The combination of EGFR-TKIs and anlotinib as a first-line therapy for EGFR-mutant advanced non-small cell lung cancer: A multicenter, single-arm, phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9030-9030
Author(s):  
Zhiyong He ◽  
Jinghui Lin ◽  
Yueming He ◽  
Jing Zhang ◽  
Dongyong Yang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Advanced Nsclc ◽  
De Novo ◽  
Egfr Mutations ◽  
Treatment Naïve ◽  
Pre Treatment ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

A multi-center phase II study of toripalimab with chemotherapy in patients with EGFR mutant advanced NSCLC patients resistant to EGFR TKIs: Efficacy and biomarker analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21618-e21618 ◽  
Author(s):  
Shengxiang Ren ◽  
Jie Zhang ◽  
Yanqiu Zhao ◽  
Xiaoqian Mu ◽  
Jianying Zhou ◽  
...  
Keyword(s):  
Phase Ii ◽  
Advanced Nsclc ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Biomarker Analysis ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

e21618 Background: Immune checkpoint blocker (ICB) monotherapy showed a lack of response in advanced NSCLC patients with EGFR mutations. This Phase II study aimed to evaluate the efficacy and safety of toripalimab, a humanized PD-1 mAb plus platinum doublets chemotherapy in EGFR mutant advanced NSCLC patients, who developed resistance to 1st/2nd generation of EGFR TKIs and without T790M mutation. Methods: Patients received toripalimab (240 or 360 mg) intravenously combined with carboplatin (AUC = 5) and pemetrexed (500mg/m2) on day 1, Q3W, for up to 6 cycles, followed by toripalimab and pemetrexed maintenance until disease progression or unacceptable toxicity. Efficacy was evaluated every six weeks according to RECIST v1.1. PD-L1 expression (JS311 assay) and co-mutation status by whole exome sequencing were further analyzed. Results: From Apr 2018 to March 2019, 40 patients were enrolled from 8 centers in China. The median age was 57 years with 53% female, 57.5% EGFR exon19 deletion and 42.5% L858R mutation. By the cutoff date of Jan 2, 2020, 20 partial response and 15 stable disease were observed (ORR 50% and DCR 87.5%) with a median DOR of 7.0 months. The median PFS was 7.0 months and the median OS was still not reached. 52.6% (20/38) patients were PD-L1+ (TPS≥1%) and had numerically higher ORR (60% vs 39%, p= 0.33) and longer PFS (median 8.3 vs 5.7 months, p= 0.61) than PD-L1- patients. Co-mutations analysis revealed common genetic alternations including TP53 (79%), RB1 (18%), ERBB2 (15%), PIK2CA (12%), CDKN2A (12%), HDAC9 (12%) and MET (9%). Patients with TP53 co-mutation responded significantly better in ORR than TP53 wild type patients (62% vs 14%, p= 0.04) . Most frequent TRAE included leukopenia (78%), neutropenia (70%), anemia (70%), ALT elevation (48%), AST elevation (48%) and nausea (48%). Grade 3+ TRAE occurred in 55% patients, including neutropenia (43%), leukopenia (20%) and anemia (13%). Dose delay due to TRAE occurred in 40% patients while 10% patients discontinued treatment due to TRAE. Conclusions: Toripalimab in combination with chemotherapy showed promising anti-tumor activity with a manageable safety profile for advanced NSCLC patients with EGFR mutations refractory to TKI therapies. Patients with PD-L1+ tumor biopsy or TP53 co-mutation preferentially responded to the combination. A randomized phase III trial is ongoing to further validate the finding in this study (NCT03924050). Clinical trial information: NCT03513666.

Clonal dominance of EGFR and efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21501-e21501
Author(s):  
Xinghao Ai ◽  
Rongrong Chen ◽  
Jiuwei Cui ◽  
Jiexia Zhang ◽  
Wen Lin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phylogenetic Trees ◽  
Advanced Nsclc ◽  
Early Stage ◽  
Egfr Mutations ◽  
Rank Test ◽  
Sequencing Data ◽  
Dominance Analysis ◽  
The Impact ◽  
Egfr Tkis

e21501 Background: Though EGFR mutations in lung cancer are identified most often on the trunks of tumor phylogenetic trees in early stage, whether EGFR would always be the dominant clone in the advanced stage is unknown, as cancer evolution often follows a branched trajectory, with divergent subclones evolving simultaneously. The impact of clonal dominance of EGFR on outcomes with targeted therapies has not been explored. Methods: Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve patients with advanced NSCLC in the clinical trial (NCT03059641). cfDNA and tumor DNA were sequenced by target-capture deep sequencing of 1021 genes related to solid tumors, with blood cells as the germline control. Clonal dominance analysis was performed on the basis of the CCF determined for SNVs and clustered in plasma or tumor sequencing data using a modified version of Pyclone. PFS was estimated using Kaplan-Meier method and compared using log-rank test. Results: From February 2017 to December 2019, 300 advanced NSCLC patients were enrolled prospectively from 14 centers cross China. One hundred and fourteen EGFR mutant patients treated with EGFR-TKI were followed until disease progression (PD). The medium follow-up time was 10 month (1-27 months) and 92 (80.7%) patients have reached PD, with the ORR of 74.6% (85/114), mPFS of 10.5 months. Clonal dominance analysis of EGFR showed 76 patients had EGFR as the dominant clone according to tissue NGS results, and 66 patients as the dominant clone according to plasma cfDNA NGS results (p = 0.04). The ORR was significantly higher for patients with EGFR as dominant clone according to plasma cfDNA NGS results (84.8% vs 60.9%, p = 0.016), and PFS was significantly longer (12 vs 8 months, HR = 2.58). There was no difference when using tissue NGS results to analyze EGFR clonal dominance. However, if comparing patients who were defined as EGFR dominant clone by both tissue and plasma (n = 44) with those defined as EGFR nondominant (n = 9), EGFR dominance was associated with higher ORR (84.1% vs 44.4%, p = 0.01), and longer PFS (11 vs 6 months, HR = 9.88) significantly. Moreover, multivariate Cox proportional hazard ratio analysis demonstrated it as an independent prognostic indicator of EGFR-TKIs. Conclusions: Clonal dominance of EGFR in the pretreatment plasma cfDNA is associated with the efficacy of EGFR-TKIs in NSCLC. This study indicated the importance of evaluating clonal dominance in the current clinical practice and future trial designs. Clinical trial information: NCT03059641.

scholarly journals Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study)

2020 ◽  
Vol 12 ◽  
pp. 175883592096725
Author(s):  
Kei Morikawa ◽  
Hisashi Tanaka ◽  
Hidetoshi Itani ◽  
Saori Takata ◽  
Satoshi Watanabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Japanese Patients ◽  
Advanced Lung Cancer ◽  
Treatment Naïve ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

Interim analysis of the data of non-interventional study to determine the prevalence of EGFR mutations in advanced NSCLC Russian patients (ORTUS).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13109-e13109
Author(s):  
Konstantin K. Laktionov ◽  
Irina Demidova ◽  
Aleksandr Ageev ◽  
Valeriy Vladimirovich Breder ◽  
Pavel Grigoriev ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Advanced Nsclc ◽  
Gene Mutations ◽  
Stage Iv ◽  
Tumor Burden ◽  
Egfr Mutations ◽  
Plasma Samples ◽  
Stage Iv Disease ◽  
Treatment Naïve ◽  
Nsclc Patients

e13109 Background: There is a little information of correlation between EGFRm rate in cytology and plasma samples in Russian NSCLC population. The interim analysis of the study aimed to evaluate the prevalence and types of EGFR mutations in paired cytology and plasma samples in treatment-naive patients with advanced NSCLC. Methods: ORTUS is a multicenter, non-interventional, prospective study to determine EGFR mutations rate in treatmentnaive Russian patients with advanced NSCLC. ClinicalTrials.gov identifier: NCT02321046. The study enrolled 426 patients in stage IIIB / IV of NSCLC. Interim analysis covered the data of 214 cytology verified patients (mean age - 62.6 (range 32-86) years, 58,4% of men) with EGFRm test results in paired cytology and ctDNA samples. 99.5% cases were adenocarcinoma. The proportion of non-smokers/smokers/exsmokers was 46.3%/36%/17.8% respectively. Stage IV disease was in 81% of cases; 84.1% of patients had symptoms. DNA isolation performed using QIAamp DNA FFPE Tissue Kit for cytology and Qiagen Circulating Nucleic Acid Kit for ctDNA according to the manufacturer’s instructions. EGFR gene mutations were analyzed using THerascreen RGQ EGFR PCR Kit in cytology samples and RGQ Plasma EGFR PCR kit in plasma (Qiagen). Results: EGFRm was identified in 17,8% cytology samples (38/214) that is close to 20,2% (1759/8716) in Russian tissue EGFRm study (Imyanitov et al., 2016). 10,3% of paired ctDNA samples were EGFRm positive. Sensitivity and specificity for ctDNA were 42.1%, and 97.1% respectively. The EGFRm rate was 3,9% and 2,6% in smokers, 5,3% and 0% in ex-smokers and 33,3% and 21,2% in nonsmokers in cytology and plasma samples respectively. EGFRm rate and concordance between cytology and ctDNA are presented in a table. EGFRm in ctDNA were detected more frequently in M1a/b groups (p = 0,028). Conclusions: Cytology samples are appropriate for EGFRm testing in NSCLC patients in comparison with tumor tissue ones. High tumor burden (positive metastatic status) is an important factor for successful mutation analysis in ctDNA. [Table: see text]

Phase II study of apatinib combined with vinorelbine in second-line treatment failure non-driver gene mutation advanced non-small cell lung cancer (NCT03652857).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20669-e20669
Author(s):  
Yongchang Zhang ◽  
Fang Wu ◽  
Yi Xiong ◽  
Xiangyu Zhang ◽  
Nong Yang
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Adverse Events ◽  
Gene Mutation ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Driver Gene ◽  
Small Cell Lung ◽  
Prior Chemotherapy ◽  
Nsclc Patients

e20669 Background: There is currently no standard treatment strategy for non-driver gene mutation advanced non-small cell lung cancer (NSCLC) patients experiencing progression after two or more lines of chemotherapy. Our study assessed the efficacy and safety of apatinib combined with vinorelbine in non-driver gene advanced NSCLC patients for whom at least two lines of prior chemotherapy had failed. Methods: This is a Phase II, single arm clinical trial. 30 advanced NSCLC patients who had two or more prior lines of chemotherapy had failed enrolled in this study. All the patients received treatment of apatinib 500mg, po qd plus vinorelbine 60mg/m2 po qweek. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall (OS), progression-free survival (PFS), disease control rate (DCR) and safety. Results: Between January 2016 and November 2018, 30 patients were enrolled. 25 patients finished all the treatment. 5 patients discontinued the treatment for adverse events. The ORR of all the patients was 36.3 %( 11/30). The DCR of all the patients was 76.3 %( 23/30). The median PFS of all the patients was 4.5months (95% CI 2.4-6.6m). The median OS of all the patients was 10months (3.8m-16.2m). The most common grade 3 to 4 adverse events were non-hematologic including hand-foot syndrome. Moreover, medicine reduction seem not be an important role in disease prognosis. Conclusions: These data show that apatinib combined with vinorelbine can be a good choose with an acceptable safety profile in non-driver gene mutation advanced NSCLC patients refractory to two or more lines of prior chemotherapy. Clinical trial information: NCT03652857.

scholarly journals 172P: Antacid and de novo brain metastases in EGFR-mutant NSCLC patients treated with first-line, first-generation EGFR-TKIs

2016 ◽  
Vol 11 (4) ◽  
pp. S132
Author(s):  
Y.-M. Chen ◽  
M.-C. Lin ◽  
C.-H. Lai ◽  
W.-F. Fang ◽  
H.-C. Chang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
First Generation ◽  
De Novo ◽  
First Line ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2581-2581 ◽  
Author(s):  
Rosario García Campelo ◽  
Enriqueta Felip ◽  
Bartomeu Massuti ◽  
Margarita Majem ◽  
Enric Carcereny ◽  
...  
Keyword(s):  
Dose Level ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

Response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with de novo epidermal growth factor receptor (EGFR) T790M and S768I resistance mutations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20557-e20557
Author(s):  
Deirdre Kelly ◽  
Lisa Mary Prior ◽  
Jack Patrick Gleeson ◽  
Lynda M. McSorley ◽  
Rachel Kearns ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stable Disease ◽  
De Novo ◽  
Objective Response ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Resistance Mutations ◽  
Free Survival ◽  
Nsclc Patients ◽  
Egfr Tkis

e20557 Background: Patients with synchronous de novo EGFR sensitising and resistance mutations are rare. Little is known about the response of these patients to EGFR TKIs, especially in a Caucasian population. Methods: We identified NSCLC patients found to have EGFR mutations using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing using a large multi-institutional database. Baseline clinical characteristics, response rate, progression free survival (PFS) and overall survival (OS) were calculated. Results: From 2008-2015, we observed de novo synchronous EGFR sensitising and resistance mutations in 12 patients representing an overall incidence of 3.6% of EGFR mutants and 0.4% of all NSCLC patients tested. Seven patients were treated using EGFR TKI therapy with erlotinib. In all cases, T790M (n = 4,50%) or S768I (n = 4, 50%) occurred concurrently with another sensitising EGFR mutation, either L858R (n = 4, 34%) or exon 19 deletion (n = 8, 66%). Objective responses were seen in two patients (29%). Three further patients had stable disease lasting 6, 23 and 54 months respectively. The median progression-free survival was 24 months and the median overall survival was 34 months. All patients with baseline EGFR S768I mutations (n = 3) had an objective response or stable disease on erlotinib while two of four patients with T790M demonstrated de novo resistance. Conclusions: This is the largest Irish review of synchronous de novo EGFR mutations. The incidence of co-occurring EGFR mutations was 0.4% and erlotinib demonstrated activity in this cohort of patients. Ongoing trials will determine whether next-generation EGFR TKIs such as osimertinib are preferable as first-line therapy in these patients.

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