Clinical significance of chronic pulmonary aspergillosis in lung cancer patients undergoing anticancer drug therapy.

BACKGROUND: Advances in anticancer drugs for lung cancer (LC) have improved the prognosis of LC. Chronic pulmonary aspergillosis (CPA) is a progressive and often exacerbating respiratory disease with a poor prognosis. To date, the prognosis of LC complicated by CPA has not been elucidated. This study investigated the clinical implications of concomitant CPA in patients with LC undergoing anticancer drug treatment. METHODS: Between January 2010 and May 2020, we consecutively enrolled patients with LC complicated with CPA at five different institutions in Japan. We analyzed patients with LC complicated by CPA who received anticancer drug treatment. RESULTS: A total of 10 patients with LC complicated by CPA received anticancer drug treatment. The median overall survival (OS) was 14.57 months (95% confidence interval [CI]: 5.37-21.67). The cause of death in all patients was LC. Six of the seven patients with LC did not show worsening pulmonary aspergillosis lesions during the anticancer drug treatment. Although two patients discontinued anticancer drug treatment due to pneumonitis, CPA complications did not interfere with the continuation of anticancer drug treatment. In univariate analyses, squamous histology (p = 0.01) and body mass index (<18.5 kg/m2) (p = 0.0008) were significantly associated with poorer OS. CONCLUSIONS: This study demonstrated that the cause of death in LC patients with concomitant CPA who received anticancer drug treatments and effective antifungal treatment was LC progression. Further large-scale studies are needed to identify the effect of CPA in patients with LC.

Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. METHODS: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. FINDINGS: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. INTERPRETATION: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. FUNDING: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

A randomized, open-label phase II study on the preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: The OLCSG2101 study protocol.

BACKGROUND: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX. METHODS: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled. DISCUSSION: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL. ETHICS AND DISSEMINATION: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION: Japan Registry of Clinical Trials (registration number jRCTs061210047).

Transbronchial Cryoablation as Local Treatment for Central Airway Malignant Tumor.

INTRODUCTION: Transbronchial cryoablation has been performed for peripheral but not central airway malignant tumor. We demonstrate transbronchial cryoablation in 2 patients with central airway lesions. CASE PRESENTATION: Case 1 was an 86-year-old woman who developed intratracheal metastasis associated with postoperative recurrence of lung adenocarcinoma. The tumor was resected using a high-frequency electrosurgical snare and three transbronchial cryoablations. There was no tracheal recurrence in the 5 months after the third procedure. Case 2 was an 83-year-old man who developed intermediate bronchial metastasis associated with postoperative recurrence of lung squamous cell carcinoma. The tumor was resected using a high-frequency electrosurgical snare and one transbronchial cryoablation. There was no tumor recurrence in the bronchus intermedius for 12 months after treatment. In both cases, the only adverse event was minor bleeding. CONCLUSION: Transbronchial cryoablation deserves consideration as local treatment for central airway malignant tumors.

Prediction of prognosis in lung cancer using machine learning with inter-institutional generalizability: A multicenter cohort study (WJOG15121L: REAL-WIND).

OBJECTIVES: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. MATERIALS AND METHODS: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. RESULTS: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9-17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88-0.91), 0.85 (0.84-0.87), 0.83 (0.81-0.85), and 0.85 (0.82-0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84-0.92), 0.84 (0.78-0.88), 0.84 (0.76-0.89), and 0.84 (0.75-0.90) at 180, 360, 720, and 1,080 days, respectively. CONCLUSION: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.

Tepotinib-induced hand-foot skin reaction.

Tepotinib may cause hand-foot skin reactions with keratotic changes. When such changes are observed in the hands or toes after starting tepotinib treatment, its side effects should be considered, and corticosteroid ointment or withdrawal of tepotinib should be considered if necessary.

A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

BACKGROUND: Bevacizumab with platinum doublet therapy including paclitaxel + carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel + carboplatin led to Grade > 3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination in a Japanese population. METHODS: Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6 cycles of carboplatin (area under the concentration-time curve = 6 on Day 1) + nanoparticle albumin-bound paclitaxel (100 mg/m2 on Days 1, 8 and 15) + bevacizumab (15 mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel + bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. RESULTS: The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42 months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade ≥ 3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). CONCLUSIONS: All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer.

BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.

Impacts of probiotics on the efficacies of immune checkpoint inhibitors with or without chemotherapy for patients with advanced non-small-cell lung cancer.

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non-small-cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG-ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG-ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression-free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p < .001; OS not attained vs. 13.1 months, HR 0.45, p < .001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p = .43; OS not attained vs. 22.6 months, HR 0.61, p = .03). Patients on probiotics experienced better outcomes following ICI treatment.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

A Phase 2 Single-Arm Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis NSCLC: Results for the First-Line Cohort of the OCEAN Study (LOGIK 1603/WJOG 9116L).

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%-90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%-99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo-not reached). The overall response rate was 64.0% (95% CI: 45.2%-82.8%), median PFS was 11.5 months (95% CI: 6.9 mo-not reached), and median survival time was 23.7 months (95% CI: 16.5 mo-not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Lack of Association of Plasma Levels of Soluble Programmed Cell Death Protein 1, Programmed Death-Ligand 1, and CTLA-4 With Survival for Stage II to IIIA NSCLC After Complete Resection and Adjuvant Chemotherapy.

Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.

Osimertinib as first-line treatment for elderly patients with advanced EGFR mutation-positive non-small cell lung cancer in a real-world setting (OSI-FACT-EP).

OBJECTIVES: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. MATERIALS AND METHODS: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. RESULTS: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001). CONCLUSION: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events.

Liquid biopsy detects genomic drivers in NSCLC without EGFR mutations by single-plex testing: WJOG13620L.

BACKGROUND: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. METHODS: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. RESULTS: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days). CONCLUSION: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.

Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L).

BACKGROUND: The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). METHODS: B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. DISCUSSION: The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. TRIAL REGISTRATION: jRCT identifier: jRCTs041210103.