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Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non-small Cell Lung Cancer

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Abstract
Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer (NSCLC).

Patients and Methods: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naive. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.

Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in I patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 55-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of 1790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.

Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.
Author(s)
이대호Bo H ChaoDavid PlanchardHelena A YuHuzhang MaoJames Chih-Hsin YangJoo-Hang KimKeunchil ParkKi Hyeong LeeLing GaoLuis G Paz-AresPilar GarridoRebecca R Hozak
Issued Date
2021
Type
Article
Keyword
Acrylamides - administration & dosageAcrylamides - adverse effectsAgedAged80 and overAniline Compounds - administration & dosageAniline Compounds - adverse effectsAntibodiesMonoclonalHumanized - administration & dosageAntibodiesMonoclonalHumanized - adverse effectsAntineoplastic Combined Chemotherapy Protocols - administration & dosageAntineoplastic Combined Chemotherapy Protocols - adverse effectsCarcinomaNon-Small-Cell Lung - diagnosisCarcinomaNon-Small-Cell Lung - drug therapyCarcinomaNon-Small-Cell Lung - geneticsCarcinomaNon-Small-Cell Lung - mortalityDisease-Free SurvivalErbB Receptors - antagonists & inhibitorsErbB Receptors - geneticsFemaleHumansLung Neoplasms - diagnosisLung Neoplasms - drug therapyLung Neoplasms - geneticsLung Neoplasms - mortalityMaleMiddle AgedMutationNeoplasm StagingProgression-Free SurvivalResponse Evaluation Criteria in Solid TumorsVascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
DOI
10.1158/1078-0432.CCR-20-1690
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8448
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_crossref_primary_10_1158_1078_0432_CCR_20_1690&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Phase%20I%20Study%20of%20the%20Efficacy%20and%20Safety%20of%20Ramucirumab%20in%20Combination%20with%20Osimertinib%20in%20Advanced%20T790M-positive%20EGFR-mutant%20Non-small%20Cell%20Lung%20Cancer&offset=0&pcAvailability=true
Publisher
CLINICAL CANCER RESEARCH
Location
미국
Language
영어
ISSN
1078-0432
Citation Volume
27
Citation Number
4
Citation Start Page
992
Citation End Page
1002
Appears in Collections:
Medicine > Medicine
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