Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.

Autor:	Rudin CM; Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org., Pietanza MC; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Bauer TM; Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA., Ready N; Duke University Medical Center, Durham, NC, USA., Morgensztern D; Washington University School of Medicine in St Louis, St Louis, MO, USA., Glisson BS; University of Texas MD Anderson Cancer Center, Houston, TX, USA., Byers LA; University of Texas MD Anderson Cancer Center, Houston, TX, USA., Johnson ML; Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA., Burris HA 3rd; Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA., Robert F; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA., Han TH; Stemcentrx Inc, South San Francisco, CA, USA., Bheddah S; Stemcentrx Inc, South San Francisco, CA, USA., Theiss N; Ventana Medical Systems Inc, Tucson, AZ, USA., Watson S; Ventana Medical Systems Inc, Tucson, AZ, USA., Mathur D; Ventana Medical Systems Inc, Tucson, AZ, USA., Vennapusa B; Ventana Medical Systems Inc, Tucson, AZ, USA., Zayed H; Stemcentrx Inc, South San Francisco, CA, USA., Lally S; Stemcentrx Inc, South San Francisco, CA, USA., Strickland DK; Sarah Cannon Research Institute, Nashville, TN, USA., Govindan R; Washington University School of Medicine in St Louis, St Louis, MO, USA., Dylla SJ; Stemcentrx Inc, South San Francisco, CA, USA., Peng SL; Stemcentrx Inc, South San Francisco, CA, USA., Spigel DR; Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2017 Jan; Vol. 18 (1), pp. 42-51. Date of Electronic Publication: 2016 Dec 05.
DOI:	10.1016/S1470-2045(16)30565-4
Abstrakt:	Background: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. Methods: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. Findings: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). Interpretation: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. Funding: Stemcentrx Inc. (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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