Comparing Three Different Anti-Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study.

Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

TTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1-positive groups than in TTF-1-negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1-positive groups than in TTF-1-negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1-positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Comprehensive Kinase Activity Profiling Revealed the Kinase Activity Patterns Associated with the Effects of EGFR Tyrosine Kinase Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients with Sensitizing EGFR Mutations.

EGFR mutations are strong predictive markers for EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with non-small-cell lung cancer (NSCLC). Although NSCLC patients with sensitizing EGFR mutations have better prognoses, some patients exhibit worse prognoses. We hypothesized that various activities of kinases could be potential predictive biomarkers for EGFR-TKI treatment among NSCLC patients with sensitizing EGFR mutations. In 18 patients with stage IV NSCLC, EGFR mutations were detected and comprehensive kinase activity profiling was performed using the peptide array PamStation12 for 100 tyrosine kinases. Prognoses were observed prospectively after the administration of EGFR-TKIs. Finally, the kinase profiles were analyzed in combination with the prognoses of the patients. Comprehensive kinase activity analysis identified specific kinase features, consisting of 102 peptides and 35 kinases, in NSCLC patients with sensitizing EGFR mutations. Network analysis revealed seven highly phosphorylated kinases: CTNNB1, CRK, EGFR, ERBB2, PIK3R1, PLCG1, and PTPN11. Pathway analysis and Reactome analysis revealed that the PI3K-AKT and RAF/ MAPK pathways were significantly enriched in the poor prognosis group, being consistent with the outcome of the network analysis. Patients with poor prognoses exhibited high activation of EGFR, PIK3R1, and ERBB2. Comprehensive kinase activity profiles may provide predictive biomarker candidates for screening patients with advanced NSCLC harboring sensitizing EGFR mutations.

Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer.

BACKGROUND: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. METHODS: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. RESULTS: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). CONCLUSION: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

High levels of AXL expression in untreated EGFR-mutated non-small cell lung cancer negatively impacts the use of osimertinib.

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

Osimertinib and Bevacizumab Cotreatment for Untreated EGFR-Mutated NSCLC With Malignant Pleural or Pericardial Effusion (SPIRAL II): A Single-Arm, Open-Label, Phase 2 Clinical Trial.

Introduction: First-line treatment of EGFR-mutated NSCLC with erlotinib plus antiangiogenic inhibitor exhibits promising results. However, the efficacy of this combination has not been fully investigated. Therefore, we evaluated the efficacy and safety of osimertinib plus bevacizumab in patients with EGFR-mutated NSCLC complicated with malignant pleural or pericardial effusion (MPE) for whom combination therapy may be particularly effective. Methods: This single-arm, open-label, phase 2 study aimed to investigate the clinical benefits of the bevacizumab (15 mg/kg) and osimertinib (80 mg) combination in the first-line setting for advanced EGFR-mutated NSCLC with MPE. The primary end point of this study was 1-year progression-free survival (PFS). The secondary end points were objective response rate, PFS, overall survival, drainage-free survival without the need for thoracic or pericardial drainage, and safety. Results: Between January 2019 and August 2020, a total of 31 patients with EGFR-mutated NSCLC were enrolled from Japan in the study. The median PFS was 8.5 months (95% confidence interval [CI]: 5.3-11.3), the 1-year PFS was 32.1% (80% CI: 21.4-43.3), and the objective response rate was 74.2% (95% CI: 56.8-86.3). The median overall survival was not reached. The median drainage-free survival was 18.4 months (95% CI: 10.3-not estimable). Anorexia was the most common grade 3 or higher adverse event (four patients, 12.9%), followed by fatigue and dyspnea (three patients, 9.7%). No treatment-related deaths were recorded. Conclusions: Osimertinib and bevacizumab combination in patients with advanced EGFR-mutated NSCLC with MPE were safe but did not effectively increase PFS when compared with the inferred value from previous literature.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

Background: Topoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors. Methods: This study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method. Results: A total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034). Conclusions: These results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

Efficacy and Safety of Paclitaxel/nab-paclitaxel Chemotherapy for Patients With Relapsed Small Cell Lung Cancer.

BACKGROUND/AIM: Systemic chemotherapy is effective for patients with untreated advanced small cell lung cancer (SCLC); however, most patients eventually experience recurrence. Therefore, development of novel beneficial and tolerable treatments for patients with relapsed SCLC is important. PATIENTS AND METHODS: In this retrospective observational study, we analyzed patients with relapsed SCLC who were treated with paclitaxel (PTX) or nab-paclitaxel (nab-PTX) at five institutions in Japan between April 2015 and September 2020. The relationships between the outcomes of PTX or nab-PTX and patient characteristics were examined. RESULTS: A total of 31 patients with SCLC treated with PTX or nab-PTX were enrolled. The response rate and disease control rate (DCR) were 9.7% and 67.7%, respectively. The median time-to-treatment failure (TTF) was 69.0 days (95% confidence interval=39.0-97.0). In multivariate analysis, TTF showed a significant difference in serum albumin level (≥3.6 g/dl) and platelet-to-lymphocyte ratio (≥250). Adverse events of any grade and grade ≥3 occurred in 23 (74.2%) and 15 (48.4%) patients, respectively. Among patients with grade ≥3 adverse events, hematological and non-hematological toxicities occurred in 12 (38.7%) and 6 (19.4%) patients, respectively. No treatment-related deaths were observed. Seven patients with interstitial lung disease were included in the study, and the efficacy and safety of treatment were equivalent to those of other patients. CONCLUSION: Treatment with PTX or nab-PTX is effective and tolerable for patients with relapsed SCLC, including those with interstitial lung disease. Our observations suggest that pretreatment inflammatory and nutritional indices may be useful biomarkers for treatment with PTX or nab-PTX.

Pembrolizumab monotherapy for untreated PD-L1-Positive non-small cell lung cancer in the elderly or those with poor performance status: A prospective observational study.

Objectives: We investigated the efficacy and safety of pembrolizumab monotherapy as first-line treatment for poor Eastern Cooperative Oncology Group performance status (PS) and elderly patients with programmed cell death-ligand 1 (PD-L1)-positive advanced non-small cell lung cancer (NSCLC). We also investigated clinical prognostic factors for the efficacy of pembrolizumab monotherapy, based on patient characteristics. Materials and methods: In this prospective observational study, PS-2 and elderly NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1% who received first-line pembrolizumab monotherapy, from October 2019 to March 2021, at 10 institutions in Japan were enrolled. Patients judged eligible by their physicians for combined chemotherapy and PD-1/PD-L1 inhibitors as first-line treatment were excluded. Clinicopathological characteristics and adverse events were investigated for correlation with clinical outcomes. Results: Forty patients were enrolled in the study. The median progression-free survival (PFS) of patients with PS 2 and those aged ≥ 75 years were 4.4 (95% confidence interval [CI]: 0.9-14.4) months and 5.3 (95% CI 2.9-9.4) months, respectively. The median overall survival (OS) of patients with PS 2 and those aged ≥ 75 years were 11.6 (95% CI: 1.4-not evaluable [NE]) months and 11.6 (95% CI 7.4-18.1) months, respectively. Immune-related adverse events (irAEs) were observed in 19 patients; 6 patients had severe irAEs of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher. Patients who achieved stable disease or better, had a statistically significant increase in PFS (p < 0.001) and OS (p < 0.001). In the multivariate analysis, the acquisition of disease control with pembrolizumab monotherapy was an independent prognostic factor for PFS and OS. Conclusion: Pembrolizumab monotherapy was relatively effective and tolerable as a first-line treatment for patients with PD-L1-positive advanced NSCLC who had poor PS or were elderly. Our results suggest that disease control might be an independent prognostic factor for PFS and OS in this population. (UMIN000044052 https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050176).

A Real-World Analysis of Immune Checkpoint Inhibitor-Based Therapy After Osimertinib Treatment in Patients With EGFR-Mutant NSCLC.

Introduction: The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC with EGFR mutations is limited. Previous studies have not evaluated the efficacy of ICI treatment after osimertinib treatment in real-world settings. Methods: This study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients with EGFR-mutant NSCLC treated with ICIs after osimertinib treatment at 12 institutions in Japan from March 2016 to March 2021. Results: Among 80 patients with EGFR-mutant lung cancer, 42 received ICI monotherapy and 38 received chemoimmunotherapy. In the chemoimmunotherapy group, the progression-free survival (PFS) was significantly longer in the group that exhibited PFS more than 10 months with osimertinib than in the group that exhibited PFS less than or equal to 10 months with osimertinib (8.4 mo versus 3.8 mo, p = 0.026). Nevertheless, there was no significant difference in PFS in the ICI monotherapy group (1.7 mo versus 1.5 mo, p = 0.45). Regardless of the EGFR mutation subtype, PFS of osimertinib treatment was a predictor of the PFS of chemoimmunotherapy (exon 19 deletion mutation: p = 0.03 and exon 21 L858R mutation: p = 0.001). Conclusions: The PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with EGFR-mutant NSCLC. Further clinical investigations on the predictors of efficacy of administering ICIs after osimertinib treatment are required.

Efficacy and Safety of Programmed Death-Ligand 1 Inhibitor Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC: A Prospective Observational Study.

Introduction: To date, the efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy for patients with extensive-stage SCLC (ES-SCLC), with real-world evidence, stratified on the basis of age and performance status (PS), have not been fully investigated. The aim of this study was to evaluate the efficacy and safety of PD-L1 inhibitor plus platinum-etoposide chemotherapy in patients with ES-SCLC. Methods: This multicenter prospective study evaluated patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy between September 2019 and October 2021. Results: A total of 45 patients with ES-SCLC received the aforementioned treatment, including 18 elderly (≥75 y old) patients and six patients with a PS of 2. Multivariate analysis indicated that a PS of 2 was a significant independent prognostic factor for progression-free survival and overall survival (p = 0.008 and p = 0.001, respectively). Of patients with PS of 2 at the initial phase, those that achieved PS improvement during treatment had significantly longer progression-free survival and overall survival than those who did not (p = 0.02 and p = 0.02, respectively). The incidence of adverse events accompanied with treatment discontinuation was significantly higher in the elderly patients than in the non-elderly patients (p = 0.03). Conclusions: This real-world prospective study found that PD-L1 inhibitor plus platinum-etoposide chemotherapy had limited efficacy in patients with ES-SCLC with a PS of 2, except for cases with improvement of PS during treatment. Owing to the emergence of adverse events and treatment discontinuation, this treatment should be administered with caution in elderly patients with ES-SCLC.

Safety and Immunogenicity of mRNA Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Lung Cancer Receiving Immune Checkpoint Inhibitors: A Multicenter Observational Study in Japan.

INTRODUCTION: Patients with cancer have been prioritized for vaccination against severe acute respiratory syndrome coronavirus 2. Nevertheless, there are limited data regarding the safety, efficacy, and risk of developing immune-related adverse events (irAEs) associated with mRNA vaccines in patients with lung cancer, especially those being actively treated with immune checkpoint inhibitors. METHODS: This multicenter observational study was conducted at nine hospitals in Japan. Patients with lung cancer (≥20 y) actively treated with immune checkpoint inhibitors between 4 weeks prefirst vaccination and 4 weeks postsecond vaccination were enrolled. The primary end point was the incidence of irAEs of any grade on the basis of an assumed incidence without vaccination rate of 35%. Immunogenicity was assessed by measuring anti-spike (S)-IgG antibody levels against severe acute respiratory syndrome coronavirus 2. RESULTS: A total of 126 patients with lung cancer (median age, 71 y; interquartile range, 65-74) were enrolled from May to November 2021 and followed up until December 2021. There were 26 patients (20.6%, 95% confidence interval: 13.9%-28.8%) and seven patients (5.6%, 95% confidence interval: 2.3%-11.1%) who developed irAEs of any grade pre- and postvaccination, respectively, which was lower than the predicted incidence without vaccination. None of the patients experienced exacerbation of preexisting irAE postvaccination. S-IgG antibodies were seroconverted in 96.7% and 100% of the patients with lung cancer and controls, respectively, but antibody levels were significantly lower in patients with lung cancer (p < 0.001). CONCLUSIONS: Patients with lung cancer who were actively treated with ICIs were safely vaccinated without an increased incidence of irAEs; however, their vaccine immunogenicity was lower. This requires further evaluation.

Prognostic Nutritional Index and Lung Immune Prognostic Index as Prognostic Predictors for Combination Therapies of Immune Checkpoint Inhibitors and Cytotoxic Anticancer Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer.

Combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapies (chemoimmunotherapy) is associated with significantly better survival outcomes than cytotoxic chemotherapies alone in patients with advanced non-small cell lung cancer (NSCLC). However, there are no prognostic markers for chemoimmunotherapy. The prognostic nutritional index (PNI) and lung immune prognostic index (LIPI) are prognostic biomarkers for immune checkpoint inhibitor (ICI) monotherapy or cytotoxic chemotherapies. Thus, we aimed to examine whether these factors could also be prognostic markers for chemoimmunotherapy. We retrospectively examined 237 patients with advanced NSCLC treated with chemoimmunotherapy. In the total group, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 8.6 months. Multivariate analysis of OS and PFS revealed significant differences based on PNI and LIPI. Programmed cell death ligand 1 (PD-L1) was also significantly associated with OS and PFS. PNI and a PD-L1 tumor proportion score (TPS) of <50% and poor LIPI (regardless of PD-L1 TPS) were associated with poor prognosis. PNI and LIPI predicted survival outcomes in patients with advanced NSCLC treated with chemoimmunotherapy, especially in patients with PD-L1 TPS <50%. For patients in this poor category, chemoimmunotherapy may result in a worse prognosis than expected.

Early discontinuation of induction therapy in chemoimmunotherapy as an effective alternative to the standard regimen in patients with non-small cell lung cancer: a retrospective study.

PURPOSE: We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy. METHODS: We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy. RESULTS: On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38-3.37, p < 0.001 and HR 2.32, 95% confidence interval: 1.40-3.84, p = 0.001, respectively). There was no obvious difference in PFS between the group in which induction chemotherapy ended in two or three courses leading to partial or complete response, and the group that continued at least four courses of induction chemotherapy (log-rank test p = 0.53). CONCLUSION: Treatment efficacy may be maintained if induction chemotherapy is completed in less than four courses owing to development of AEs, and is administered for more than two courses with partial or complete response; efficacy is maintained even on transitioning to maintenance therapy.

Impact of docetaxel plus ramucirumab in a second-line setting after chemoimmunotherapy in patients with non-small-cell lung cancer: A retrospective study.

BACKGROUND: Chemoimmunotherapy has become a standard treatment option for patients with untreated advanced non-small-cell lung cancer (NSCLC). However, numerous patients with advanced NSCLC develop disease progression. Therefore, the selection of second-line treatment after chemoimmunotherapy is crucial for improving clinical outcomes. METHODS: Of 88 enrolled patients with advanced NSCLC who received chemoimmunotherapy, we retrospectively evaluated 33 who received second-line chemotherapy after progression of chemoimmunotherapy at six centers in Japan. Among them, 18 patients received docetaxel plus ramucirumab and 15 patients received single-agent chemotherapy. RESULTS: The objective response rate in patients treated with docetaxel plus ramucirumab was significantly higher than that in patients treated with a single-agent chemotherapy regimen (55.6% vs. 0%, p < 0.001). The median progression-free survival (PFS) of patients who received docetaxel plus ramucirumab and single-agent chemotherapy was 5.8 months and 5.0 months, respectively (log-rank test p = 0.17). In the docetaxel plus ramucirumab regimen group, patients who responded to chemoimmunotherapy for ≥8.8 months had a significantly longer response to docetaxel plus ramucirumab than those who responded for <8.8 months (not reached vs. 4.1 months, log-rank test p = 0.003). In contrast, in the single-agent chemotherapy group, there was no significant difference in PFS between the ≥8.8- and <8.8-month PFS groups with chemoimmunotherapy (5.0 vs. 1.6 months, log-rank test p = 0.66). CONCLUSION: Our retrospective observations suggest that the group with longer PFS with chemoimmunotherapy might be expected to benefit from docetaxel plus ramucirumab treatment in second-line settings for patients with advanced NSCLC.

Impact of maintenance therapy following induction immunochemotherapy for untreated advanced non-small cell lung cancer patients.

PURPOSE: The primary objective of this study was to identify the potential predictors to assess the impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at 8 hospitals in Japan between January 2019 and December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. RESULTS: Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents, whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas, among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). CONCLUSIONS: This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

Impact of tumor programmed death ligand-1 expression on osimertinib efficacy in untreated EGFR-mutated advanced non-small cell lung cancer: a prospective observational study.

BACKGROUND: Osimertinib monotherapy is currently the standard of care as a first-line treatment for patients harboring epidermal growth factor receptor (EGFR) mutations; however, some EGFR-mutated non-small cell lung cancer (NSCLC) patients exhibit primary resistance and an insufficient response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Elevated programmed death-ligand 1 (PD-L1) expression in tumors was reported as a negative predictive factor for outcomes of first- or second-generation EGFR-TKIs. METHODS: We prospectively assessed advanced NSCLC patients with EGFR mutations who were treated with osimertinib at 14 institutions in Japan between September 2019 and December 2020. Relationships between outcomes of osimertinib monotherapy and patients' characteristics were reviewed. RESULTS: Seventy-one patients who underwent the tumor PD-L1 test were enrolled. Multivariate analysis identified tumor PD-L1 expression as an independent predictor for progression-free survival (PFS) with osimertinib treatment (P=0.029). The objective-response and disease-control rates for osimertinib treatment were significantly lower in patients demonstrating elevated PD-L1 levels relative to those with low or negative PD-L1 level (P=0.043 and P=0.007, respectively). Furthermore, among patients treated with osimertinib, those with high PD-L1 levels exhibited shorter PFS relative to those with low plus negative PD-L1 level (median PFS: 5.0 vs. 17.4 months; P<0.001). CONCLUSIONS: Elevated tumor PD-L1 expression is associated with poor outcomes of osimertinib monotherapy in previously untreated advanced NSCLC patients with EGFR mutation. Further clinical trials are warranted to accumulate evidence demonstrating the effectiveness of combination therapy with osimertinib for EGFR-mutated advanced NSCLC patients with elevated tumor PD-L1 expression. TRIAL REGISTRATION: UMIN000043942.

Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.

OBJECTIVES: Combination therapy of immune checkpoint inhibitors and chemotherapy is considered to be one of the standard treatment options for patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical significance of immune checkpoint inhibitors combined with chemotherapy in elderly patients with NSCLC has not yet been fully understood. Therefore, this study aimed to evaluate how aging affects the therapeutic impact of chemotherapy combine with immune checkpoint inhibitors in elderly patients. MATERIALS AND METHODS: We retrospectively analyzed 203 patients with advanced NSCLC who were treated with the combination therapy of pembrolizumab and chemotherapy between January 2019 and December 2019 at 12 institutions in Japan. We analyzed the clinical impacts of age on the following two groups: those who received pembrolizumab with platinum and pemetrexed (pemetrexed regimen) and those who received pembrolizumab with carboplatin and nab-paclitaxel/paclitaxel (paclitaxel regimen). Progression-free and overall survival were assessed via the Kaplan-Meier method. RESULTS: Multivariate analysis demonstrated that progression-free and overall survival were significantly shorter in elderly patients (aged ≥75 years) with NSCLC than in non-elderly patients (aged <75 years) with NSCLC in the pemetrexed regimen group. In contrast, there were no significant differences in progression-free and overall survival between elderly patients and non-elderly patients with NSCLC in the paclitaxel regimen group. In elderly patients with NSCLC, a programmed death-ligand 1 tumor proportion score of ≥50% was significantly associated with progression-free survival, and performance status of ≥2 was significantly associated with overall survival. Low albumin level (<3.5 g/dL) was significantly associated with both progression-free and overall survival. CONCLUSION: The results of this retrospective study show that the pemetrexed regimen, but not the paclitaxel regimen, was related to poor clinical outcomes in elderly patients with NSCLC.