males; 41 never smokers), 200 (63%), 68 (22%), and 48 (15%) received chemotherapy combined with anti-programmed cell death protein 1 (PD-1), anti-PD-L1, and anti-PD-1/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies, respectively. The median overall survival times were 28.6, 23.1, and 24.4 months (P = .41), and the median progression-free survival times were 9.4, 7.2, and 8.7 months (P = .28) in the anti-PD-1/Chemo, anti-PD-L1/Chemo and anti-PD-1/CTLA-4/Chemo groups, respectively. The anti-PD-1/CTLA-4/Chemo group had the lowest incidence of hematologic toxicity (P = .13) and the highest incidence of nonhematologic toxicity (P = .07). The incidence of grade ≥3 pneumonitis was significantly lower in the anti-PD-L1/Chemo group (P = .049). CONCLUSIONS: Despite comparable survival benefits, adverse events differed among three regimens in patients with low PD-L1 expression. Notably, anti-PD-L1 antibody combination chemotherapy may reduce the risk of severe pneumonitis.

A 60-year-old male patient with metastasis from sigmoid colon cancer in the pancreatic uncinate process who received chemotherapy was treated with edoxaban (EDO) because of deep vein thrombosis. The pancreatic metastasis appeared to shrink, but the patient had repeated acute pancreatitis. An upper gastrointestinal endoscopy was performed to determine the cause. Bleeding from the major papilla and the minor papilla was detected, and he was diagnosed with hemosuccus pancreaticus. Pancreatic duct stenting was conducted from the minor papilla. The pancreatitis was then improved and the EDO dosage was reduced. The pancreatic duct stent fell off during the course. Hemosuccus pancreaticus has not relapsed after 1 year from the dropout of the stent. EDO was considered responsible for hemosuccus pancreaticus.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

BACKGROUND: The increasing prevalence of lung cancer in the elderly population necessitates a closer evaluation of diagnostic and therapeutic approaches. This study aimed to compare the safety and diagnostic efficacy of transbronchial lung cryobiopsy (TBLC) between patients ≥ 80 years and younger patients. METHODS: A retrospective review was conducted of 96 patients diagnosed with peripheral lung cancer who underwent TBLC between April 2021 and October 2023. The patients were categorized into two groups: the elderly group (age ≥ 80 years, n = 20) and younger group (age < 80 years; n = 76). Data regarding the biopsy yield, complications, and feasibility of molecular analyses were collected and analyzed. RESULTS: The diagnostic yield of TBLC was comparable between the elderly and younger groups (95% vs. 89.5%, p = 0.679). Biomarker testing, including programmed death-ligand 1 expression and genetic mutations, were feasible in all cases diagnosed with cancer using TBLC samples. No significant differences were observed in major complications such as pneumothorax or bleeding. CONCLUSIONS: TBLC was found to be a safe and effective diagnostic tool for peripheral lung cancer in elderly patients and provided adequate samples for molecular testing. Since the complication rates did not significantly differ between the two age groups, age alone should not be considered a contraindication for the procedure.

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 (TKIs). 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 molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment 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/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes. CONCLUSION: 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.

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): 5.0-9.4] vs 4.1 months [95% CI: 2.7-6.1], p=0.03, OS: 17.9 months [95% CI: 15.2-28.1] vs 9.4 months [95% CI: 6.3-17.0], 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: 6.4-11.0] vs 6.0 months [95% CI: 3.6-12.6], p=0.59, OS: 25.0 months [95% CI: 18.0-49.2] vs 21.3 months [95% CI: 9.8-28.8], 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.

The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 =  ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.

BACKGROUND: The treatment of lung cancer has made dramatic progress in the past decade, but due to the high cost of drugs, the total pharmaceutical cost has been rising explosively. There are currently no data available in Japan on which regimens are used, to what extent they are used, and what their total cost is. METHODS: Sixty Japanese centers belonging to the Lung Cancer Study Group of the Japan Clinical Oncology Group were surveyed for information about the first-line treatment for advanced lung cancer in practice from July 2021 to June 2022. Three types of cancer were included: driver gene mutation-negative NSCLC, EGFR mutation-positive NSCLC, and extensive-stage small cell lung cancer (ES-SCLC). RESULTS: Recent treatment costs for ICIs or ICI plus chemotherapy were about 20-55 times higher than those for conventional chemotherapy. Of the 3738 patients with driver gene aberration-negative NSCLC, 2573 (68.8%) received treatments with monthly cost of 500 000 Japanese yen (JPY) or more; 2555 (68.4%) received ICI therapy. Of the 1486 patients with EGFR mutation-positive NSCLC, 1290 (86.8%) received treatments with a monthly cost of 500 000 JPY or more; 1207 (81.2%) received osimertinib. ICI treatments with a monthly cost of 500 000 JPY or more were administered to 607 (56.3%) of 1079 patients with ES-SCLC. Elderly NSCLC patients received slightly more high-cost treatment than younger patients. CONCLUSION: Recent treatments cost many times more than conventional chemotherapy. This study revealed that high-cost treatments were widely used in advanced lung cancer and some of high-cost treatments were used despite the lack of clear evidence. Physicians should pay attention to the cost of treatments they use.

BACKGROUND: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. METHODS: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. FINDINGS: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. INTERPRETATION: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. FUNDING: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

INTRODUCTION: Increasing numbers of cases of mild asymptomatic pulmonary alveolar proteinosis (PAP) are being reported with the recent increase in chest computed tomography (CT). Bronchoscopic diagnosis of mild PAP is challenging because of the patchy distribution of lesions, which makes it difficult to obtain sufficient biopsy samples. Additionally, the pathological findings of mild PAP, particularly those that differ from severe PAP, have not been fully elucidated. This study aimed to clarify the pathological findings of mild PAP and the usefulness of optical biopsy using probe-based confocal laser endomicroscopy (pCLE). METHODS: We performed bronchoscopic optical biopsy using pCLE and tissue biopsy in five consecutive patients with PAP (three with mild PAP and two with severe PAP). We compared the pCLE images of mild PAP with those of severe PAP by integrating clinical findings, tissue pathology, and chest computed tomography images. RESULTS: pCLE images of PAP showed giant cells with strong fluorescence, amorphous substances, and thin alveolar walls. Images of affected lesions in mild PAP were equivalent to those obtained in arbitrary lung lesions in severe cases. All three patients with mild PAP spontaneously improved or remained stable after ≥3 years of follow-up. Serum autoantibodies to granulocyte-macrophage colony-stimulating factor were detected in all five cases. CONCLUSION: Optical biopsy using pCLE can yield specific diagnostic findings, even in patients with mild PAP. pCLE images of affected areas in mild and severe PAP showed similar findings, indicating that the dysfunction level of pathogenic alveolar macrophages in affected areas is similar between both disease intensities.

Despite innovative advances in molecular targeted therapy, treatment strategies using immune checkpoint inhibitors (ICIs) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) have not progressed significantly. Accumulating evidence suggests that ICI chemotherapy is inadequate in this population. Biomarkers of ICI therapy, such as programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), are not biomarkers in patients with EGFR mutations, and the specificity of the tumor microenvironment has been suggested as the reason for this. Combination therapy with PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors is a concern because of its severe toxicity and limited efficacy. However, early-stage NSCLC may differ from advanced-stage NSCLC. In this review, we comprehensively review the current evidence and summarize the potential of ICI therapy in patients with EGFR mutations after acquiring resistance to treatment with EGFR-tyrosine kinase inhibitors (TKIs) with no T790M mutation or whose disease has progressed on osimertinib.

INTRODUCTION: The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO. METHODS: We retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching. RESULTS: Of the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group. CONCLUSIONS: ECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%.

INTRODUCTION: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. METHODS: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. RESULTS: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). DISCUSSION: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

BACKGROUND: Bronchial thermoplasty (BT) is a recently developed non-pharmacological therapy for refractory bronchial asthma. Although increasing evidence has suggested that BT is effective for various phenotypes of severe asthma, its safety and efficacy in patients with severe irreversible impaired lung function are unclear. OBJECTIVES: To assess the efficacy and safety of BT in patients with refractory asthma, including patients with a severely impaired forced expiratory volume in 1 second (FEV1). DESIGN: This was a single-center, retrospective, observational cohort study. METHODS: We retrospectively reviewed the medical records of 15 patients with refractory asthma (Global Initiative for Asthma step 4 or 5), including patients with severely impaired airflow limitation (% predicted pre-bronchodilator FEV1 <60%), who had undergone BT between June 2016 and January 2022. We analyzed the efficacy (change in asthma symptoms, exacerbation rate, pulmonary function, asthma medication, and serum inflammatory chemokine/cytokines before and after BT) and complications in all patients. We compared these data between patients with severe obstructive lung dysfunction [group 1(G1)] and patients with FEV1 ⩾ 60% [group 2 (G2)]. RESULTS: Six patients were in G1 and nine were in G2. Clinical characteristics, T2 inflammation, and concurrent treatment were equivalent in both groups. BT significantly improved asthma-related symptoms (measured using the Asthma Control Test and Asthma Quality of Life Questionnaire scores) in both groups. FEV1 was significantly improved in G1 but not in G2. Four patients in G2, but none in G1, experienced asthma exacerbation requiring additional systemic corticosteroids (including two requiring prolonged hospitalization) after BT. Long-term responders (patients who reduced systemic or inhaled corticosteroid without newly adding biologics in a follow-up > 2 years) of BT were identified in G1 and G2 (n = 2, 33.3% and n = 4, 44.4%, respectively). CONCLUSION: BT in patients with refractory asthma and severe airflow limitation is equally safe and efficacious as that in patients with moderate airflow limitation.

BACKGROUND: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. METHODS: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. FINDINGS: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. INTERPRETATION: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. FUNDING: Eli Lilly Japan K.K.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. OBJECTIVE: The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. PATIENTS AND METHODS: A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. RESULTS: The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50-89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. CONCLUSIONS: In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy.

BACKGROUND: Although concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard treatment for patients with stage III non-small cell lung cancer (NSCLC), only half of the patients are allowed to receive CCRT in real-world settings. We evaluated the efficacy and safety of durvalumab after radiation monotherapy for NSCLC patients who are ineligible for chemoradiotherapy. METHODS: A single-arm, prospective, open-label, multicenter phase II trial was conducted in Japan. The patients received radiation (54-66 Gy) followed by durvalumab (10 mg/kg every 2 weeks for up to 12 months). The primary endpoint was the 1-year progression-free survival (PFS) rate. The secondary endpoints were the objective response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Between September 2019 and April 2021, 33 patients were enroled from eight institutions. The median patient age was 79 years, and the majority of patients were male (78.8%). The 1-year PFS rate was 39.1% (90% confidence interval [CI]: 24.7-54.6%). Three patients (9.1%) had a performance status of 2. The ORR was 42.4% (95% CI: 27.2-59.2%). The median PFS and OS were 8.9 (95% CI: 7.4-19.4) and 20.8 (95% CI: 15.8-not estimable) months, respectively. The most common adverse event was radiation pneumonitis (51.5%). The median treatment duration was 6.4 (range: 0.50-12.0) months for durvalumab. At the endpoint, 30.3% (10/33) of the patients had completed 1 year of durvalumab therapy. CONCLUSIONS: Durvalumab is an effective treatment with tolerable toxicity following radiation monotherapy in stage III NSCLC patients who are ineligible for chemoradiotherapy. TRIAL REGISTRATION: JMA-IIA00434 (jRCT).

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.

IMPORTANCE: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear. OBJECTIVE: To clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023. EXPOSURE: ICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment. MAIN OUTCOMES AND MEASURES: The primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics. RESULTS: A total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups. CONCLUSIONS AND RELEVANCE: This cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.

BACKGROUND: The Cockcroft-Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown. METHODS: We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin-pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. RESULTS: Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76-1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65-1.17; p = 0.363), with higher grade 3-4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20-0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23-0.82; p = 0.010). CONCLUSIONS: Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.