The remarkable antitumor efficacy of corticosteroid treatment in patients with refractory thymomas.

BACKGROUND: Some case reports have found that corticosteroid treatments shrunk thymoma lesions remarkably after the failure of chemotherapy or surgery. However, few studies have comprehensibly evaluated the antitumor effects of corticosteroids in patients with invasive thymomas. METHODS: We reviewed the medical records of 13 consecutively enrolled patients with locally advanced or metastatic thymomas treated via corticosteroid monotherapies from January 2010 to March 2021 in our institute. A Cox's proportional hazard model and the Kaplan-Meier method were used to identify factors associated with survival. RESULTS: The median follow-up time was 26 months (range, 13-115 months). The median initial dose of corticosteroid was 0.90 mg/kg/day prednisolone equivalent (range, 0.4-1.1 mg/kg/day). Of the 13 cases, 7 (53.8%, 95% CI: 0.25-0.81) exhibited a partial response and 5 (38.5%, 95% CI: 0.14-0.68) stable disease. The median progression-free survival was 5.7 months [95% confidence interval (CI): 1.5-9.6 months]. The median overall survival was 25.3 months (95% CI: 7.1-not attained). The median duration of corticosteroid use was 3 months (range, 1-64 months). Patients with WHO subtype B thymomas exhibited a better overall response rate to corticosteroids than did patients with other disease subtypes (75%, 95% CI: 0.19-0.99). Adverse events of Grade 3 or more were not observed. CONCLUSIONS: Corticosteroids are clinically valuable for patients with thymomas.

Top 20 EGFR+ NSCLC Clinical and Translational Science Papers That Shaped the 20 Years Since the Discovery of Activating EGFR Mutations in NSCLC. An Editor-in-Chief Expert Panel Consensus Survey.

The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Non-Squamous EGFR-Wildtype NSCLC in the Phase 2 LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage 1) and expand the selected group for efficacy evaluation (stage 2). Stage 2 enrolled patients with non-squamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 prior lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in non-squamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg every 2 weeks. Primary endpoint was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with non-squamous EGFR-wildtype NSCLC received Teliso-V in stages 1 and 2. ORR was 28.6% (95% CI, 21.7-36.2; c-Met high, 34.6% [24.2-46.2]; c-Met intermediate, 22.9% [14.4-33.4]). Median duration of response was 8.3 months (95% CI, 5.6-11.3; c-Met high, 9.0 [4.2-13.0]; c-Met intermediate: 7.2 [5.3-11.5]). Median overall survival was 14.5 months (95% CI, 9.9-16.6; c-Met high, 14.6 [9.2-25.6]; c-Met intermediate, 14.2 [9.6-16.6]). Median progression-free survival was 5.7 months (95% CI, 4.6-6.9; c-Met high, 5.5 [4.1-8.3]; c-Met intermediate: 6.0 [4.5-8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing non-squamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations.

BACKGROUND: In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. METHODS: We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. RESULTS: We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. CONCLUSIONS: Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.

Treatment patterns and clinical outcomes of resectable clinical stage III non-small cell lung cancer in a Japanese real-world setting: Surgery cohort analysis of the SOLUTION study.

BACKGROUND: To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings. METHODS: We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018. RESULTS: Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone. CONCLUSIONS: Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.

Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis.

PURPOSE: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared. RESULTS: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%). CONCLUSION: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability.

DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

Distinct Progression and Efficacy of First-Line Osimertinib Treatment According to Mutation Subtypes in Metastatic NSCLC Harboring EGFR Mutations.

Introduction: Osimertinib (OSI), a third-generation EGFR tyrosine kinase inhibitor, is the standard treatment for patients with naive EGFR-mutant NSCLC. Nevertheless, information on how the mutation subtype affects disease progression after the failure of OSI treatment is scarce. Methods: We retrospectively reviewed patients with EGFR-mutant NSCLC who received OSI as a first-line treatment between April 2015 and December 2021. Results: This study included 229 patients. The objective response rate was 71%, with intracranial and extracranial response rates of 71% and 90%, respectively. The median progression-free survival was 23.3 mo (95% confidence interval [CI]: 19.6-26.7), and the median overall survival was 33.7 mo (95% CI: 31.3-58.6). Multivariate analysis revealed that the EGFR exon 21 L858R point mutation (L858R) (hazard ratio [HR] = 1.56, 95% CI: 1.04-2.34, p = 0.0328) and liver metastasis (HR = 2.63, 95% CI: 1.53-4.49, p = 0.0004) were significant predictors of progression-free survival in OSI treatment. The concomitant disease progression involving the central nervous system metastasis was significantly more common in patients with L858R (p = 0.048), whereas concomitant disease progression involving primary lesions was significantly more common in patients with exon 19 deletion mutation (p = 0.01). In addition, the probability of disease progression over time was higher for L858R compared with that for exon 19 deletion mutation, in patients with central nervous system metastasis (log-rank test, p = 0.027). Conclusions: The mutation subtype had an impact not only on the clinical outcome of the first-line OSI treatment but also on progression patterns after OSI treatment in patients with NSCLC harboring EGFR mutations.

First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence.

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy.

INTRODUCTION: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. METHODS: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. RESULTS: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93). CONCLUSIONS: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors.

Introduction: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs). Methods: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II-expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo. Results: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti-programmed cell death protein 1 monoclonal antibody. Conclusions: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.