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

Abstract

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.

Conflict of interest statement

Declaration of interests

CMR reports consulting fees from Bristol-Myers Squibb, Medivation, and Novartis, outside the published work. MCP reports consulting fees from Celgene, Abbvie, Clovis, Novartis, and Bristol-Myers Squibb; and is currently employed by Merck Research Laboratories, outside the submitted work. DMo reports personal fees from Celgene, Heat Biologics, Bristol-Myers Squibb, and Genentech for advisory board membership, and from Boehringer Ingelheim and Genentech for speakers bureau attendance, outside the submitted work. BSG reports clinical trial contracts with Amgen, Oncomed, and MedImmune, and trial support from Bristol-Myers Squibb and ISA Pharmaceuticals, outside the submitted report. LAB reports consulting fees from Biomarin, AstraZeneca, and Abbvie, outside the submitted work. FR reports personal fees for speakers bureau attendance from Boehringer Ingelheim and Merck, outside the submitted work. RG reports personal fees for consulting or honoraria from GlaxoSmithKline, Celgene, Roche, Bayer, Genentech, Clovis, Helsinn Healthcare, Baxalta, Pfizer, Astellas, and ARIAD, outside the submitted work. THH, SB, HZ, SL, SJD, and SLP were employees of Stemcentrx during the conduct of this study. THH is a shareholder in Stemcentrx and has a patent pending for use of DLL3 antibody-drug conjugates. SJD is a shareholder in Stemcentrx and has several patents issued that are relevant to the current work: USPN 9,089,617; USPN 9,173,959; USPN 9,352,091; USPN 9,358,304; USPN 9,089,616; USPN 9,133,271; USPN 9,155,803; and USPN 9,345,784. NT, SW, DMa, and BV were employees of Ventana Medical Systems during the conduct of this study. TMB, NR, MLJ, HAB, DKS, and DRS declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Waterfall plot showing best change in tumour burden from baseline at active treatment doses (n=60)

Investigator-assessed best change from baseline was the change in the sum of longest diameters of target lesions for patients treated with 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. Grey dotted line at 20% indicates the threshold for progressive disease and the line at –30% the threshold for partial response. One patient did not have a measurable target lesion.

Figure 2. Swimmer’s plot showing time on study and duration of response for patients treated with active treatment doses (n=60)

Outcomes are shown for patients treated with 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. Lines without an arrow indicate deaths (patients who withdrew were still followed up). Duration of response includes confirmed and unconfirmed responses.