Lack of Association Between Immunotherapy and Improvement of Survival for Non-small Cell Lung Cancer Patients With Hemodialysis: A Nationwide Retrospective Cohort Study.

BACKGROUND: The number of patients undergoing hemodialysis continues to increase globally, and the incidence of cancer is high among these patients. Immune checkpoint inhibitors are widely used in patients with advanced cancer, especially non-small cell lung cancer (NSCLC); however, their effectiveness in hemodialysis patients is poorly documented. METHODS: This retrospective cohort study used data from a nationwide database. Patients diagnosed with NSCLC, undergoing hemodialysis, and who started chemotherapy between September 2008 and January 2023 were included. In the intention to treat (ITT) analysis, patients were divided into immune checkpoint inhibitor (ICI) and conventional chemotherapy group, and in the chronological analysis, patients were divided into 2 groups before and after ICI approval. Overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards analyses. A propensity score approach was applied to address confounding factors, and analyses were performed by weighting each patient with the inverse of the estimated propensity score. RESULTS: We identified 322 and 389 patients in the ITT and chronological analyses respectively. In both analyses, there were no notable difference of OS between 2 groups (P values by log-rank test 0.933 and 0.248, respectively). The hazard ratios for OS were 0.980 (95% confidence interval [CI]: 0.678-1.415) in the ITT analysis and 0.805 (95% CI: 0.531-1.219) in the chronological analysis. CONCLUSION: The ICI treatment and approval were not significantly associated with improvement of survival in patients with NSCLC undergoing hemodialysis.

Analysis of Risk Factors for Febrile Neutropenia in Patients with Small-Cell Lung Cancer Receiving Carboplatin plus Etoposide Therapy.

Introduction Febrile neutropenia (FN) is an oncologic emergency requiring immediate empiric antibiotic therapy. Although carboplatin plus etoposide combination chemotherapy is associated with a relatively high frequency of FN, the risk factors are unclear. Hence, this retrospective study aimed to identify predictive markers of carboplatin/etoposide-induced FN. Methods We conducted a retrospective cohort analysis of patients with previously untreated small-cell lung cancer who received combination chemotherapy with carboplatin (area under the concentration curve: 5 mg/mL·min, day 1) and etoposide (80 or 100 mg/m2, days 1-3) between July 2007 and June 2022. FN was assessed during the 21 days after initiation of carboplatin and etoposide therapy according to the Japanese Society of Medical Oncology's definition. Fisher's exact test for categorical variables and Mann-Whitney U-test for continuous variables were used to compare the two groups. Statistical significance was set at p values <0.05. Explanatory variables with p values <0.05 in the univariate analysis were included in the multivariate logistic regression analysis. Results Among the 176 eligible patients, the incidence of FN during the first cycle of chemotherapy was 25.0% (44/176). Multivariate analysis revealed that co-administration of proton pump inhibitors (PPIs) or potassium-competitive acid blockers (PCABs) and body mass index (BMI) were significantly associated with FN (p=0.0035 and 0.0011, respectively). Patients with both co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 presented with significantly higher frequencies of FN compared with the other patients (13/24 [54.2%] vs. 31/152 [20.4%] patients; odds ratio: 4.56, 95% confidence interval: 1.70-12.48; p=0.00147). Conclusion Patients who received carboplatin plus etoposide for SCLC with co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 more frequently present with FN than those without the two factors.

RBM17 Expression Is Associated With the Efficacy of ICI Monotherapy in NSCLC With Low PD-L1 Expression.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. PATIENTS AND METHODS: Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. RESULTS: Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). CONCLUSION: RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.

Clinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer.

PURPOSE: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. METHODS: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. RESULTS: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10-2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 - 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). CONCLUSION: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes.

Vimentin expression correlates with immune checkpoint inhibitor efficacy in non-small cell lung cancer.

BACKGROUND: Although vimentin is often expressed in non-small cell lung cancer (NSCLC), the association between vimentin expression and immune-checkpoint inhibitor (ICI) efficacy remains unclear. METHODS: This retrospective multicenter study enrolled patients with NSCLC who received ICI treatment between December 2015 and July 2020. The authors constructed tissue microarrays and performed immunohistochemical staining with vimentin. They analyzed the relationship between vimentin expression rate and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Immunohistochemically evaluable specimens on microarray blocks were available for 397 patients, of whom 343 (86%) were negative (<10%), 30 (8%) were positive (10%-49%), and 24 (6%) were highly positive (≥50%) for vimentin expression. Both rates of programmed death-ligand 1 (PD-L1) tumor proportion score ≥1% and ≥50% were significantly higher in the vimentin-positive group (≥10%) than the vimentin-negative group (<10%) (96% vs. 78%, p = .004; 64% vs. 42%, p = .006, respectively). In patients treated with ICI monotherapy, ORR, PFS, and OS were significantly better in the vimentin-positive group (10%-49%) than in the vimentin-negative group (<10%) (54% vs. 25%, p = .003, median = 7.9 vs. 3.2 months, p = .011; median = 27.0 vs. 13.6 months, p = .015, respectively), whereas there was no significant difference in PFS and OS between the vimentin highly positive group (≥50%) and the vimentin-negative group (<10%) (median = 3.4 vs. 3.2 months, p = .57; median = 7.2 vs. 13.6 months, p = .086, respectively). CONCLUSIONS: Vimentin expression correlated with PD-L1 expression and ICI efficacy. PLAIN LANGUAGE SUMMARY: We constructed tissue microarrays and performed immunohistochemical staining with vimentin on 397 patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitor (ICI). The vimentin-positive group who were treated with ICI monotherapy showed significantly better objective response rate, progression-free survival, and overall survival than the vimentin negative group. The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies.

Influence of Smoking History on the Effectiveness of Immune-checkpoint Inhibitor Therapy for Non-small Cell Lung Cancer: Analysis of Real-world Data.

BACKGROUND/AIM: There is no real-world data in an Asian population to investigate the difference between the outcome of immune-checkpoint inhibitor (ICI) monotherapy and combination therapy for non-small cell lung cancer (NSCLC) based on smoking status. In this study, we investigated the correlation between smoking status and the efficacy of ICI therapy for NSCLC patients. PATIENTS AND METHODS: This multicentre retrospective study enrolled patients with recurrent or metastatic NSCLC who were treated using ICI therapy between December 2015 and July 2020. We analysed the objective response rate (ORR) of patients who received ICI monotherapy or combination therapy, based on smoking status using Fisher's exact test, and progression-free survival (PFS) and overall survival (OS) based on smoking status using the Kaplan-Meier method, the log-rank test, and Cox proportional hazards model. RESULTS: A total of 487 patients were included in the study. In the ICI monotherapy group, non-smokers showed significantly lower ORR and shorter PFS and OS than smokers (10% vs. 26%, p=0.002; median: 1.8 vs. 3.8 months, p<0.001; median: 8.0 vs. 15.4 months, p=0.026). In the ICI combination therapy group, non-smokers showed significantly longer OS than smokers (median: not reached vs. 26.3 months, p=0.045), and there was no significant difference in ORR and PFS between non-smokers and smokers (63% vs. 51%, p=0.43; median: 10.2 vs. 9.2 months, p=0.81). In the multivariate analysis of patients who received ICI combination therapy, the "non-smoker" status was not significantly associated with PFS [hazard ratio (HR)=1.31; 95% confidence interval (CI)=0.70-2.45, p=0.40] and OS (HR=0.40; 95% CI=0.14-1.13, p=0.083). CONCLUSION: Non-smokers showed worse outcomes than smokers with ICI monotherapy, but not with ICI combination therapy.

The Impact of Estrogen Receptor Expression on Mutational Status in the Evolution of Non-Small Cell Lung Cancer.

BACKGROUND: The role of estrogen receptor (ER) status in the carcinogenesis of lung cancer and its impact on prognosis remain unclear. MATERIALS AND METHODS: We previously reported a prospective, multicenter, molecular epidemiology study (Japan Molecular Epidemiology for Lung Cancer Study [JME]). We examined the relationship of ER status with reproductive and hormonal factors, mutational profile, and survival using JME study data. Patients were enrolled between July 2012 and December 2013, with follow-up until November, 2017. RESULTS: Among 441 ever- and 435 never-smokers, ER expression was observed in 46.4% and 53.5%, respectively (P = .022). Hormone use and reproductive history of female patients were not associated with ER status. Mutations in EGFR (P = .003), TP53 (P = .007), and CTNNB1 (P = .027) were significantly associated with ER expression. Multivariate analysis showed that mutations in EGFR (P = .032) and CTNNB1 (P = .026) were significantly associated with ER expression, whereas TP53 mutations exhibited a trend toward significance (P = .059). Relapse-free survival (RFS) was longer in all the patients with ER-positive tumors than those with ER-negative tumors (P = .021). RFS and overall survival were longer (P = .024, P = .011, respectively) in the stage I patients with ER-positive tumors than those with ER-negative tumors. CONCLUSION: ERß expression is positively associated with EGFR mutations and negatively with TP53 and CTNNB1 mutations. ER-positive tumors can be associated with better prognosis of the patients, suggesting that ER expression with coexisting EGFR mutations and wild-type TP53 contribute to the biology of non-small cell lung cancer.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

Association of thyroid transcription factor-1 with the efficacy of immune-checkpoint inhibitors in patients with advanced lung adenocarcinoma.

BACKGROUND: We aimed to identify the relationship between thyroid transcription factor-1 (TTF-1) expression of lung adenocarcinoma and the efficacy of immune-checkpoint inhibitor (ICI) therapy. METHODS: This retrospective multicenter study comprised patients with advanced lung adenocarcinoma treated with ICI monotherapy. We collected clinical medical records including data on TTF-1 expression and analyzed the relationship between TTF-1 expression and programmed death-ligand 1 tumor proportion score (PD-L1 TPS), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 108 patients with lung adenocarcinoma were analyzed. The rate of TPS ≥1% and ≥50% in patients with positive TTF-1 expression was significantly higher than that in patients with negative TTF-1 expression (88% vs. 60%, p < 0.001; 65% vs. 24%, p < 0.001). The ORR was significantly higher in TTF-1 positive patients than in TTF-1-negative patients (38% vs. 8%, p = 0.003). Among patients with TPS ≥50% and 1%-49%, the ORR in TTF-1 positive and negative patients was 48% (26/54) versus 17% (1/6) (p = 0.21), and 32% (6/19) versus 11% (1/9) (p = 0.37), respectively. The ORR for patients with TPS <1% was 0% in both the TTF-1 negative and positive cases. The median PFS and OS was significantly longer in TTF-1-positive patients than in TTF-1-negative patients (5.4 vs. 1.6 months, p < 0.001; 18.2 vs. 8.0 months, p = 0.041). Multivariate analysis revealed that TTF-1-negative status was an independent unfavorable prognostic factor for PFS. CONCLUSION: Patients with TTF-1-positive status receiving ICI monotherapy showed better outcomes than those with TTF-1-negative lung adenocarcinoma.

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival, and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.

Safe Concurrent Use of Anti-tuberculosis Drugs and Pembrolizumab in a Patient with Non-small-cell Lung Cancer Who Was Infected with Mycobacterium tuberculosis.

A 68-year-old Japanese man was diagnosed with lung adenocarcinoma stage IVB. We introduced a first-line chemotherapy of four cycles of carboplatin and pemetrexed and pembrolizumab, followed by pemetrexed and pembrolizumab maintenance therapy. Approximately four months after anticancer therapy, a small nodule appeared in the right peripheral S3 lesion. After five months, the nodule was confirmed as a Mycobacterium tuberculosis (TB) nodule. We initiated anti-TB therapy without stopping pembrolizumab, and the right S3 nodule shrank immediately. This report supports the concurrent use of anti-TB treatment with an immune checkpoint inhibitor when the TB infection area is limited.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in advanced non-small cell lung cancer: a subanalysis of Asian patients in CheckMate 9LA.

BACKGROUND: CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall survival (OS) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (4 cycles). We present results for the Asian subpopulation enrolled in Japan and China. METHODS: Patients aged ≥ 18 years with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0-1 and no sensitizing EGFR/ALK mutations were randomized 1:1 to nivolumab [360 mg every 3 weeks (Q3W)] plus ipilimumab (1 mg/kg Q6W) combined with chemotherapy (Q3W for 2 cycles), or chemotherapy alone (Q3W for 4 cycles). Primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Twenty-eight patients received nivolumab plus ipilimumab combined with chemotherapy and 30 received chemotherapy. At a minimum follow-up of 12.7 months, median OS was not reached with nivolumab plus ipilimumab combined with chemotherapy versus 13.3 months with chemotherapy [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.80]. Median PFS was 8.4 versus 5.4 months (HR 0.47; 95% CI 0.24-0.92) and ORR was 57% versus 23%, respectively. Grade 3-4 treatment-related adverse events were observed in 57% versus 60% of patients, respectively. CONCLUSION: Consistent with results in the all randomized population, nivolumab plus ipilimumab combined with chemotherapy improved efficacy in the Asian subpopulation versus chemotherapy alone and had a manageable safety profile, supporting its use as first-line treatment for advanced NSCLC in Asian patients.

SP142 evaluation contributes to the prediction of immune checkpoint inhibitor efficacy in non-small cell lung cancer with high PD-L1 expression assessed by 22C3.

Background: It remains unclear whether assessing programmed death-ligand 1 (PD-L1) expression by SP142 plus 22C3 adds value for predicting the response to immunotherapy in non-small cell lung cancer (NSCLC). Methods: This retrospective multicenter study included patients with advanced NSCLC treated with immune-checkpoint inhibitors. We constructed tissue microarrays (TMAs) and performed immunohistochemical staining with 22C3 and SP142 assays. We denoted the PD-L1 tumor proportion score (TPS) obtained from clinical medical records based on 22C3 staining as "22C3 (C)" and that obtained with 22C3 staining using our TMA as "22C3 (TMA)". SP142 staining was evaluated in both tumor cells and immune cells. We assessed the concordance between each PD-L1 assessment method and analyzed the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) based on the PD-L1 expression level determined using the 22C3 and SP142 assays. Results: In total, 288 patients were included. Among those with 22C3 (TMA) ≥50%, 60% of patients showed SP142 TC3 or IC3; among patients with 22C3 (C) <1%, 9% and 18% exhibited 22C3 (TMA) ≥1% and SP142 TC1/2/3 or IC1/2/3, respectively. Among patients with 22C3 (C) ≥50% treated with immune-checkpoint inhibitor monotherapy, the SP142 TC1/2/3 or IC1/2/3 group showed significantly better ORR, PFS and OS than the SP142 TC0 and IC0 group (54% vs. 29%, P=0.040, median =11.0 vs. 3.2 months, P=0.002, median =27.9 vs. 12.6 months, P=0.030, respectively). Multivariate analysis revealed that SP142 TC0 and IC0 was an independent unfavorable prognostic factor for PFS and OS in patients with 22C3 (C) ≥50% treated with immune-checkpoint inhibitor monotherapy. For those with 22C3 (C) ≥50% and SP142 TC0 and IC0, immune-checkpoint inhibitor concurrent with chemotherapy tended to result in a longer PFS and OS than immune-checkpoint inhibitor monotherapy (median =13.7 vs. 2.3 months, P=0.054, median = not estimable vs. 12.0 months, P=0.064, respectively). Conclusions: SP142 evaluation contributes to the prediction of immune-checkpoint inhibitor efficacy in NSCLC with high PD-L1 expression assessed by 22C3.

Pretreatment Platelet Count and Neutrophil/Lymphocyte Ratio Are Predictive Markers for Carboplatin Plus Pemetrexed Therapy-induced Thrombocytopenia.

BACKGROUND/AIM: This study aimed to identify the predictive markers for carboplatin-induced severe thrombocytopenia. PATIENTS AND METHODS: We conducted a retrospective cohort analysis of inpatients who received carboplatin and pemetrexed. RESULTS: Among the 106 eligible patients, the incidence rate of grade ≥3 thrombocytopenia was 29.2% (31/106). Multivariate analysis revealed that grade ≥3 thrombocytopenia was associated with platelet count ≤26.6×104/mm3 [odds ratio (OR)=24.70, 95% confidence interval (CI)=5.75-106.00; p<0.001], neutrophil/lymphocyte ratio (NLR) >2.856 (OR=15.10, 95%CI=2.89-78.60; p=0.0013) and prognostic nutritional index ≤42.511 (OR=6.25, 95%CI=1.53-25.60; p=0.011). In particular, patients with both platelet counts ≤26.6×104/mm3 and NLR >2.856 presented with significantly higher frequencies of thrombocytopenia compared to those without these two factors [23/34 patients (67.6%) vs. 8/72 patients (11.1%), OR=16.1, 95%CI=5.40-53.6; p<0.001]. CONCLUSION: Platelet counts ≤26.6×104/mm3 and NLR >2.856 are predictive markers for carboplatin-induced thrombocytopenia.

Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non-small cell lung cancer patients with asymptomatic brain metastases.

OBJECTIVES: The study was designed to investigate the safety of ramucirumab administered in combination with erlotinib or osimertinib for patients with untreated EGFR-mutated non-small cell lung cancer (NSCLC) and asymptomatic brain metastases, a patient subgroup in which these regimens have remained untested. MATERIALS AND METHODS: This phase 1b study (RELAY-Brain) consisted of two cohorts with three patients each. Patients with asymptomatic brain metastases received ramucirumab every 2 weeks plus either daily oral erlotinib or osimertinib until disease progression or intolerable toxicity. The primary objective was to assess dose-limiting toxicity (DLT), defined as central nervous system (CNS) hemorrhage of grade ≥ 2. RESULTS: Six patients were enrolled. Neither DLT nor serious or unexpected adverse events were observed. One treatment-related adverse event of grade ≥ 3 (hypertension of grade 3) was apparent. Common adverse events were generally manageable. The median number of ramucirumab administrations was 18.5 (range, 13 to 31), and there were no detected episodes of CNS hemorrhage. Five of the six patients showed an objective systemic response. Although only one patient had a measurable CNS lesion at baseline, a confirmed intracranial partial response was observed. CONCLUSION: Ramucirumab in combination with erlotinib or osimertinib showed safety for EGFR-mutated NSCLC with brain metastases.

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

BACKGROUND: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). METHODS: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance. RESULTS: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib. CONCLUSIONS: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.

Tumor microenvironment disparity in multiple primary lung cancers: Impact of non-intrinsic factors, histological subtypes, and genetic aberrations.

INTRODUCTION: Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity. MATERIALS AND METHODS: In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0-2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes. RESULTS: Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones. CONCLUSION: Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.

Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Clinical benefit for clinical sequencing using cancer panel testing.

BACKGROUND: Clinical sequencing using a panel of genes has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospital. METHODS: A total of 39 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 36 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors. RESULTS: Pathogenic alterations were detected in 28 (78%) of the 36 patients. The most common mutation was TP53 (55%), followed by KRAS (22%), and the highest frequency of gene amplification was ERBB2 (17%). Nine of the 36 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but only one case ended up receiving novel targeted therapy following the genetic tests. CONCLUSIONS: Our current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. However, molecular target based on actionable genomic alteration does not always bridge to subsequent therapy due to clinical deterioration, refusal for unapproved drug, and complexity of clinical trial access. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.

5-Hydroxytryptamine-3 receptor antagonist and dexamethasone as prophylaxis for chemotherapy-induced nausea and vomiting during moderately emetic chemotherapy for solid tumors: a multicenter, prospective, observational study.

BACKGROUND: Of patients receiving moderate emetic risk chemotherapy (MEC), 30-90% experience chemotherapy-induced nausea and vomiting (CINV); however, the optimal antiemetic treatment remains controversial. METHODS: In this multicenter, prospective, observational study of adults treated with MEC while receiving chemotherapy for various cancer types in Japan, the enrolled patients kept diaries documenting CINV. All participants received a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. RESULTS: Of the 400 patients enrolled from May 2013 to January 2015, 386 were eligible for evaluation. The median age was 64 (range, 26-84). The overall complete response (CR; no emetic events and no antiemetic measures) rate was 64%. The proportion of patients showing CR was low in the carboplatin (CBDCA)- and oxaliplatin-based chemotherapy groups, especially among women. We showed that the CR rates in men were high in the CBDCA (AUC5) + etoposide (ETP) (80%), capecitabine plus oxaliplatin (CAPOX) (78%), and CBDCA+ paclitaxel (PTX) groups for lung cancer (73%). Total control (TC; no emetic events, no antiemetic measures, and no nausea) and complete control (CC; no emetic events, no antiemetic measures, and less than mild nausea) were achieved in 51 and 61% of patients, respectively. Logistic regression analysis revealed history of motion sickness, history of pregnancy-associated vomiting and CBDCA-based chemotherapy as risk factors for CR and history of motion sickness and history of pregnancy-associated vomiting as risk factors for TC. Additional, Ages ≥65 years is an independent predictive factor for achieving TC. CONCLUSIONS: Our data showed that two antiemetics were insufficient to control CINV in patients receiving CBDCA- or oxaliplatin-based chemotherapy. However, two antiemetics may be sufficiently effective for elderly male patients receiving CBDCA (AUC5) + ETP, CBDCA+PTX for lung cancer, or CAPOX. Additionally, we consider that three antiemetics are necessary for women with colorectal cancer receiving CAPOX. Risk factor analysis related to CR showed that CINV prophylaxis in patients treated with CBDCA-based chemotherapy was generally supportive of the guideline-recommended three antiemetics. However, the control of nausea in patients receiving non-CBDCA-based chemotherapy is a key point to note. The further individualization of antiemetic regimens for patients receiving MEC based on both types of chemotherapy regimens and sex is needed.