Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.

Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear. Methods: This retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database. Results: Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively). Conclusions: Our study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

A Single-Institute Experience with C-ros Oncogene 1 Translocation in Non-Small Cell Lung Cancers in Taiwan.

(1) Background: The C-ros oncogene 1 (ROS1) gene translocation is an important biomarker for selecting patients for crizotinib-targeted therapy. The aim of this study was to understand the incidence, diagnostic algorithm, clinical course and objective response to crizotinib in ROS1 translocated lung non-small cell lung cancers (NSCLCs) in Taiwan. (2) Methods: First, we retrospectively studied the ROS1 status in 100 NSCLC samples using break-apart fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) staining to establish a diagnostic algorithm. Then, we performed routine ROS1 IHC tests in 479 NSCLCs, as crizotinib was available from 2018 in Taiwan. We analyzed the objective response rate and the survival impact of crizotinib. (3) Results: Four ROS1 translocations were clustered in epidermal growth factor receptor (EGFR) wild-type adenocarcinomas but not in cases with EGFR mutations. Strong ROS1 expression was positively correlated with ROS1 translocation (p < 0.001). NSCLCs with ROS1 translocation had a poor prognosis compared to those without ROS1 translocation (p = 0.004) in the pre-crizotinib stage. Twenty NSCLCs were detected with ROS1 translocation in 479 wild-type EGFR specimens from 2018. Therefore, the incidence of ROS1 translocation is approximately 4.18% in EGFR wild-type NSCLCs. In these 20 ROS1 translocation cases, 19 patients received crizotinib treatment, with an objective response rate (ORR) of 78.95% (confidence interval = 69.34% to 88.56%), including 1 complete response, 14 partial responses, 3 stable cases and 1 progressive case. Overall survival and progression-free survival were better in the 19 ROS1-translocated NSCLCs of the prospective group with crizotinib treatment than the four ROS1-translocated NSCLCs of the retrospective group without crizotinib treatment. (4) Conclusions: ROS1-translocated NSCLCs had a poor prognosis and could have a beneficial outcome with crizotinib.

Afatinib treatment in a large real-world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P < .001) and OS (HR 2.56 [95% CI, 1.37-4.75]; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; P = .016), and type-I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; P = 4.3 × 10-5 ). Tendencies of higher CNS and lower systemic progression were observed in type-II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18-4.89]; P = .016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01-0.48]; P = .021) were independent predictors of secondary T790M. Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

First- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large, real-world cohort of patients with non-small cell lung cancer.

BACKGROUND: There are limited comparisons of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in large, real-world cohorts of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. METHODS: Patients with advanced NSCLC (N = 612) with common EGFR mutations receiving first-line gefitinib/erlotinib and afatinib were grouped and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutations were analyzed. RESULTS: The gefitinib/erlotinib and afatinib groups each contained 206 patients after matching. Compared with gefitinib/erlotinib, patients receiving afatinib achieved longer median PFS (16.3 versus 14.2 months; log-rank test p = 0.020) and had a lower risk of progression [hazard ratio (HR) 0.73 (95% confidence interval (CI), 0.57-0.94); p = 0.017]. Median OS (37.3 versus 34.2 months; log-rank test p = 0.500) and reduction in risk of death [HR 0.89 (95% CI, 0.65-1.23); p = 0.476] did not differ significantly between groups. T790M positivity was significantly higher in the gefitinib/erlotinib than afatinib group (70.9% versus 44.6%, p < 0.001). Multivariate analysis demonstrated that afatinib was independently associated with lower T790M positivity [odds ratio (OR) 0.27 (95% CI, 0.14-0.53); p < 0.001], whereas ⩾12 months PFS after EGFR-TKI treatment [OR 3.00 (95% CI, 1.56-5.98); p = 0.001] and brain metastasis [OR 2.12 (95% CI, 1.08-4.26); p = 0.030] were associated with higher T790M positivity. Sequential third-generation EGFR-TKI treatment was administered to 63 patients, in whom median OS after the second-third-generation and first-third-generation EGFR-TKI sequences were 38.8 and 29.1 months, respectively. CONCLUSION: Compared with gefitinib/erlotinib, afatinib had a higher treatment efficacy and a lower secondary T790M positivity in a large, real-world cohort of Asian patients with EGFR-mutated NSCLC.

Impact of Chemotherapy-Induced Peripheral Neuropathy on Quality of Life in Patients with Advanced Lung Cancer Receiving Platinum-Based Chemotherapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic anticancer drugs that may affect quality of life (QoL). Purpose: The purposes of this study were to: assess the levels of CIPN, anxiety, depression, CIPN-related QoL, and general QoL; and identify the factors related to CIPN-related QoL and general QoL in patients with advanced lung cancer (LC) receiving platinum-based chemotherapy. This cross-sectional study examined patients with advanced LC who received platinum-based chemotherapy from the thoracic oncology inpatient wards of a medical center in northern Taiwan. Structured questionnaires were used to measure patients' CIPN (European Organization for Research and Treatment of Cancer quality of life questionnaire-chemotherapy-induced peripheral neuropathy 20), anxiety (Hospital Anxiety and Depression Scale Depression Scale [HADS]), depression (HADS), CIPN-related QoL (Functional Assessment of Cancer Therapy /Gynecologic Oncology Group-Neurotoxicity subscale [FACT/GOG-Ntx]), and general QoL (Functional Assessment of Cancer Therapy-General Input [FACT-G]). Of 93 patients with advanced LC, 53.8% reported CIPN-sensory impairment and 47.3% reported CIPN-motor impairment. The most common CIPN symptoms were difficulty getting or maintaining an erection (only for men > 65 years) and difficulty in climbing stairs or getting up out of a chair. Poor CIPN-related QoL (FACT/GOG-Ntx) was associated with more CIPN-sensory and more CIPN-motor impairment. Poor general QoL (FACT-G) was associated with a higher level of depression, a higher level of anxiety, and receipt of more chemotherapy cycles. More than half of LC patients report impairment related to CIPN, calling for holistic treatment to improve QoL.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Trajectory of smoking behaviour during the first 6 months after diagnosis of lung cancer: A study from Taiwan.

AIMS: To identify different classes of change pattern/ trajectory of tobacco smoking behaviour after diagnosis of lung cancer using multi-wave data and to explore factors associated with the class membership. DESIGN: This is a multi-wave observational study. METHODS: Smoking behaviour data were collected at diagnosis and then every month for 6 months from 133 newly diagnosed people with lung cancer who had recently quit smoking or continued to smoke at diagnosis. These patients were recruited from three medical centres and data were collected from May 2014 to January 2017. Smoking behaviour was assessed based on patients' self-reports on whether they smoked during the last month (yes/no) for a total of seven times. Mixture latent Markov model and logistic regression were used to analyse data. RESULTS: Two latent classes of smoking trajectory were identified among recent quitters or current smokers of people with lung cancer, namely "perseverance for abstinence" and "indecisive for abstinence." Patients who were younger age (OR = 0.95, p = 0.026), exposure to second-hand smoke (OR = 3.35, p = 0.012) and lower self-efficacy for not smoking (OR = 0.96, p = 0.011) were more likely to belong to the class of "indecisive for abstinence." CONCLUSIONS: Heterogeneous classes of smoking trajectory existed in newly diagnosed people with lung cancer. The risk factors associated with a less favourable smoking trajectory can be incorporated into tailored smoking-cessation programs for patients newly diagnosed with lung cancer. IMPACT: The dynamic trajectory of smoking behaviour had not been adequately explored among newly diagnosed people with lung cancer. Two classes of smoking trajectory and the predictors associated with the class membership were identified. These findings suggest that the diagnosis of cancer is a teachable moment for smoking cessation. Patients with younger age, lower self-efficacy of not smoking and exposure to second-hand smoke at home need special attention.

An Observational Study of Acquired EGFR T790M-Dependent Resistance to EGFR-TKI Treatment in Lung Adenocarcinoma Patients in Taiwan.

In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Targeted Sequencing of Circulating Cell Free DNA Can Be Used to Monitor Therapeutic Efficacy of Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients.

BACKGROUND/AIM: Circulating tumor DNA (ctDNA) bears specific mutations derived from tumor cells. The amount of mutant ctDNA may reflect tumor burden. In this study, we detected epidermal growth factor receptor (EGFR) mutations in ctDNA as a monitoring marker for the response of non-small cell lung cancer (NSCLC) patients to tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: Serial plasma samples from eight NSCLC patients during TKI treatment were collected. Libraries with barcoded adapters were constructed from ctDNA of these plasma samples using a PCR-based targeted DNA panel. The libraries were then sequenced for measuring EGFR mutations. In addition, carcinoembryonic antigen (CEA) was also measured in these patients. RESULTS: In six patients who suffered disease progression (PD), five had elevated EGFR mutation reads before PD. In the two patients who did not develop PD, EGFR mutations remained undetectable in their plasma. The CEA levels were higher than the cutoff value in most samples and had a poor correlation with disease status. CONCLUSION: The mutation count of tumor-specific mutations can be a monitoring marker of TKI treatment in NSCLC patients.

Consolidation treatment of durvalumab after chemoradiation in real-world patients with stage III unresectable non-small cell lung cancer.

BACKGROUND: Treatment for stage III non-small cell lung cancer (NSCLC) of unresectable disease mainly involves concurrent chemoradiation (CRT). Post-CRT consolidation treatment with durvalumab is a major therapeutic advance that provides survival benefit in this group of patients. However, the performance of this treatment strategy remains to be studied in a real-world setting. METHODS: A total of 31 patients who had disease control post-CRT were included in the durvalumab early access program (EAP) as an intent-to-treat cohort and retrospectively reviewed for post-CRT progression-free survival (PFS) and time to metastatic disease or death (TMDD). The neutrophil-to-lymphocyte ratio (NLR) at the initiation of durvalumab was analyzed in 29 patients. RESULTS: The median time from the completion of concurrent CRT to the initiation of durvalumb was 2.8 months. The objective response was 25.8% and the 12 month PFS and TMDD-free rate were 56.4% and 66.9%, respectively. The low NLR patients showed a significantly longer post-CRT PFS (not reach vs. 12.0 months [95% CI: 5.5-not estimable]; P = 0.040; the hazard ratio for disease progression or death, 0.23 [95% CI: 0.05-1.00]; P = 0.048) and the 12 month post-CRT PFS rate (82.5 vs. 42.6%). The post-CRT TMDD (not reach vs. 12.6 months, [95% CI: 10.8-not estimable]; P = 0.010; the hazard ratio for distant metastasis or death, 0.11 [95% CI: 0.01-0.88]; P = 0.037) and 12 month post-CRT TMDD-free rate (90.9 vs. 57.1%) were also significantly higher in the low NLR patients. CONCLUSIONS: Durvalumab consolidation treatment in real-world patients showed substantial efficacy and the correlation with the NLR level warrants further investigation.

Front-line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control.

BACKGROUND: Approximately 3%-5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum-based chemotherapy as front-line treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the direct comparison between them in the front-line setting remains lacking. METHODS: A total of 48 patients with ALK-positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front-line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed. RESULTS: Patients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression-free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log-rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08-0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause-specific hazard ratio, 0.21; 95% CI 0.06-0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment. CONCLUSION: Ceritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front-line treatment of ALK-positive advanced NSCLCs.

A Correlational Study of Skin Toxicity and Quality of Life in Patients With Advanced Lung Cancer Receiving Targeted Therapy.

BACKGROUND: Oral targeted therapy is increasingly used worldwide to treat patients with advanced lung cancer. The adverse skin toxicity that is associated with treatment with epidermal growth factor receptor inhibitors often results in acneiform rash, dry skin (xerosis), pruritus, and paronychia, which may cause discomfort in patients and affect their quality of life. PURPOSE: This study was designed to explore changes in skin toxicity and quality of life (measured overall by three subscales) as well as the correlation between skin toxicity and overall quality of life over a 3-month period for patients with advanced lung cancer receiving oral targeted therapy. METHODS: This study used a longitudinal research design. Baseline data were collected before initiating targeted therapy. Data for the effects of targeted therapy on skin toxicity and quality of life were collected at 2, 4, 8, and 12 weeks after therapy initiation. Data on skin toxicity were collected using the Common Terminology Criteria for Adverse Events Version 4.03, and quality of life was measured using the Chinese version of the Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor-18 questionnaire. Demographic and clinical data were analyzed using descriptive statistics, and Spearman's rank correlation coefficient was used to measure the correlation between skin toxicity and quality of life. RESULTS: Thirty-two patients participated in this study. The symptoms of skin toxicity that increased over the 3-month study period included xerosis and paronychia, whereas acneiform rash and pruritus fluctuated during this period. Over the study period, more than 70% of the participants exhibited symptoms of skin toxicity. Skin toxicity was the greatest and quality of life was the lowest, respectively, at the end of the study. All of the symptoms of skin toxicity were significantly correlated with quality of life, although each varied over time (r = .36-.61, p < .05). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results of this study indicate that healthcare providers should consider the impact of skin toxicity on quality of life in patients with advanced lung cancer who are receiving oral targeted therapy. These findings may be used to design interventional measures for skin and medical care to improve quality of life in patients with advanced lung cancer.

Oral vinorelbine plus cisplatin with concomitant radiotherapy as induction therapy for stage III non-small cell lung cancer: Results of a single-arm prospective cohort study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is an optimal recommended treatment for stage III non-small cell lung cancer (NSCLC). Herein, we aimed to investigate the efficacy and safety of oral vinorelbine plus cisplatin with concomitant radiotherapy for stage III NSCLC. METHODS: This prospective, open-label, single-arm, observational cohort study was performed between January 2010 and September 2016. Patients were treated with two cycles of chemotherapy with 60 mg/m2 intravenous cisplatin on day 1 and 50 mg/m2 oral vinorelbine on days 1, 8, and 15; radiotherapy was administered concurrently from day 1 when chemotherapy was initiated. A total dose of 66-70 Gy radiotherapy was delivered in daily fractions of 2 Gy for 6.5-7 consecutive weeks. The tumor response was assessed after completing concomitant treatment. RESULTS: A total of 58 patients were enrolled and analyzed; 31 patients had stage IIIA NSCLC and 27 had stage IIIB NSCLC. After induction CCRT, 31 patients achieved an objective response (complete response in one and partial response in 30; the response rate was 53.4%). The median progression-free survival was 6.73 months (95% confidence interval [CI], 5.42-7.91), duration of response was 12.30 months (95% CI, 5.59-19.01), and overall survival was 24.83 months (95% CI, 19.26-30.21). No treatment-related mortality was observed, and neutropenia was the most common grade 3 and 4 treatment-related toxicity (11 patients; 18.9%). CONCLUSIONS: CCRT with the weekly regimen of oral vinorelbine plus triweekly cisplatin was effective and safe for stage III NSCLC.

Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib.

BACKGROUND: The first (1G) and second (2G) generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show differential inhibitory capacities towards EGFR T790M-mutated non-small-cell lung cancer (NSCLC) cells. OBJECTIVE: To assess the ratio of the allele fractions of T790M (AFT790M) to EGFR-activating mutations (AFmEGFR) in patients treated with 1G and 2G EGFR TKIs who acquired T790M-mediated resistance and to determine the relationship between AF and the later efficacy of osimertinib. PATIENTS AND METHODS: The efficacy of osimertinib was reviewed for 54 T790M-positive EGFR-mutated NSCLC patients grouped by the generation of prior EGFR TKI use (1G vs. 2G). AFmEGFR and AFT790M were determined by QuantStudio digital PCR using tissues obtained upon acquired resistance. RESULTS: The progression-free survival (PFS; 20.3 vs. 11.6 months, p = 0.031) and the 1-year PFS rate (63.2 vs. 37.5%, p = 0.029) for osimertinib were significantly better for group 1G compared to group 2G. The ratio of AFT790M to AFmEGFR in group 1G was significantly higher than in group 2G (46.16 ± 5.40% vs. 25.86 ± 4.25%, p = 0.009). An unbiased analysis revealed three AF-associated clusters (ARCs) suggesting the ratio of AFT790M to AFmEGFR correlates with the efficacy of osimertinib. We found all patients in ARC2 having the highest ratio of AFT790M to AFmEGFR to have previously been treated with a 1G EGFR TKI and to show the longest osimertinib PFS compared to ARC3 (NR vs. 11.9 months, p = 0.060) and ARC1 (NR vs. 12.4 month, p = 0.045). CONCLUSIONS: Acquired T790M fraction of EGFR-mutated NSCLC is linked to different generations of prior EGFR TKI use and the later efficacy of osimertinib.

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer.

BACKGROUND: Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown. METHODS: The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed. RESULT: Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one-year (34.5 vs. 9.6%; P = 0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1-year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation. CONCLUSION: Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.

Prognostic Value and Clinical Impact of Pretreatment FDG PET in Pulmonary Lymphoepithelioma-Like Carcinoma.

PURPOSE: Compared with other forms of non-small cell lung cancer, pulmonary lymphoepithelioma-like carcinoma (LELC) is rarer and portends better outcomes. We sought to investigate the prognostic role and clinical impact of pretreatment F-FDG PET in pulmonary LELC. METHODS: A total of 71 patients with pulmonary LELC were identified through a retrospective review of clinical records. Of them, 41 underwent F-FDG PET for primary staging. Outcomes were assessed using the Kaplan-Meier method and Cox regression models with a forward stepwise selection procedure. Staging changes served as the main outcome measure for assessing the impact of F-FDG PET. For the purpose of analyses, all patients were restaged according the American Joint Committee on Cancer Staging Manual eighth edition. RESULTS: Stage and pretreatment F-FDG PET were significantly independent predictors of overall survival (OS) on multivariate analysis. Five-year OS rates for patients with stages I-II, III-IVA, and IVB were 92.3%, 70.4%, and 20.0%, respectively. The use of F-FDG PET for staging purposes was associated with a better OS (P = 0.003). Specifically, the 5-year OS rates for patients who were staged with and without F-FDG PET were 85.4% and 49.7%, respectively (P = 0.012). F-FDG PET resulted in a disease upstage in 28.6% of patients with CT-defined stages III-IVA; of them, 14.3% were upstaged to IVB disease. CONCLUSIONS: The American Joint Committee on Cancer eighth edition stage and pretreatment F-FDG PET were independent prognostic factors for OS in patients with pulmonary LELC. F-FDG PET imaging resulted in a better disease staging with a corresponding optimization of therapeutic interventions, which ultimately improved survival outcomes.

Feasibility of transumbilical anatomic "Lung" segmentectomy in a canine model.

BACKGROUND: Transumbilical approach has been shown to be feasible to perform lung wedge resection and anatomic lobectomy. This study uses a canine model to assess the feasibility of transumbilical segmentectomy. METHODS: Transumbilical segmentectomy was performed in 10 beagle dogs using a 3-cm umbilical incision combined with a 2.5-cm diaphragmatic incision. We evaluated the surgical outcomes, operative complications, physiologic changes, hemodynamic changes, and inflammatory changes of the procedures. RESULTS: Transumbilical segmentectomy was successfully completed in eight of ten animals. There was one mortality complication related to lung injury causing hemodynamic collapse. Another animal required conventional thoracotomy to complete the surgery due to limited working space. There were no notable events in the postoperative period for all eight dogs that completed the segmentectomy via the transumbilical approach. CONCLUSION: This animal study demonstrates that the pulmonary segmentectomy can be performed with current standard endoscopic instruments via a single transumbilical incision.We believe that advancing surgical innovation and good collaboration between multi-disciplinary research teams will further establish clearer roles for transumbilical segmentectomy in thoracic surgery.

Smoking Status Among Patients With Newly Diagnosed Lung Cancer in Taiwan.

BACKGROUND: Continued smoking after receiving a diagnosis of cancer seriously affects disease prognosis and survival. The prevalence and risk factors of continued smoking among patients with newly diagnosed lung cancer are unknown in Taiwan. PURPOSE: The aims of this study were to assess the smoking status of patients with newly diagnosed lung cancer and to identify the characteristics that are associated with different smoking statuses. METHODS: Baseline data of a longitudinal study on smoking behaviors after lung cancer diagnosis were analyzed in this study. Patients were consecutively recruited from three medical centers in northern Taiwan. A structured questionnaire and medical chart reviews were used to collect data. Multinomial logistic regression analysis was used to examine the factors associated with continuing to smoke after being diagnosed with lung cancer. RESULTS: Among the 406 patients with newly diagnosed lung cancer who were recruited, 47.0% were never-smokers and 53.0% were ever-smokers. Among the second group, 38% were former smokers, 18% were recent quitters, and 44% were current smokers. Compared with former smokers, current smokers were more likely to be younger (OR = 1.05), to not exercise regularly (OR = 2.74), to currently live with smokers (OR = 2.48), and to have lower self-efficacy for refusing to smoke (OR = 0.95). Compared with recent quitters, current smokers were more likely to have lower self-efficacy for refusing to smoke. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: A significant proportion of ever-smoker lung cancer patients in Taiwan will continue to smoke after receiving their diagnosis. Variables known to modify the risk factors associated with continued smoking such as regular exercise and better refusal self-efficacy should be considered and incorporated into future smoking cessation programs for patients with lung cancer.

Prognostic impact of combining whole-body PET/CT and brain PET/MR in patients with lung adenocarcinoma and brain metastases.

PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP. CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life.