ABSTRACT
BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Hepatitis B, Chronic , Hepatitis B , Jaundice , Lung Neoplasms , Humans , Hepatitis B virus , Immune Checkpoint Inhibitors/adverse effects , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/epidemiology , Hepatitis B Surface Antigens/pharmacology , Hepatitis B Surface Antigens/therapeutic use , Incidence , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/epidemiology , Cohort Studies , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Lung Neoplasms/chemically induced , Antiviral Agents/adverse effects , Immunoglobulin G/pharmacology , Immunoglobulin G/therapeutic use , Jaundice/chemically induced , Jaundice/complications , Jaundice/drug therapy , Hepatitis B/complications , Virus Activation , DNA, ViralABSTRACT
BACKGROUND: Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated. METHODS: As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm. RESULTS: In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm. CONCLUSIONS: Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.
Subject(s)
Indoles , Lung Neoplasms , Morpholines , Ovarian Neoplasms , Piperazines , Pyrimidines , Small Cell Lung Carcinoma , Sulfonamides , Humans , Female , Small Cell Lung Carcinoma/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/chemically induced , Treatment Outcome , Phthalazines/adverse effects , Ovarian Neoplasms/drug therapyABSTRACT
BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.
ABSTRACT
Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).
[Box: see text].
ABSTRACT
BACKGROUND: This retrospective study was performed to investigate the survival differences according to the pathologic status after neoadjuvant chemotherapy followed by surgery in esophageal squamous cell carcinoma (ESCC), and to investigate whether current AJCC 8th ypStage can predict survival accurately. METHODS: Data of 563 patients who received neoadjuvant therapy and esophagectomy for ESCC between 1994 and 2018 were retrospectively reviewed. RESULTS: The mean age was 62.00 ± 8.01 years, of which 524 (93.1%) were males. The median follow-up period was 29.12 months. A total of 153 (27.1%) patients showed pathologic complete response (pCR) and 92 (16.3%) patients showed pCR of the primary lesion with residual metastatic lymph nodes (ypT0N +). A total of 196 (35%) and 122 (21.6%) patients showed ypT + N + and ypT + N, respectively. The 5-year overall survival (OS) of each group was 75.1% (CR), 42.4% (ypT + N0), 54.9% (ypT0N +), and 26.1% (ypT + N +); CR patients showed better survival than the other groups, and no survival differences were found in the 5-year OS between ypT + N0 and ypT0N + patients (p = 0.811). In ypStage I, there were survival differences between ypT0N0 and ypTis-2N0 patients, and ypT1N0 (ypStage I) and ypT0N1 (ypStageIIIA) showed similar OS (5-year OS in 49.3% vs. 67.1%, p = 0.623). CONCLUSIONS: pCR offers long-term survival in patients; however, survival significantly declines with the presence of residual primary lesion and nodal metastases.
Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Male , Humans , Middle Aged , Aged , Female , Esophageal Squamous Cell Carcinoma/pathology , Prognosis , Neoadjuvant Therapy , Retrospective Studies , Esophageal Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Neoplasm Staging , Pathologic Complete ResponseABSTRACT
BACKGROUND: The current standard treatment for patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT). METHODS: Patients with locally advanced ESCC received 2 cycles of 5-fluorouracil, cisplatin, durvalumab, and tremelimumab every 3 weeks with concurrent radiation therapy (60.2 or 64.5 grays). After completing CCRT plus immunotherapy, patients received 2 cycles of consolidative durvalumab and tremelimumab followed by durvalumab monotherapy every 4 weeks for 2 years after enrollment. Their survival outcomes were compared with those from a propensity score-matched historical control group that had received CCRT alone. RESULTS: In total, 40 patients were enrolled and analyzed. The 24-month progression-free survival (PFS) and overall survival rates were 57.5% and 75%, respectively. Compared with the historical control group (n = 75), the study population had significantly longer PFS (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.97; P = .040) and overall survival (HR, 0.49; 95% CI, 0.25-0.98; P = .043). In the study population, patients who had PD-L1-positive tumors (n = 28) had significantly longer PFS (HR, 0.20; 95% CI, 0.07-0.54; P < .001) and overall survival (HR, 0.16; 95% CI, 0.05-0.56; P = .001) compared with those who had PD-L1-negative tumors (n = 11). However, there was no difference in survival outcomes according to PD-L1 status in the historical control group, indicating a strong interaction between PD-L1-positive status and survival outcomes in the treatment groups (PFS, P for interaction = .003; overall survival, P for interaction = .002). CONCLUSIONS: Durvalumab and tremelimumab with definitive CCRT had promising efficacy in patients with locally advanced ESCC. In addition, PD-L1 expression had strong predictive value in the study population.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen , Chemoradiotherapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/etiology , Esophageal Squamous Cell Carcinoma/etiology , Esophageal Squamous Cell Carcinoma/therapy , HumansABSTRACT
BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Double-Blind Method , Female , Humans , Male , Middle Aged , SurvivalABSTRACT
The evaluation of PD-L1 expression alone has limitations in predicting clinical outcome in immune-checkpoint inhibitors (ICI). This study aimed to evaluate the predictive and prognostic effects of the presence of various immune cells in pretreatment tissue samples and to identify determinants associated with response in patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1 blockade. Immune cell distribution was heterogeneous and the most dominant immune cell type was T cells. Patients with durable clinical benefit (DCB) showed significantly higher PD-L1 expression. The ratio of tumor/stroma region of T cell, B cell, and macrophage was significantly higher in patient with DCB. High intratumoral T- and B-cell density (≥median) was associated with DCB in the low PD-L1 expression (<50%) group. In univariate analyses, the overall survival (OS) benefit was shown according to intratumoral B-cell density (p = 0.0337). The incidence of hyperprogressive disease (HPD) was 13.0%. The Chi-square test revealed that HPD was significantly associated with intratumoral B-cell density but not T-cell or macrophage density. Our results demonstrate different predictive and prognostic values for infiltrating immune cells in tumor tissue, which may help in selecting patients for ICI.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Immune System/drug effects , Lung Neoplasms/drug therapy , Lymphocytes, Tumor-Infiltrating/drug effects , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/immunology , Female , Humans , Immune Checkpoint Inhibitors/immunology , Immune System/cytology , Immune System/immunology , Lung Neoplasms/immunology , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/cytology , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Prognosis , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , Treatment OutcomeABSTRACT
The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Thus, development of effective strategies to overcome resistance to EGFR TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR TKIs significantly decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR TKIs by overcoming acquired resistance.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm , ErbB Receptors , Humans , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVES: During targeted therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms. Sequential profiling of plasma cell-free DNA (cfDNA) provides a noninvasive method for early detection of patient progression. We investigated whether the genetic dynamics detected in cfDNA during treatment can act as a predictive or prognostic marker of outcome. METHODS: Patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) were included for consecutive blood sampling during EGFR-tyrosine kinase inhibitor (TKI) treatment. Blood samples were serially collected from patients at baseline, first follow-up, and progression. Extracted cfDNA was analyzed with next-generation sequencing. RESULTS: Serial plasma samples (n = 187) from 63 patients were analyzed, and 44 patients showed circulating tumor DNA (ctDNA). EGFR mutations were detected in 36 of the 44 patients at baseline (81.8%). EGFR mutations were no longer detected in 19 of 36 shedders (52.8%) at 2 months after EGFR-TKI treatment and rebounded with resistant EGFR mutations (T790M or C797S) at progression. Other driver mutations such as KRAS G12D and BRAF V600E were found at baseline regardless of tissue EGFR status, suggesting tumor heterogeneity. Detection of ctDNA (shedder) at baseline associated with poor overall survival (p = 0.04) compared to nonshedder. Furthermore, in patients showing EGFR mutations in plasma at baseline, the clearing rate of those during the first 8 weeks of treatment served as a positive predictor for clinical outcome. CONCLUSION: Longitudinal liquid biopsies capture spatial and temporal heterogeneity underlining resistance to EGFR-TKIs in NSCLC. Thus, ctDNA monitoring during EGFR-TKI treatment is useful for detecting resistance mutations or predicting response. Dense serial monitoring using blood enables early prediction of treatment failure and provides a window of opportunity for well-timed intervention.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: Because of the growing number of actionable biomarkers in non-small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue-based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay). METHODS: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment-naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]). RESULTS: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next-generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue-based NGS results (cohort 3), the ctDNA-based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA-based NGS (0.74%) was lower than that identified with the tissue-based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA-based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA-based testing uncovered 12.0% more actionable alterations when it was performed after tissue-based NGS testing. CONCLUSIONS: The results indicate that a ctDNA-based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue-based testing for NSCLC. LAY SUMMARY: Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non-small cell lung cancer. This study demonstrates the additive value of ctDNA-based testing in addition to tissue-based NGS and standard of care-based biomarker testing for detecting additional patients with actionable genomic alterations. Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA-based NGS testing.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Circulating Tumor DNA/genetics , Genomics , High-Throughput Nucleotide Sequencing/methods , Humans , Liquid Biopsy , Lung/pathology , Lung Neoplasms/pathology , Mutation , Republic of KoreaABSTRACT
The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T-cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non-small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T-cell activities leading to poor clinical outcomes. First, we verified PMN-MDSCs, monocytic-MDSCs (M-MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T-cell activities and induced T-cell exhaustion. The analysis of NSCLC patients treated with anti-PD-1 immunotherapy demonstrated that low PMN-MDSCs, M-MDSCs, and CD39+ CD8+ T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN-MDSCs, M-MDSCs, and CD39+ CD8+ T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers.
Subject(s)
Antigens, CD/immunology , Apyrase/immunology , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Non-Small-Cell Lung/immunology , Lung Neoplasms/immunology , Myeloid-Derived Suppressor Cells/immunology , Programmed Cell Death 1 Receptor/immunology , Adult , Aged , Aged, 80 and over , Female , Humans , Immunotherapy/methods , Lymphocyte Activation/immunology , Male , Middle AgedABSTRACT
INTRODUCTION: Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of nivolumab therapy for ESCC patients. METHODS: ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed. RESULTS: Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1-22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval [CI] 1.8-2.3) and 7.4 (95% CI 4.8-10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 [95% CI 1.8-13.1] vs. 1.9 [1.4-2.3] months, P = 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration. CONCLUSIONS: Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/metabolism , CD8 Antigens/metabolism , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Nivolumab/therapeutic use , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/genetics , Biomarkers, Tumor/metabolism , CD8 Antigens/genetics , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/mortality , Esophageal Squamous Cell Carcinoma/diagnosis , Esophageal Squamous Cell Carcinoma/mortality , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Programmed Cell Death 1 Receptor/immunology , Retrospective Studies , Survival AnalysisABSTRACT
Although immune checkpoint inhibitors have significantly improved clinical outcomes in various malignant cancers, only a small proportion of patients reap benefits, likely due to the low number of T cells and high number of immunosuppressive cells in the tumor microenvironment (TME) of patients with advanced disease. We developed a cancer vaccine adjuvanted with nanoemulsion (NE) loaded with TLR7/8 agonist (R848) and analyzed its therapeutic effect alone or in combination with immune checkpoint inhibitors, on antitumor immune responses and the reprogramming of suppressive immune cells in the TME. NE (R848) demonstrated robust local and systemic antitumor immune responses in both subcutaneous and orthotopic mouse lung cancer models, inducing tumor-specific T cell activation and mitigating T cell exhaustion. Combination with anti-PD-1 antibodies showed synergistic effects with respect to therapeutic efficacy and survival rate. Thus, NE (R848)-based cancer vaccines could prevent tumor recurrence and prolong survival by activating antitumor immunity and reprogramming immunosuppression.
Subject(s)
Cancer Vaccines/pharmacology , Lung Neoplasms/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Toll-Like Receptor 7/genetics , Toll-Like Receptor 8/genetics , Adjuvants, Immunologic/pharmacology , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , Emulsions/chemistry , Emulsions/pharmacology , Humans , Imidazoles/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lymphocyte Activation/drug effects , Mice , Programmed Cell Death 1 Receptor/immunology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Tumor Microenvironment/drug effectsABSTRACT
BACKGROUND: Excessive muscle loss is an important prognostic factor in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy (NACRT), as reported in our previous research. OBJECTIVE: In this pilot study, we prospectively tested the feasibility of a health coaching mobile app for preventing malnutrition and muscle loss in this patient population. METHODS: Between July 2019 and May 2020, we enrolled 38 male patients with esophageal cancer scheduled for NACRT. For 8 weeks from the start of radiotherapy (RT), the patients used Noom, a health coaching mobile app that interactively provided online advice about food intake, exercise, and weight changes. The skeletal muscle index (SMI) measured based on computed tomography and nutrition-related laboratory markers were assessed before and after RT. We evaluated the changes in the SMI, nutrition, and inflammatory factors between the patient group that used the mobile app (mHealth group) and our previous study cohort (usual care group). Additionally, we analyzed the factors associated with walk steps recorded in the app. RESULTS: Two patients dropped out of the study (no app usage; treatment changed to a definitive aim). The use (or activation) of the app was noted in approximately 70% (25/36) of the patients until the end of the trial. Compared to the 1:2 matched usual care group by propensity scores balanced with their age, primary tumor location, tumor stage, pre-RT BMI, and pre-RT SMI level, 30 operable patients showed less aggravation of the prognostic nutritional index (PNI) (-6.7 vs -9.8; P=.04). However, there was no significant difference in the SMI change or the number of patients with excessive muscle loss (∆SMI/50 days >10%). In patients with excessive muscle loss, the walk steps significantly decreased in the last 4 weeks compared to those in the first 4 weeks. Age affected the absolute number of walk steps (P=.01), whereas pre-RT sarcopenia was related to the recovery of the reduced walk steps (P=.03). CONCLUSIONS: For esophageal cancer patients receiving NACRT, a health care mobile app helped nutritional self-care with less decrease in the PNI, although it did not prevent excessive muscle loss. An individualized care model with proper exercise as well as nutritional support may be required to reduce muscle loss and malnutrition.
Subject(s)
Esophageal Neoplasms , Malnutrition , Mentoring , Mobile Applications , Chemoradiotherapy/adverse effects , Esophageal Neoplasms/therapy , Feasibility Studies , Humans , Male , Muscle, Skeletal , Neoadjuvant Therapy , Pilot Projects , Prospective StudiesABSTRACT
BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs. METHODS: Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy. RESULTS: A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism. CONCLUSION: Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Acrylamides/therapeutic use , Adult , Aged , Aged, 80 and over , Aniline Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Drug Resistance, Neoplasm , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Retrospective StudiesABSTRACT
BACKGROUND: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study. METHODS: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients). RESULTS: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/genetics , Neoplasm Recurrence, Local/drug therapy , Proto-Oncogene Proteins c-myc/genetics , Small Cell Lung Carcinoma/drug therapy , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzamides/administration & dosage , Biomarkers, Tumor/genetics , Drug-Related Side Effects and Adverse Reactions , Female , Gene Amplification/drug effects , Humans , Male , Middle Aged , Morpholines/administration & dosage , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Platinum/adverse effects , Progression-Free Survival , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Pyrimidinones/administration & dosage , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathologyABSTRACT
BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs). METHODS: Fifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab. RESULTS: For buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone. CONCLUSIONS: The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN. CLINICAL TRIAL REGISTRATION: NCT01527877.
Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cetuximab/therapeutic use , Head and Neck Neoplasms/drug therapy , Morpholines/therapeutic use , Adult , Aged , Aged, 80 and over , Aminopyridines/adverse effects , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Apoptosis/genetics , Cell Cycle Checkpoints/genetics , Cell Survival/drug effects , Cetuximab/adverse effects , DNA Copy Number Variations , Drug Resistance, Neoplasm , Female , Gene Expression Profiling , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/mortality , Humans , Male , Mice , Mice, Nude , Mice, SCID , Middle Aged , Morpholines/adverse effects , Mutation , Neoplasm Transplantation , Progression-Free Survival , Reproducibility of Results , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/mortality , Treatment Outcome , Up-Regulation/genetics , Whole Genome Sequencing/methodsABSTRACT
Entrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1 and ALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib in ROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in a ROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistant ROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition of KRAS G12C and the amplification of KRAS and FGF3. However, there were no secondary mutations in the ROS1 kinase domain. We also found that sustained ERK activation was involved in entrectinib resistance, and that combined treatment with selumetinib resensitized HCC78ER cells to entrectinib in cell viability and colony formation assays. Our data suggest that activation of the RAS signaling pathway can cause entrectinib resistance in ROS1-rearranged NSCLC, and is unlikely to be overcome by sequential single agent ROS1-targeting strategies against such tumors. Instead, co-targeting ROS1 and MEK may be an effective strategy for overcoming entrectinib resistance in ROS1-rearranged NSCLC.
Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , Indazoles/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Apoptosis/drug effects , Benzimidazoles/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Rearrangement , Humans , Lung Neoplasms/genetics , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mutation , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
BACKGROUND: Anti-PD1 inhibitors have been approved for the treatment of recurrent or metastatic head and neck cancer (HNC), as a result of Global Phase III trials. However, the clinical outcomes of immune checkpoint inhibitors in patients who are not eligible for clinical trials or have various medical conditions have not been fully elucidated. METHODS: We retrospectively reviewed 46 patients with recurrent or metastatic HNC who received pembrolizumab or nivolumab between June 2016 and June 2019. RESULTS: Thirty-five patients had head and neck squamous cell carcinoma (HNSCC) affecting the oropharynx, oral cavity, hypopharynx, larynx, nasal cavity, or paranasal sinuses, and eleven patients had nasopharyngeal cancer (NPC). The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.8 months, respectively, for patients with HNSCC, and 4.3 months and 11.8 months, respectively, for patients with NPC. The objective response rate (ORR) in all patients was 21%. Of 30 patients with HNSCC, 5 patients achieved complete response and 2 achieved partial response (ORR 23%); 1 of 8 NPC patients achieved partial response (13%). Patients who previously underwent radiotherapy had better OS than those who did not (median OS, 7.6 months vs. 2.3 months, p = 0.006). OS was longer in patients treated with pembrolizumab than in those treated with nivolumab (median OS, 11.8 months vs. 6.8 months, p = 0.017). CONCLUSION: Consistent with previous reports, immune checkpoint inhibitors showed promising efficacy in patients with previously treated recurrent or metastatic HNC in a real-world setting.