Elsevier

The Lancet Oncology

Volume 21, Issue 5, May 2020, Pages 645-654
The Lancet Oncology

Articles
Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial

https://doi.org/10.1016/S1470-2045(20)30068-1Get rights and content

Summary

Background

Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy.

Methods

In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972.

Findings

Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5–25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2–45·2). The most common grade 3–4 adverse events (irrespective of causality) were haematological abnormalities—namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported.

Interpretation

Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial.

Funding

Pharma Mar.

Introduction

Small-cell lung cancer (SCLC) comprises about 13–15% of all lung cancer cases at diagnosis. Treatment and survival have not changed substantially during the past two decades. Even limited-stage disease is rarely cured with radical local therapy (surgery or radiotherapy), and systemic chemotherapy (platinum plus etoposide) remains the cornerstone of first-line treatment in SCLC.1 Atezolizumab,2 which has been approved by the US Food and Drug administration as first-line therapy, or durvalumab3 combined with carboplatin plus etoposide have been shown to improve overall survival compared with chemotherapy alone in patients with SCLC in the first-line treatment setting.

When patients with SCLC relapse, few therapeutic options are available. Topotecan is the only approved drug for second-line treatment of patients with a chemotherapy-free interval longer than 60 days. However, topotecan use is challenging because of associated haematological toxicities and its relatively modest clinical benefit (response in around 16% of patients and median overall survival of 6–8 months).4, 5, 6, 7, 8, 9 Several novel therapeutic strategies have not improved outcomes compared with topotecan in the second-line setting. These treatments include nivolumab, atezolizumab, and rovalpituzumab tesirine,10, 11, 12 as well as a switch-maintenance strategy after first-line chemotherapy using nivolumab and nivolumab plus ipilimumab,13 creating an unmet need for more effective and less toxic treatment options than topotecan.

Research in context

Evidence before this study

We searched PubMed for reports published since inception up to May 31, 2015, in any language using the terms “small cell lung cancer (SCLC)”, “chemotherapy”, “relapsed”, and “second-line”. Additionally, we examined abstracts from major international conferences of the same period (American Society of Clinical Oncology, European Society of Medical Oncology, and International Association for the Study of Lung Cancer annual meetings). We also searched clinical trial registers on ClinicalTrials.gov. With this search, we identified that after disease progression to first-line treatment, few therapeutic options are available for patients with SCLC, and that topotecan was the only drug approved during the past two decades for patients with disease sensitive to treatment. No approved therapies are accessible for patients with resistant disease (topotecan is approved for relapses at least 60 days after initiation of a platinum-containing first-line regimen). This search also showed that use of topotecan is challenging because of the associated haematological toxicity and the modest clinical benefit (overall response of around 16% was recorded in randomised clinical trials since 2014). In a phase 1 study in combination with doxorubicin, lurbinectedin showed remarkable activity in second-line SCLC; this finding led us to investigate lurbinectedin as a monotherapy in patients with SCLC.

Added value of this study

This study provides, to our knowledge, the first clinical evidence of anti-tumour activity for lurbinectedin as a single drug in patients with relapsed SCLC, with notable durable responses. Results detected by the investigators are robust and confirmed by an independent review committee. Our study also shows that lurbinectedin has an acceptable and manageable safety profile.

Implications of all the available evidence

Lurbinectedin appears to be a new valuable treatment option. The benefit observed with lurbinectedin compares favourably with that seen historically with topotecan, the current standard of care, in terms of both anti-tumour activity and safety. This drug profile is relevant for patients with relapsed SCLC, who are currently a population with a dismal prognosis.

SCLC is difficult to treat without actionable molecular targets.14, 15 It is a transcription-dependent disease, for which four molecular subtypes have been described, defined by differential expression of four key transcription regulators.15 Lurbinectedin is a selective inhibitor of oncogenic transcription that binds preferentially to guanines located in the GC-rich regulatory areas of DNA gene promoters.16, 17 The drug thus prevents binding of transcription factors to their recognition sequences, inhibiting oncogenic transcription and leading to tumour cell apoptosis.18 By inhibiting activated transcription in tumour-associated macrophages, lurbinectedin also affects the tumour microenvironment landscape.19

Promising activity of lurbinectedin in combination with doxorubicin was observed in patients with second-line SCLC in a phase 1 trial.20 In this study, we evaluated the activity of lurbinectedin alone in terms of response rate in a cohort of patients with SCLC treated in the second-line setting.

Section snippets

Study design and participants

In this single-arm, open-label, phase 2 basket trial, we recruited patients with nine different tumour types. This report focuses on the cohort of patients with SCLC treated at 26 hospitals in Belgium, France, Italy, Spain, Switzerland, the UK, and the USA (appendix p 1). Patients were recruited by the study investigators at each hospital. Adult patients aged at least 18 years with a pathologically proven diagnosis of SCLC were included if they had: pre-treatment with only one previous

Results

Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled into the study (appendix p 1). All 105 patients were treated with lurbinectedin and included in the analysis for the primary endpoint (table 1). One patient with CNS metastases at baseline was included, and another patient had rechallenge with carboplatin plus etoposide and atezolizumab as previous line of therapy; these two cases were considered protocol deviations, but they were minor and were included in the primary analysis.

Discussion

This phase 2 trial met its primary endpoint and showed that lurbinectedin was active as a second-line treatment for patients with SCLC. Overall response assessed by the investigators was 35·2% and its lower 95% CI boundary of 26·2% met the per-protocol statistical boundaries to show anti-tumour activity. The overall response results are supported by the durability of responses, with duration of 6 months or longer in 43% of patients who had a response. At data cutoff, 63% of the patient

Data sharing

Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrolment in 2015. Posting of clinical trial summary results will be placed in the European Clinical Trials Database (EudraCT; https://eudract.ema.europa.eu) upon completion of all cohorts included in this study.

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