bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world effectiveness of nab-paclitaxel plus carboplatin as first-line therapy for patients with advanced NSCLC: Results of the second interim analysis of the NEPTUN study.
Authors: Dechow Tobias Nicolaas , Riera-Knorrenschild Jorge , Hackanson Björn , Fischer von Weikersthal Ludwig , Schulz Holger , Chiabudini Marco , Timm Barbara , Zerbes Ralf , Potthoff Karin
Published: May 2020

e21611

Background: Collecting real-world evidence is required not only to evaluate effectiveness and safety in routine clinical practice, but to improve clinical cancer outcomes. Methods: NEPTUN is a prospective, multicenter, non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of first-line nab-Paclitaxel plus carboplatin in patients (pts) with advanced or metastatic non-small cell lung carcinoma (NSCLC) in the real-world setting in Germany. The primary endpoint was 6-months progression free survival rate (PFSR). Descriptive statistics were used to analyze data. Results: Between August 2016 and June 2019, 408 pts were enrolled at 75 active sites, 373 pts started treatment according to label. The cut-off date for this interim analysis (07 Dec 2019) was after all pts were observed for at least 6 months. The 6-months PFSR was 40.8% (95% CI, 35.3-46.2), median PFS 5.2 months (95% CI, 4.5-5.7). Overall response rate was 41.5% (95% CI, 36.3-46.8) with a complete response documented in 6 pts (1.7%) and a partial response in 142 pts (39.8%). Disease control rate was 61.6% (95% CI, 56.4-66.7). Employing a multivariable cox regression model for PFS adjusted for ECOG, histology, age group, renal impairment, and smoking status, elderly patients and patients with squamous histology were identified as being of favorable risk (HR squamous vs. non-squamous histology 0.76 (95% CI, 0.58-1.01); HR for ≥70 vs. < 70 years of age 0.80 (95% CI, 0.59-1.08)). Median overall survival (OS) was 10.5 months (95% CI, 9.2-11.6) with 9.6 months (95% CI, 7.7-11.2) for non-squamous and 11.8 months (95% CI, 9.2-13.8) for squamous histology. 12-months OS rate was 43.1% (95% CI, 37.3-48.7). The most common treatment-emergent AEs (TEAEs) were anemia (26.5%), leukopenia (25.7%) and thrombocytopenia (16.6%). Polyneuropathy was documented for 11.3% of pts. 54.2% of pts developed TEAE grade 3/4 including leukopenia (10.2%), anemia (8.6%) and pneumonia (5.1%). 9.9% pts discontinued nab-paclitaxel due to nab-paclitaxel-related TEAEs. EQ-5D-5L visual analogue scale and FACT-L total score remained stable during therapy. Conclusions: nab-Paclitaxel plus carboplatin given first-line according to German SmPC in advanced NSCLC patients in a real-world clinical setting is an effective and safe therapy commonly applied. These results were similar to those reported in the phase iii clinical trial setting. QoL scores remained stable during first-line treatment. No new safety signals emerged. Clinical trial information: NCT02799862.
The predictive values of mutation patterns, concurrent mutations and efficacy of different generations of EGFR-TKIs in advanced non-small cell lung cancer harboring non-resistant uncommon EGFR mutations.
Authors: Deng Pengbo , Tan Jiarong , Hu Chengping , Cao Liming , Yang Huaping , Li Min , Gu Qihua , Li Yuanyuan , An Jian , Han-Zhang Han
Published: May 2020

e21612

Background: The efficacy of EGFR-TKIs in patients with non-resistant uncommon EGFR mutations is controversial. The predictive values of mutation patterns, the presence of concurrent mutations and the choice of different generations of EGFR-TKI have not been well elucidated. Methods: We retrospectively enrolled 190 NSCLC patients with non-resistant uncommon EGFR mutations, defined as mutations other than single L858R, 19del, T790M or 20ins. Among them, 72 were advanced/recurrent patients who received 1st (N = 55) or 2nd generation (N = 17) EGFR-TKIs as first-line therapy and with retrievable PFS data; therefore, were enrolled for subsequent survival analyses. Results: Patients were categorized according mutation patterns: group1 patients harboring EGFR uncommon mutation in combination with EGFR 19 del/L858R; group 2 patients harboring single or complex EGFR uncommon mutations. Our analyses revealed that the median PFS (mPFS) of group 1 was significantly longer than those in groups 2 (14.65months vs 8.05 months; P = 0.004). Next, we investigated whether the presence of concurrent mutations in tumor suppressor genes or oncogenes would affect PFS. The mPFS of patients with no concurrent mutation, patients with concurrent tumor-suppressor genes mutations and patients with concurrent oncogenic driver mutations were 13.57m, 8.05m and 16.92m, respectively (p = 0.04). Patients with no concurrent mutation had a significantly longer mPFS than patients with concurrent tumor-suppressor genes mutations (p = 0.013). Collectively, multivariate analysis revealed that patients receiving 2nd generation TKI (p = 0.006, HR:0.277,95%CI:0.112-0.688) and coexist with 19del/L858R (p < 0.001, HR: 0.148,95% CI:0.065-0.333) were independently associated with favorable PFS; while concurrent TP53 mutation was independently associated with worse PFS (p = 0.008, HR: 2.530,95% CI:1.270-5.042). Conclusions: Our study revealed NSCLC patients harboring non-resistant uncommon EGFR mutations in combination with 19del/L858R were associated with favorable PFS. The presence of concurrent tumor-suppressor genes mutations especially TP53 is associated with worse prognosis. Patients treated with 2nd generation EGFR-TKI showed a longer PFS than those treated with 1st generation TKI.
Sputum supernatant as an alternative source for liquid biopsy in patients with advanced lung cancer.
Authors: Guo Ting , Hu Chengping , Qin Ling , Yang Huaping , Gu Qihua , Cao Liming , Deng Pengbo , Han-Zhang Han , Li Bing , Ye Junyi , Zhang Lu , Chen Zhiqiu
Published: May 2020

e21617

Background: With the advancements in the development of targeted therapy, the detection of actionable genes has become routine practice in diagnosing lung cancer. Plasma-based mutation profiling is widely used in clinical settings. Profiling using other body fluids is actively explored. In this study, we investigated the potential of induced sputum obtained from non-small cell lung cancer (NSCLC) patients for mutation profiling. Methods: We performed targeted sequencing on matched FFPE, plasma and induced sputum samples of 41 treatment-naïve advanced NSCLC using a panel consisting of 168 lung cancer-related genes. 10ml of whole blood and 8 ml of induced sputum were obtained from each patient. Induced sputum samples were fractionated into supernatant (sup) and precipitates (ppt). The cohort had a median age of 65 with a majority (32/41) diagnosed with lung adenocarcinoma. 7 of them were diagnosed with squamous cell carcinoma and the remaining 2 patients were diagnosed with neuroendocrine tumor. All patients had advanced disease (stage III or IV). Results: First, we investigated the optimal sputum fraction for mutation profiling by comparing the detection rates and maximum allelic fraction (maxAF) between sputum sup and ppt samples using matched tissue and plasma as references. The detection rate was defined as any mutation detected from the panel used; while maxAF was defined as the highest mutation allelic fraction among all mutations detected. Tissue, plasma, sputum sup and ppt achieved a rate of detection of 100%, 76.9%, 72.4% and 65.7% respectively, revealing comparable detection rates between plasma and sputum sup (p = 0.89). Sup had a significantly higher average maxAF than plasma (p = 0.03) and ppt samples (p < 0.01). Using driver mutations detected from tissue samples as references, sup, ppt and plasma samples achieved a sensitivity of 63.2%, 50% and 67.8%, respectively. Next, we investigated whether induced sputum obtained from smokers would be more informative than non-smokers. Our analysis revealed that sup from smokers had a significantly higher average AF than sup from non-smokers (p < 0.001). Furthermore, there was a statistical significant difference in average AF between sup and ppt obtained from smoker (p < 0.001) but such difference was non-existent in non-smokers (p = 0.46). Conclusions: Our study demonstrated that sputum sup demonstrates a comparable performance as plasma samples and is as a better sampling source than its ppt. Induced sputum from advanced stage NSCLC patients is an alternative media for mutation profiling.
Thyroid dysfunction in lung cancer patients treated with immune checkpoint inhibitors (ICI): Role of race, gender, and concurrent chemotherapy in a multiethnic urban cohort.
Authors: D'Aiello Angelica , Gucalp Rasim A. , Tabatabaie Vafa , Cheng Haiying , Bloomgarden Noah A. , Halmos Balazs
Published: May 2020

e21622

Background: Immune-related adverse events (irAE) associated with ICI have been reported, but remain poorly understood. We sought to characterize patterns of thyroid dysfunction—one of the most common irAE—in a large cohort of ethnically-diverse lung cancer patients treated with ICI. Methods: A retrospective chart review of lung cancer patients receiving an anti-PD1 or PD-L1 agent from January 2016 to July 2019 was performed. Subjects included had normal baseline thyroid function. Thyrotoxicosis and hypothyroidism was defined as thyroid-stimulating hormone level less than 0.4 and greater than 4.6, respectively. Time to event analysis with inverted Kaplan Meier curves and log-rank tests were used to compare thyroid dysfunction among race, gender, and treatment subgroups. Results: We identified 256 subjects: 206 had normal baseline thyroid function and 76 went on to develop thyroid dysfunction. Rates of thyroid dysfunction by one year occurred at similar frequencies among all races. Thyrotoxicosis occurred at significantly higher rates in Black (25, 31.7%) than in White (8, 12.9%) and Hispanic (7, 16.7%) subjects. In contrast, hypothyroidism occurred more often in White (13, 21.0%) and Hispanic (18, 42.9%) than in Black (12, 15.2%) subjects. Gender and concurrent chemotherapy showed no significant association with thyroid dysfunction. Of subjects with thyrotoxicosis (N = 42), hypothyroidism followed in 33.3% (N = 14) with 1 subject receiving methimazole and 13 levothyroxine. In those subjects, median time to thyrotoxicosis and hypothyroidism was 4.0 and 7.2 weeks, respectively. Conclusions: Despite the higher prevalence of non-ICI-related thyroid disease among females and the anticipated immunosuppressive effect of chemotherapy, neither gender nor chemotherapy correlated with thyroid dysfunction; however, race did. Black subjects exhibited significantly higher rates of thyrotoxicosis. Our findings are consistent with prior research showing that thyrotoxicosis, including Graves’ disease, occurs more often in Blacks. While the pathogenesis of ICI-related thyroid dysfunction is unclear, the early onset of thyrotoxicosis demonstrated by our study calls for careful monitoring, especially for particular races. [Table: see text]
Safety and efficacy of atezolizumab (atezo) in patients (pts) with autoimmune disease (AID): Subgroup analysis of the TAIL study.
Authors: Newsom-Davis Thomas , Rubio Viqueira Belen , Rodriguez-Abreu Delvys , Alatorre-Alexander Jorge , Smit Hans J.M. , Yu Jinming , Syrigos Konstantinos N. , Patel Hina , Tolson Jonathan , Cardona Andrés , Vollan Hans Kristian , Azevedo Sergio Jobim , Choy Ernest , Ardizzoni Andrea
Published: May 2020

e21628

Background: Atezo showed improved survival and a manageable safety profile in advanced NSCLC. The Phase III/IV TAIL study (NCT03285763) evaluated atezo in pts with previously treated advanced NSCLC, including pts often excluded from pivotal trials. We analyzed outcomes in pts with a history of AID in TAIL. Methods: Pts had stage IIIb/IV NSCLC that progressed after 1-2 lines of chemo and ECOG PS ≤ 2. Eligible pts included those with preexisting AID. Pts received atezo 1200 mg IV q3w. The primary endpoint was safety as measured by the incidence of treatment-related (TR) serious AEs (SAEs) and TR immune-related AEs (irAEs). Secondary endpoints included OS, PFS, ORR and other safety measures. Results: Of the 619 pts enrolled, 615 received atezo, including 30 pts with AID. In AID pts, the median age was 67 y, 43.3% were male and 86.7% had ECOG PS 0-1; common preexisting conditions included psoriasis (n = 7) and rheumatoid arthritis (n = 5). 23 pts had active AID at baseline. At data cutoff (Jun 4 2019), median follow-up was 12.7 mo. TR SAEs occurred in 6.7% and 7.9% of AID vs non-AID pts, respectively; TR irAEs occurred in 10.0% and 8.2% (table). AEs occurring in AID pts at a ≥ 10% difference vs non-AID pts were decreased appetite (26.7%), nausea (26.7%), dyspnea (23.3%) and pneumonitis (13.3%). G3-4 AE incidences were similar between groups (30.0% vs 29.9%). AEs leading to treatment discontinuation occurred in 16.7% and 4.3% of AID vs non-AID pts and included G1-2 pneumonitis (6.7%), G3-4 pleural infection (3.3%) and G3-4 pneumonia (3.3%). AEs of special interest (AESI) occurred more frequently in AID (40.0%) vs non-AID (34.2%) pts, with pneumonitis (13.3% vs 3.1%), rash (13.3% vs 10.6%) and hypothyroidism (6.7% vs 9.6%) as the most common AESIs in either group. Exploratory efficacy analyses in AID vs non-AID pts showed an mOS of 10.1 vs 11.1 mo, an mPFS of 2.9 vs 2.7 mo and ORRs of 10.0% vs 11.1%. Conclusions: Despite the small number of AID pts, safety and efficacy outcomes of atezo in TAIL pts with a history of AID were similar to those of pts with no history of AID. Moderate AE increases seen in AID pts tended to be respiratory in nature or GI disorders. These data may inform treatment decisions in pts with advanced NSCLC and AID. Clinical trial information: NCT03285763. [Table: see text]
Osimertinib in previously EGFR-TKI treated non-small cell lung cancer (NSCLC) patients without T790M mutation: Real-world evidence.
Authors: Luo Yung-Hung , Liu Han , Wampfler Jason A. , Tazelaar Henry D. , Li Yalun , Peikert Tobias , Liu Dan , Leventakos Konstantinos , Chen Yuh-Min , Yang Yanan , Chiou Shih-Hwa , Yang Ping
Published: May 2020

e21631

Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p < 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop > 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.
Towards patient-centric drug discovery: Drug action in malignant pleural effusions and ascites using high content imaging and deep learning.
Authors: Krall Nikolaus , Sehlke Robert , Taubert Christina , Alt Isabella , Rohrer Florian , Fuchs Elisabeth , Vilagos Bojan , Schumacher Michael , Maurer Dominik , Hackner Klaus , Lafleur Judith , Hefler Lukas , Minichsdorfer Christoph , Fuereder Thorsten , Vladimer Gregory Ian
Published: May 2020

e21633

Background: Many anticancer drugs found to be active in preclinical development later do not show desired effect clinically. This suggests that currently used preclinical models do not fully recapitulate the complexity of the disease. The study of drug activity in primary samples could provide a more immediate picture of a molecule’s activity in a patient. Factors that have so far hampered the use of primary tissue samples for drug discovery and development include access in sufficient quantity as well as robust analytical methods. We hypothesised that malignant pleural effusions and ascites (MPAs) of solid tumour patients are a promising model system to study preclinical drug activity. MPAs are easily accessible and contain cancer cells as well as recruited immune cells. Following previous successes in studying drug action in primary tissues of patients with haematological malignancies with automated microscopy (Snijder et al 2017, Lanc Haem, NCT03096821) we describe advances in using high content imaging and deep learning-based image analysis to study drug action in MPAs of solid tumour patients. Methods: MPAs from patients with metastatic breast, pancreatic and ovarian cancer (at least n = 10 of each) were collected. The response of EpCam+/CD45- and CD45+ cells against small molecule drugs was evaluated using high content microscopy. Drug response was quantified at single cell resolution using regional convolutional neural networks (R-CNNs) comprising object detection and single cell classification. Results: MPAs contain both cancer cells and recruited myeloid and lymphoid immune cells with varying activation. Ex vivo drug responses from each patient sample were measured and the EC50 of each molecule determined by curve fitting. Sensitivity mirrored drug approvals for some indications, and also revealed drugs with potential off label use. On target and off-target response curves, along with integrative scores are used to visualize the effects. Conclusions: Single-cell phenotypic analysis of MPAs enables the study of anticancer drug action in a setting that is one step closer to the clinic than cell line or outgrown organoid models of solid tumor. While initial response patterns can be observed that mirror current approvals, further biological and clinical validation must occur to understand in how far these data can be used for drug discovery and translational research purposes.
DNA damage response and repair (DDR) mutations predict the efficacy of platinum-based chemotherapy for advanced non-small cell lung cancer: A retrospective cohort study.
Authors: Xiao Zhiwei , Sun Lingling , Zheng Yating , Chen Hanrui , Zheng Xinting , Luo Jiamin , Gu Chuying , Xie Wenzhuan , Huang Mengli , Lin Lizhu
Published: May 2020

e21635

Background: DNA damage response and repair (DDR) pathway alteration is known as a predictive biomarker of platinum-based chemotherapy sensitivity in urothelial carcinoma, breast cancer, ovarian cancer, and prostate cancer. However, the predictive value of DDR in patients with non-small cell lung cancer (NSCLC) is still uncertain. This study investigated the DDR mutations (MUT) of NSCLC to identify potential predictive biomarker. Methods: A retrospective analysis of patients with NSCLC was performed. Targeted exon sequencing with the Next Generation Sequencing (NGS) were performed for 298 patients, and they were divided into two groups based on the presence or absence of mutations in 36 DDR genes. Results: 50 patients treated with platinum-based chemotherapy were identified, of which 17 harbored alterations in DDR genes. The median age was 60.5 years (range, 43 to 79 years). A total of 50 patients were evaluated, the objective response rate (ORR) of patients with DDR MUT was 17.6%, ORR 0% for DDR wild-type (WT), and the disease control rate (DCR) was 76.4% for DDR MUT, 48.5% for DDR WT. In terms of survival analysis, patients with DDR MUT had significantly improved median progression-free survival (mPFS) of 9.2 months compared with 4.8 months for DDR WT (Hazard Ratio (HR) = 0.4134, log-rank P = 0.0117). When EGFR and ALK mutations were excluded, there was no significant difference in mPFS between DDR MUT and WT, but DDR MUT has a tendency to be higher than WT (mPFS: 8.0 vs. 4.7 months, HR = 0.5060, log-rank P = 0.1022). Nevertheless, there was no significant difference in the median overall survival (mOS) between two groups (DDR MUT vs. DDR WT: 21.7 vs. 29.4 months, HR = 1.537, log-rank P = 0.3756), even after EGFR and ALK mutations were excluded, no significant difference can also be gained (HR = 1.818, log-rank P = 0.3972). Conclusions: DDR mutations may be a positive predictive biomarker for response to platinum-based chemotherapy in patients with NSCLC.
Efficacy of immune checkpoint blockade alone or combined with chemotherapy and smoking status in NSCLC: A systematic review and meta-analysis.
Authors: Wang Shanshan , Lin You-En , Yang Dan , Wang Guoqiang , Cai Shangli , Qian Jun , Chen Chuan , Xiong Jianping , Xu Yu
Published: May 2020

e21661

Background: Tobacco smoking is a critical cause of mutational burden and immuno-microenvironmental alteration in non-small cell lung cancer (NSCLC). However, the association between tobacco consumption and the synergetic effect of chemotherapy on single-agent immunotherapy remains controversial. Methods: We systematically searched PubMed, the Cochrane Central library and Embase, for the RCTs of ICI in NSCLC with HR for both PFS and OS according to smoking status. Random-effects model were used to pool estimates of survival HR and 95%CI. Subgroup analysis and meta-regression were implemented to investigate the source of heterogeneity. Results: In total, 13 eligible RCTs of 8154 NSCLC patients (6800 ever-smokers and 1354 never-smokers) were included. PFS benefit from immunotherapy comparing standard treatment remarkably differed between ever-smokers and never-smokers (P = 0.005), where significant PFS benefit was observed in ever-smokers (pooled HR = 0.72, 95%CI 0.63-0.81, P < 0.001) instead of never-smokers (pooled HR = 0.98, 95%CI 0.73-1.31, P = 0.90). In never-smokers, the choice of regimen (monotherapy vs. combination therapy) considerably impacted the benefit of PFS (HR = 2.21, 95%CI 1.35-3.61, P = 0.005) and OS (HR = 1.99, 95%CI 1.03-3.82, P = 0.041). Compared to standard treatment, monotherapy worsened PFS (HR = 1.39, 95%CI 1.01-1.90, P = 0.046) and did not improve OS (HR = 0.91, 95%CI 0.72-1.14) in never-smokers, while combination therapy dramatically delayed both progression (HR = 0.63, 95%CI 0.49-0.81, P < 0.001) and death (HR = 0.45, 95%CI 0.25-0.82, P = 0.010). Conclusions: Tobacco smoke was associated with larger PFS, but not OS benefit from immunotherapy. In never-smokers, not ever-smokers, combination with chemotherapy compared to single-agent ICI might confer significantly greater delays of both progression and death. [Table: see text]
High incidence of brain metastasis in young patients with lung adenocarcinoma.
Authors: Ramirez Ilene , Brandon Maximiliano , Abal Mariana , Martin Reinas Gaston , Marin Ordoñez Alba , Montiel Monica , Gonzalez Liliana D , Gil Deza Ernesto , Morgenfeld Eduardo L. , Rivarola Edgardo G. J. , Gercovich Felipe G.
Published: May 2020

e21677

Background: Young patients with lung cancer are unusual. This paper focuses on our experience with Young Patients (<45 yo) with Lung Adenocarcinoma (YPLA), treated at Instituto Oncológico Henry Moore (IOHM). Methods: Out of all lung cancer patients, we selected YPLA admitted between September 2012 and September 2019. We analyzed their medical history forms, electronic clinical records, treatments and outcomes. Results: We included 31 out of 1,119 Pt (3%) patients. Median Age: 39 (24-44). Sex F/M: 15/16. The table shows the clinical characteristics of population and outcomes. Conclusions: 1) Young patients with lung adenocarcinoma presented aggressive tumors, as evidenced by: advanced stages, poor performance status and CNS compromise. 2) In our series, smoking is a predominant etiological factor. 3) Further research will analyze genomic profiles of these tumors. 4) Screening for CNS metastasis should be mandatory in this population. [Table: see text]
Progression free survival (PFS) in Asian vs non-Asian patients (pts) with EGFR mutant non-small cell lung cancer (NSCLC) receiving osimertinib.
Authors: Cytryn Samuel , Punekar Salman Rafi , Tenet Megan , Ullah Tasfiq , Wang Bin , Goldberg Judith D. , Velcheti Vamsidhar , Wong Kwok-Kin , Chachoua Abraham , Shum Elaine , Sabari Joshua K.
Published: May 2020

e21679

Background: Third generation EGFR tyrosine kinase inhibitor (TKI) osimertinib demonstrated superior PFS and OS compared to earlier generation TKIs in pts with EGFR+ NSCLC. These pts are disproportionately Asian, female, and never-smokers. Contradictory data has been reported regarding the PFS and OS to osimertinib in Asian pts as compared to 1st and 2nd generation EGFR TKI. These inconsistencies warrant further investigation. The purpose of this study is to evaluate the PFS in Asian vs non-Asian pts with EGFR+ NSCLC receiving osimertinib. Methods: We conducted a single institution IRB approved retrospective study of pts with EGFR+ NSCLC. PFS was evaluated in pts treated from 1/2013 – 12/2019. Disease and treatment characteristics were summarized using frequency distributions and Kaplan-Meier curves for comparison of subgroups. Results: Of 190 EGFR+ pts: 52 (27%) Asian, 108 (57%) Caucasian, 125 (66%) female, 172 (91%) advanced disease, 107 (56%) never-smokers. Baseline characteristics in Asian and non-Asian pts were similar in regards to de-novo stage IV disease (71% vs 65%, p = 0.80), brain metastases (42% vs 54%, p = 0.48), and differed with regards to ever-smoking (29% vs 56%, p = 0.04). Treatment: 126/172 (73%) pts with advanced disease received TKI across all lines of therapy; 92/126 received osimertinib (22 (24%) 1st line; 45 (49%) 2nd line; 18 (19%) 3rd line; 7 (8%) ≥4th line). There were insufficient number of pts who received osimertinib in the 1st line to comment on differences in PFS between Asian and non-Asian pts. In the 2nd line, 19 Asian pts and 26 non-Asian pts received osimertinib, with no observed difference in PFS (median 15.4 v 13.8 months, p = 0.20). Moreover, Asian pts who received osimertinib as second line therapy had superior PFS (median 15.4 vs 9.6 months, p < 0.01) compared to Asian pts who received earlier generation TKIs, likely due to T790M resistance. Conclusions: Among second line advanced EGFR+ NSCLC, we did not observe a difference in PFS between Asian and non-Asian pts treated with osimertinib. Median PFS in Asian pts treated with osimertinib was longer compared to those treated with 1st or 2nd generation TKIs in the 2nd line setting. Our study highlights the the role of ethnic background in response to EGFR therapies and may warrant further study.
Interim results from the OPTIMAL trial: A phase II clinical trial of combination nivolumab, ipilimumab, and taxane in patients with untreated metastatic non-small cell lung cancer (NSCLC).
Authors: Clarke Jeffrey Melson , Wang Xiaofei F. , Gu Lin , Stevenson Marvaretta Miesha , Stinchcombe Tom , Ramalingam Sundhar , Antonia Scott Joseph , Shariff Afreen , Garst Jennifer , Crawford Jeffrey , Ready Neal E.
Published: May 2020

e21683

Background: Combination chemo-immunotherapy is a well-established frontline therapeutic option for treatment naïve NSCLC. Dual immune checkpoint blockade (ICB) with nivolumab (nivo) and ipilimumab (ipi) has demonstrated improved clinical outcomes compared with chemotherapy alone in this setting. Combination dual ICB with low-dose chemotherapy may have advantages of preventing early disease progression and potentiating immunogenic response to treatment. Methods: We are conducting a single arm phase II clinical trial of nivo 360 mg IV Q3 weeks, ipi 1 mg/kg IV Q6 weeks, and weekly paclitaxel 80 mg/m2 IV on d1 and d8 of a 21 day cycle in ECOG 0-1 patients (pts) with treatment naïve NSCLC. Paclitaxel is stopped after a total of 4-6 cycles. The primary endpoint of the trial is progression free survival (PFS) with secondary endpoints of safety and objective response rate (ORR) by independent radiologic review. Interim results are presented from the first 23 evaluable pts, of a planned sample size of 49. Results: 23 pts were enrolled and evaluable with a mean age 63.8 years, 56.5% ECOG 0, 87% current/previous smoking history, and 70% adenocarcinoma. PDL1 score for < 1%, 1-49%, ³ 50% was seen in 9 (39.1%), 4 (17.4%), and 10 (43.5%) pts, respectively. Median time of follow up was 6.5 months (range 1.4–15.0). Partial response was observed in 14 pts, stable disease was seen in 8 pts, and 1 pt progressed during cycle 1, resulting in an ORR of 61%. Grade 3 or higher toxicity at least possibly attributed to study treatment was seen in 47.8% of 23 AE evaluable patients, of which included 4 cases of secondary adrenal insufficiency. Other toxicity rates were as expected for the respective agents. Conclusions: This is the first trial to evaluate weekly paclitaxel with nivo plus ipi in pts with untreated NSCLC. This regimen has demonstrated highly encouraging clinical activity with a manageable toxicity profile. The study is ongoing and updated results will be presented at the annual meeting. Clinical trial information: NCT03573947.
SAF-189s in previously treated patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC): Results from the dose-finding portion in a single-arm, first-in-human phase I/II study.
Authors: Yang Jin-Ji , Zhou Jianying , Yang Nong , Wu Zhuli , Sun Juan , Hui Ai-Min , Wu Yi-Long
Published: May 2020

e21689

Background: Patients(pts) with ALK-rearranged non-small cell lung cancer (NSCLC) are sensitive but progress in 8–11 months with treatment of ALK inhibitor crizotinib, with leading progression in brain metastasis. SAF-189s is a novel and selective ALK inhibitor, can penetrate through blood brain barrier, and overcome multiple resistance mutation. This study aimed to explore the safety, efficacy, and pharmacokinetic properties of SAF-189s in patients with advanced ALK-rearranged NSCLC. Methods: In this multicenter I/II study, SAF-189s was orally administered under fasting condition at doses ranging from 20–210 mg once daily in a 21-day cycle to 36 pts with advanced ALK-positive NSCLC who had failed to prior systemic therapy. In this analysis report, anti-tumor activity of SAF-189s was evaluated in 34 pts received 40(n = 6), 80(n = 8), 120(n = 8), 160(n = 9) and 210(n = 3) mg doses daily. Safety was evaluated in all 36 pts who received ≥1 treatment. This study is registered with clinicaltrials.gov, NCT04237805. Results: 36 pts were enrolled in total, 22 pts had CNS metastases at baseline and 26 pts had progressed to prior TKIs therapy. There was no treatment-related SAE among the 36 pts. The most common drug-related events were nausea (14 [38.9%] of 36 pts), vomiting (10[27.8%] of 36 pts), QT prolongation (9 [25.0%] of 36 pts), sinus bradycardia (7 [19.4%] of 36 pts), ALT increase (10 [27.8%] of 36 pts), diarrhea (6 [16.7%] of 36 pts). Only one DLT of grade 3 blood glucose increase occurred at 210 mg out of the first 3 pts, so another 3 pts will be enrolled to determine RP2D/MTD. SAF-189s had shown response in the starting dose of 20mg, with 1of 2 pts achieving partial response (PR) over 43 cycles until clinical data cut off. All 34 pts in efficacy analysis set had achieved tumor shrinkage, with 17 confirmed PR (50%) (95% CI, 32.4–67.6%) and 4 unconfirmed PR (11.7%). 11 (45.8%) pts had confirmed PR among 24 pts who had failed to Crizotinib or Ceritinib and 10 (47.6%) pts had confirmed PR among 21pts who had CNS metastases. PFS data is pre-mature, with only median PFS of the 80 mg cohort being inferred as 19.42 months. Conclusions: In the dose-escalation portion of this study, SAF-189s was safe, very tolerable, and demonstrated both systemic and intracranial activity in pts with advanced ALK-positive NSCLC who had failed to at least 1 prior systemic therapy. Therefore, this study warrants further investigation to prove SAF-189s as an effective therapeutic option for pts who have ALK+ NSCLC. Clinical trial information: NCT04237805.
Culture of circulating tumour cells derived from non-small cell lung cancer.
Authors: O'Byrne Kenneth John , Kapeleris Joanna , Kulasinghe Arutha , Warkiani Majid E , O'Leary Connor Gerard , Ladwa Rahul , Vela Ian , Leo Paul , Sternes Peter , Punyadeera Chamindie
Published: May 2020

e21692

Background: Tumour tissue-based information is limited. Liquid biopsy can provide valuable real-time information through circulating tumour cells (CTCs). Profiling and expanding CTCs may provide avenues to study transient metastatic disease. Methods: 70 NSCLC patients were recruited. CTCs were enriched using the spiral microfluidic chip and a RosetteSep™ using bloods from NSCLC patients. CTC cultures were carried out using the Clevers media under hypoxic conditions. CTCs were characterized using immunofluorescence and mutation-specific antibodies for samples with known mutation profiles. Exome sequencing was used to characterized CTC cultures. Results: CTCs ( > 2 cells) were detected in 38/70 (54.3%) of patients ranging from 0-385 CTCs per 7.5ml blood. In 4/5 patients where primary tumours harboured an EGFR exon 19 deletion, this EGFR mutation was also captured in CTCs. ALK translocation was confirmed on CTCs from a patient harbouring an ALK-rearrangement in the primary tumour. Short term CTC cultures were successfully generated in 9/70 NSCLC patients. Whole exome sequencing confirmed the presence of somatic mutations in the CTC cultures with mutational signatures consistent with NSCLC. Conclusions: This study demonstrates a workflow for ex vivo culture of CTCs from NSCLC blood samples.
Immunotherapy efficacy of programmed cell death 1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in non-small cell lung cancer (NSCLC) patients: A systematic review and meta-analysis.
Authors: Yang Danrong , Cui Longgang , Zhang Yuzi , Zhao Zhengyi , Bai Yuezong
Published: May 2020

e21700

Background: Immune checkpoint inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have been new standard of care for non-small cell cancer patients. However, little is known about the difference in efficacy between these two types of drugs. In this study, we aimed to assess the differences between anti-PD-1 and anti-PD-L1 in NSCLC treatment through a systematic review and meta-analysis. Methods: We systematically searched PubMed, CENTRAL, and Embase from January, 2000 to November, 2019. We also reviewed abstracts and presentations from all major conference proceedings. All randomized controlled trials that compared anti-PD-1/anti-PD-L1 with standard treatment in NSCLC cancer patients were selected as candidates. Studies with anti-PD-1 and anti-PD-L1 were screened and paired upon the mirror principle. The primary outcome was the difference in overall survival (OS). As the main results, indirect comparison of anti-PD-1 and anti-PD-L1 were calculated for each mirror group and then pooled using a random-effects model. Results: 16 randomized controlled trials were included for the meta-analysis. Overall, anti-PD-1 exhibited superior OS (HR 0.80, 95% CI 0.68-0.95, P= .01) over anti-PD-L1. Subgroup analysis showed that anti-PD-1 exhibited superior OS over anti-PD-L1 ICIs in combination therapy (HR 0.67, 95% CI 0.54-0.82, P <.01), but not in monotherapy (HR 0.89, 95% CI 0.74-1.06), 2nd line therapy (HR 0.84, 95% CI 0.66-1.06) or 1st line therapy (HR 0.77, 95% CI 0.58-1.03). Conclusions: The results demonstrated that anti-PD-1 exhibited favorable survival outcomes compared to anti-PD-L1 in NSCLC treatment, which provides an important guide for clinicians.
Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small-cell lung cancer (NSCLC): A phase II clinical trial.
Authors: Ozawa Yuichi , Nakashima Kazuhisa , Daga Haruko , Imai Hisao , Tamiya Motohiro , Tokito Takaaki , Kawamura Takahisa , Akamatsu Hiroaki , Tsuboguchi Yuko , Takahashi Toshiaki , Yamamoto Nobuyuki , Mori Keita , Murakami Haruyasu
Published: May 2020

e21704

Background: Osimertinib has been shown to be effective against epidermal growth factor receptor ( EGFR) T790M-positive non-small cell lung cancer (NSCLC), but so far all clinical trials have targeted performance status (PS) 0 to 1 cases. The efficacy and safety of osimertinib in EGFR T790M-positive NSCLC patients with poor PS remain elusive. Methods: We conducted an open-label, multi-center, single-arm phase II study to evaluate the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2 to 4. Patients received 80 mg of osimertinib once daily. The primary endpoint was progression-free survival (PFS). The planned sample size was 18 patients to achieve power of at least 80% with one-sided alpha of 0.05 and expected and threshold PFS as 8.2 months and 3.0 months. Results: Eighteen patients (4 men and 14 women) were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55–85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and were previously treated with first- or second-generation EGFR- tyrosine kinase inhibitors, and 10 patients (56%) had central nervous system (CNS) metastasis. The overall median PFS was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate (ORR) was 53%, the median time to first response was 1.5 months, the median duration of response was 6.7 months, and the median overall survival (OS) was 12.7 months. Moreover, improved PS scores were observed in 13 patients (72%) including six with PS 2, six with PS 3, and one with PS 4. Osimertinib also showed an ORR of 60% in the patients with CNS metastasis, and the median PFS and OS were 6.5 months and 22.0 months, respectively. Although anemia, rash, and anorexia were frequently reported, the incidence of grade 3 adverse events was low, and no grade 4 or 5 events were observed. Interstitial lung disease (ILD) was observed in three patients (two with grade 2, one with grade 1). All three patients discontinued osimertinib treatment and recovered from ILD. Conclusions: Osimertinib therapy could be a promising treatment option for patients with EGFR T790M mutation-positive advanced NSCLC who have poor PS. Clinical trial information: UMIN000027655.
The impact of comorbidities and adverse events on quality of life in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) receiving epidermal growth factor receptor tyrosine kinase inhibitors therapy: A multicenter prospective study.
Authors: Chen Jung Yueh , Chen Kuan-Yu , Wei Yu-Feng , Liang Sheng-Kai , Chuang Tsu-Yi
Published: May 2020

e21708

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, the impact of comorbidities and treatment-related adverse events (AE) on quality of life (QOL) in patients receiving EGFR-TKI therapy was seldom investigated in a prospective setting. Methods: We conducted a prospective observational study to evaluate the association of comorbidity, AEs, and QOL in patients with EGFR-mutated advanced NSCLC receiving EGFR-TKI as first-line therapy among four hospitals in Taiwan. The questionnaires for QOL and AEs were obtained at baseline, the 2nd, 4th, 12th, and 24th week. Comorbidities were evaluated at baseline by using Simplified Comorbidity Score (SCS). The QOL was assessed by using EORTC QLQ-C30, QLQ-LC-13, and dermatology life quality index (DLQI). Paronychia related to oncologic treatments (SPOT) scale was used for paronychia severity evaluation. Visual analogue score (VAS) was applied for pain and itching evaluation. AE was recorded by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The correlations between QOL and comorbidities as well as AEs were analyzed by generalized estimating equation. Results: A total of 110 patients were included. Comorbidities were not associated with QOL deterioration (p= 0.209). While assessed by QLQ-LC13, mucositis (p= 0.001), elevated aminotransferase levels (p= 0.046), and use of oral antibiotic for dermatitis (p= 0.009) were associated with QOL deterioration. There was no significant difference in QOL among patients receiving afatinib, erlotinib, or gefitinib therapy. Gefitinib and afatinib showed a trend of improved QOL assessed by QLQ-C30 and LC13, whereas erlotinib with a trend of deteriorated QOL by LC13 (effect size = 0.07). For dermatological toxicities, a trend of deterioration in QOL was observed by DLQI assessment in patients received erlotinib (effect size = 7.44) or afatinib (effect size = 0.71). SPOT scale was higher in patients taking afatinib (p= 0.002). VAS pain score was higher in those taking afatinib (p= 0.005) or erlotinib (p= 0.049). Conclusions: Comorbidities and the choice of EGFR-TKI have no impact on overall QOL in advanced NSCLC patients receiving EGFR-TKI therapy. Mucositis, impaired liver function, and dermatitis needed oral antibiotics use may lead to a QOL deterioration.
Correlation of gefitinib and its metabolites with gefitinib induced rash in patients with non-small cell lung cancer (NSCLC).
Authors: Guan Shaoxing , Chen Xi , Huang Min , Zhang Li , Wang Xueding
Published: May 2020

e21712

Background: Gefitinib induced rash is the most common adverse reaction and severe rash of gefitinib often leads to discontinuation or termination of treatment. The concentrations of drug and its metabolites may affect drug induced toxicities, however, the association of gefitinib/metabolites with gefitinib-induced rash are poorly investigated. Therefore, we explored the association between concentrations of gefitinib and its four metabolites with gefitinib-induced rash in non-small cell lung cancer (NSCLC) patients. Methods: A total of 180 advanced NSCLC patients carrying EGFR sensitive mutations receiving gefitinib were enrolled. The concentrations of gefitinib, and its four metabolites including M537194, M387783, M523595 and M605211 were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The associations between concentration of gefitinib/its metabolites and gefitinib-induced rash were analyzed by Mann-Whiney U test. Operating characteristic curves(ROC) were used to determine gefitinib/metabolites cutoff values for gefitinib-induced rash. Results: M605211 was first detected in plasma in NSCLC patients. The concentrations of gefitinib and M605211, M537194 were found to be correlated with the incidence of gefitinib-induced rash ( P= 0.0002, 0.027 and 0.0097, respectively), moreover, the concentration of gefitinib was correlated with severe rash (Grade 0,1 vs. 2+, P= 0.017). Multivariate Logistic regression analysis showed that only gefitinib concentration was independent risk factor for gefitinib-induced rash (grade 0 vs grade1+, OR = 1.006, 95%CI (1.002-1.009), P = 0.00078; grade0,1 vs grade2+, OR = 1.003, 95%CI (1.001-1.005), P = 0.015, respectively). The cutoff values of gefitinib were 160.2 ng/ml (grade 0 vs grade1+, sensitivity = 78.7%, specificity = 47.7%, area under the curve (AUC) = 0.686, P = 0.0002, 95% CI (0.592-0.779)) and 201.7ng/ml (grade0,1 vs grade2+, sensitivity = 69.3%, specificity = 47.6%, AUC = 0.605, P = 0.0168, 95%CI (0.521-0.689)). Conclusions: This research demonstrated that the concentration of gefitinib and its metabolites were associated with gefitinib induced rash in NSCLC patients. Therapeutic drug monitoring of gefitinib concentration may have potential improvement for optimization of treatment with gefitinib. Clinical trial information: NCT01994057.
Sequential serum let-7a to predict accelerated reproliferation of lung cancer cells during chemotherapy and long-term survival.
Authors: Xie Peng , Li Xiaolin , Guan Yan , Tang Wenjie , Xie Xueqi , Wang Chungang , Sun Xindong , Yu Jinming
Published: May 2020

e21721

Background: Accelerated reproliferation during radiation is a classic theory in radiobiology. The long intervals between cycles of chemotherapy provides a better micro-circumstance to reproliferate of cancer cells. Few studies explored the accelerated reproliferation among cycles of chemotherapy. Methods: Patients with inoperable stage III and stage IV lung cancer from Shandong Cancer Hospital and Institute were enrolled prospectively. Tumor tissue and sequential peripheral blood were obtained before treatment and among cycles of chemotherapy to detect Ki-67 and let-7a expression. All patients were followed up to observe the occurrence and survival. Results: Fifty-two consecutive consenting patients were enrolled prospectively. The median follow-up was 13 months (range, 2–62 months). A strong correlation was found between serum let-7a and tissue Ki-67 before treatment (r = − 0.667, P < 0.001). The serum let-7a expression level was significantly upregulated at the time point after 2 and 4 cycles of chemotherapy, respectively, compared with the original. Then, at the time point after 6 cycles of chemotherapy, the expression levels of let-7a returned to relatively low level (F = 7.994, P < 0.001). Patients with high level of baseline serum let-7a had significantly better OS and PFS than patients with relatively low level of baseline serum let-7a (The 1-year OS and PFS rates were 80.6% VS 33.3%, X2 = 12.81, P < 0.001, and 54.2% VS 20%, X2 = 8.001, P = 0.005, respectively). Conclusions: The study showed that serum let-7a could reflect the proliferation of tumor tissue reliably in lung cancer, with high prognostic value. Furthermore, the study showed that accelerated reproliferation exists during treatment of cancer, not only in radiotherapy, but also in chemotherapy, which can give us a new perspective to overcome drug resistance of lung cancer, and would help in determining individual treatment strategy. This project was supported by National Natural Science Foundation of China (Grant No. 81502667) and Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167).