Elsevier

The Lancet Oncology

Volume 18, Issue 1, January 2017, Pages 42-51
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(16)30565-4Get rights and content

Summary

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.

Introduction

Small-cell lung cancer is a tumour with neuroendocrine features that comprises about 13–15% of all lung cancers, accounting for more than 275 000 new cases worldwide every year.1 It is characterised by aggressive growth and early metastasis to distant sites, resulting in most patients being diagnosed with extensive-stage disease.

Treatment and survival of patients with small-cell lung cancer has not changed substantially in more than 40 years. The disease is rarely cured with local therapy alone (surgery, radiotherapy, or both), and systemic chemotherapy remains a cornerstone of treatment. Standard, initial, systemic chemotherapy for all patients with adequate performance status consists of a platinum salt (eg, carboplatin or cisplatin) in combination with a second agent (eg, etoposide).2, 3 Responses to first-line treatment are high, but recurrence is frequent, and is universal in patients with extensive-stage disease: median survival is 14–20 months for limited-stage disease and 9–11 months for extensive-stage disease.2, 3 When small-cell lung cancer recurs, prognosis is especially poor, and few therapeutic options are available. Topotecan is the only treatment approved by the US Food and Drug Administration (FDA) for second-line treatment of recurrent small-cell lung cancer.3 However, this drug is challenging to use because of haematological toxic effects and modest antitumour activity, with reported responses in 5–24% of patients and median survival of roughly 25 weeks. In the third-line setting, no approved treatments for small-cell lung cancer exist, and current guidelines recommend best supportive care, consideration of investigational drugs, or systemic treatment in patients who maintain a good performance status.2, 3 Development of novel and more durably effective treatments for small-cell lung cancer is needed desperately. However, by contrast with non-small-cell lung cancer, progress in small-cell lung cancer has been hampered by the scarcity of specific molecular targets.1, 2, 4, 5

Research in context

Evidence before this study

We searched PubMed between July 22, 2003, and July 22, 2013, with the terms “SCLC”, “second-line”, “third-line”, “phase 1”, “phase 2”, “phase 3”, “relapsed”, “refractory”, “recurrent”, “DLL3”, and “rovalpituzumab”. We focused on reports and meta-analyses for treatment options and outcomes after failure of first-line treatment in patients with small-cell lung cancer that were published during the 10-year period before the start of our study. Recurrent, refractory, and relapsed small-cell lung cancer shows very poor survival outcomes, with no approved drugs beyond topotecan as second-line treatment, and no identified molecular biomarkers to guide targeted treatments.

Added value of this study

Our study shows activity of rovalpituzumab tesirine in small-cell lung cancer. Patients with relapsed or refractory disease, a population with few treatment options, achieved objective responses and had manageable toxic effects. The novel therapeutic target DLL3 is a potential predictive biomarker for small-cell lung cancer.

Implications of all the available evidence

These data have prompted the initiation of several trials in small-cell lung cancer, including in relapsed and refractory disease (NCT02674568) and as part of a first-line chemotherapeutic regimen (NCT02819999). Moreover, a trial in other DLL3-expressing neuroendocrine cancers has begun (NCT02709889).

Growing evidence supports a tumour-suppressor role for Notch-1 signalling in neuroendocrine tumours. Delta-like protein 3 (DLL3) is an atypical member of the Notch receptor ligand family that, unlike related family members, seems to inhibit Notch receptor activation.6, 7 DLL3 has been identified as a novel putative therapeutic target in high-grade neuroendocrine carcinomas including small-cell lung cancer, based initially on whole transcriptome sequencing of tumour-initiating cells isolated from small-cell lung cancer and large-cell neuroendocrine cancer patient-derived xenografts.8 DLL3 was expressed in most small-cell lung cancers and large-cell neuroendocrine tumours, by contrast with non-malignant adult tissues and non-neuroendocrine tumour types in which membrane protein expression is scant. DLL3 has been implicated in the regulation of cell-fate decisions during development and might function as an oncogenic driver in high-grade neuroendocrine tumours, including small-cell lung cancers; in these tumours, DLL3 appears to be a downstream transcriptional target of the ASCL1 transcription factor. By inhibiting the Notch receptor pathway, DLL3 might promote neuroendocrine tumorigenesis.6, 7, 8

Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate consisting of the humanised DLL3-specific IgG1 monoclonal antibody SC16, the DNA cross-linking agent SC-DR002 (D6.5), and a protease-cleavable linker that covalently links SC-DR002 to SC16. We aimed to do a first-in-human, open-label, phase 1 study to investigate the safety, tolerability, pharmacokinetics, and antitumour activity of rovalpituzumab tesirine in patients with small-cell lung cancer or large-cell neuroendocrine tumours. Most patients had relapsed metastatic small-cell lung cancer and represent the focus of this report.

Section snippets

Study design and participants

We did a first-in-human, open-label, phase 1 study of single-agent rovalpituzumab tesirine at ten cancer centres in the USA (appendix p 4). 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

Results

Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled in our study (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. At the time of data cutoff (May 11, 2016), the median duration of follow-up was 3·9 months (IQR 2·2–7·4; range 0·4–22·0). No patients remained on active treatment, and seven (9%) remained in follow-up. The entire study cohort received a median of two doses

Discussion

This first-in-human, phase 1 study of rovalpituzumab tesirine, a novel DLL3-targeted antibody-drug conjugate, defined a dose range in which the drug is well tolerated and shows encouraging single-agent antitumour activity in recurrent small-cell lung cancer. Expression of DLL3 in tumours can identify patients who are more likely to achieve a response and better long-term outcomes during treatment with rovalpituzumab tesirine, suggesting DLL3 as a potential biomarker and tractable therapeutic

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