We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non-small cell lung cancer (NSCLC) using a large-scale prospective ...screening cohort (LC-SCRUM-Liquid).
Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing.
Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months.
Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA. See related commentary by Jacobsen Skanderup et al., p. 1381.
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer ...(NSCLC)
. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC
. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Abstract
Lung cancer is the most common cause of cancer-related death globally. In addition, its incidence increases with age, with approximately half of all cases diagnosed in patients aged ≥70. ...Molecular targeted therapies and immunotherapies for advanced non-small-cell lung cancer have markedly improved outcomes over the past two decades. Despite the high incidence of lung cancer in older people, most trials excluded such patients from enrollment. Therefore, the optimal treatment strategies for older patients remain unclear. The present review summarizes the published literature and provides guidance on the treatment of older patients with lung cancer within three broad stages: (i) early-stage lung cancer, (ii) locally advanced lung cancer and (iii) metastatic lung cancer. We also discuss the use of the latest evidence for older patients.
•Osimertinib 80 mg showed limited efficacy for NSCLC with EGFR ex20ins mutations.•The mutation type-specific concentration-dependency of osimertinibwas highlighted.•This study proposes higher dose ...osimertinib for NSCLC with EGFR ex20ins mutations.
Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC.
From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy.
Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC.
Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.
Abstract
Background
Superior sulcus tumours (SSTs) are relatively uncommon and one of the most intractable lung cancers among non-small cell lung cancer (NSCLC). We planned a multicenter, single-arm ...confirmatory trial of new multidisciplinary treatment using immune-checkpoint inhibitor. The aim is to evaluate the safety and efficacy of new multidisciplinary treatment with perioperative durvalumab after chemoradiotherapy (CRT).
Methods
The primary endpoint is 3-year overall survival. Patients receive induction CRT with sequential two courses of durvalumab, followed by surgical resection for resectable SST. The regimen for CRT is two courses of cisplatin and S-1, and concurrent radiotherapy (66 Gy/33 Fr). After surgery, 22 courses of post-operative durvalumab therapy are administered. For unresectable SST, an additional 22 courses of durvalumab are administered after induction durvalumab.
Results
In two cases as a safety cohort, the safety of intervention treatment up to 30 days after surgery was examined, and there were no special safety signals. Patient enrollment has now resumed in the main cohort.
Conclusions
The results of this study may contribute to the establishment of a new standard of care for SST, which is an intractable NSCLC.
The aim was to evaluate the safety and efficacy in multidisciplinary treatment of perioperative durvalumab after CRT followed by surgery for resectable SST and durvalumab maintenance for unresectable SST.
The treatments for advanced non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the 5-year survival of patients with Stage III NSCLC who underwent ...surgical resection alone has been dismal. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy is considered to be an appropriate treatment approach for Stage IIIA NSCLC patients; although, optimal treatment strategies are still evolving. When N2 nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy confers an overall survival benefit. The addition of postoperative radiotherapy might be considered for patients with nodal metastases. Although definitive chemoradiation remains a standard of care for cN2 NSCLC, alternative approaches such as induction chemotherapy or chemoradiotherapy and surgery can be considered for a selective group of patients. When surgical resection can be performed after induction therapy with low risk and a good chance of complete resection, the outcome may be optimal. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection.
The aim of this study was to identify patients with pathological stage I lung adenocarcinoma at high risk of recurrence.
We retrieved data from 536 patients with pathological stage I lung ...adenocarcinoma who underwent lobectomy and were enrolled in a prospective multiinstitutional study (the JCOG0201 study). Invasive component size, excluding lepidic component, was used as the tumor size. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method, and a multivariable Cox proportional hazards model identified independent prognostic factors associated with worse RFS.
The all-patient 10-year RFS was 83.9% (median follow-up 10.2 years). Multivariable Cox analysis revealed that age greater than 65 years (hazard ratio HR, 2.60; 95% confidence interval (CI), 1.66-4.07), invasive component size greater than 2 cm (HR, 2.70; 95% CI, 1.40-5.23), visceral pleural invasion (HR, 2.17; 95% CI, 1.23-3.81), and vascular invasion (HR, 2.59; 95% CI, 1.47-4.55) were potential independent prognostic factors for RFS. When patients were divided into a high-risk group for recurrence (invasive component size >2 cm or positive for visceral pleural invasion or for vascular invasion; n = 124) and a low-risk group (invasive component size ≤2 cm and negative for visceral pleural invasion and vascular invasion; n = 408), there was a significant difference in RFS between the high-risk and low-risk groups (high-risk group: HR, 3.61; 95% CI, 2.35-5.55).
Pathological stage I lung adenocarcinoma patients with an invasive component size greater than 2 cm, visceral pleural invasion, or vascular invasion were at high risk for recurrence.
The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose ...(RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)‐mutated non–small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty‐one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate eGFR ≥ 50 mL/min/1.73 m2) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30‐50 mL/min/1.73 m2); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m2 or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose‐limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.
This study aimed to investigate the safety, pharmacokinetics, and recommended dose of osimertinib in patients with EGFR‐mutated NSCLC with impaired renal function and low body weight. This study demonstrated that the PK parameters of osimertinib were similar across all cohorts but toxicity occurred more frequently in patients with impaired renal function and low body weight.
•The presence of tertiary lymphoid structures (TLS) was associated with significantly lower risk of recurrence.•TLS presence was not associated with PD-L1 expression.•Tumors with TLS have specific ...gene expression related to antitumor immune responses.
Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS.
A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed.
Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS−) (hazard ratio HR, 0.47; 95 % confidence interval CI: 0.23–0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18–0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS− patients (p = 0.54). TMB in TLS+ was similar to that in TLS− patients (p = 0.39); however, it tended to be lower than that in TLS− especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+.
TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.
Background
It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the ...impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs.
Methods
We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS).
Results
A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007).
Conclusions
The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.
Concomitant medication had no significant effect on the efficacy and safety of immune checkpoint inhibitors. Opioid use was associated with shorter overall survival and further study of this possible effect is required. This study is the first to demonstrate the impact of angiotensin receptor blockers or vitamin D on ICI treatment in patients with non‐small cell lung cancer.
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