Elsevier

The Lancet Oncology

Volume 14, Issue 2, February 2013, Pages 134-140
The Lancet Oncology

Articles
Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study

https://doi.org/10.1016/S1470-2045(12)70572-7Get rights and content

Summary

Background

Low-grade serous carcinoma of the ovary is chemoresistant but mutations in the MAPK pathway could be targeted to control tumour growth. We therefore assessed the safety and activity of selumetinib, an inhibitor of MEK1/2, for patients with this cancer.

Methods

In this open-label, single-arm phase 2 study, women (aged ≥18 years) with recurrent low-grade serous ovarian or peritoneal carcinoma were given selumetinib (50 mg twice daily, orally) until progression. The primary endpoint was the proportion of patients who had an objective tumour response according to RECIST version 1.1, assessed for all the treated patients. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551070.

Findings

52 patients were enrolled between Dec 17, 2007, and Nov 23, 2009. All were eligible for analyses. Eight (15%) patients had an objective response to treatment—one patient had a complete response and seven had partial responses. 34 (65%) patients had stable disease. There were no treatment-related deaths. Grade 4 toxicities were cardiac (one), pain (one), and pulmonary events (one). Grade 3 toxicities that occurred in more than one patient were gastrointestinal (13), dermatological (nine), metabolic (seven), fatigue (six), anaemia (four), pain (four), constitutional (three), and cardiac events (two).

Interpretation

Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum. The findings suggest that inhibitors of the MAPK pathway warrant further investigation in these patients.

Funding

National Cancer Institute.

Introduction

Low-grade serous carcinoma (LGSC) of the ovary differs from high-grade serous carcinoma (HGSC) in pathological features, associated molecular changes, and natural clinical course (table 1).1, 2, 3, 4 Serous ovarian tumours of low malignant potential, and LGSCs of the ovary have a higher frequency of KRAS and BRAF mutations, a higher frequency of expression of active MAPK, and a lower frequency of TP53 mutations than do HGSCs.1, 2, 5, 6, 7, 8 Additionally, gene expression profiles of LGSC and serous tumours of low malignant potential are similar and very distinct from the expression profiles of HGSCs.6, 7, 9

Equally compelling are clinical results that suggest a link between serous tumours of low malignant potential and LGSC and show differences between low malignant potential tumours and HGSCs.10 Patients with LGSC are diagnosed at a younger age and have a longer overall survival than do women with HGSC. LGSC is chemoresistant, not only to first-line agents, but also in the setting of recurrent disease.11, 12 Only about 2% of patients with platinum-resistant disease, and 4% of those with platinum-sensitive disease, respond to chemotherapy.12 Therefore, a continued search for active targeted agents for these tumours is important, and is focused on our improved understanding of the molecular origins of the tumours.

Selumetinib (AZD6244, ARRY-142886) is a potent, selective, orally available, and non-ATP competitive small molecule inhibitor of MEK1/2.13 Because of the high frequency of mutational alterations in the MAPK pathway in low-grade serous ovarian cancers, molecular inhibitors of this pathway's activation could be a targeted strategy to control tumour growth. Based on this preliminary information, we tested selumetinib in patients with recurrent LGSC of the ovary or peritoneum in a phase 2 trial.

Section snippets

Patients

Women with an initial primary diagnosis of serous borderline or biopsy-proven recurrent LGSC (invasive micropapillary serous carcinoma, or invasive grade 1 serous carcinoma) of the ovary or peritoneum that was confirmed by masked pathological review of the recurrent tumour were eligible for enrolment in this open-label, single-arm, phase 2 study. Women had to be at least 18 years of age; have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2; have disease measurable by

Results

52 patients were accrued and enrolled between Dec 17, 2007, and Nov 23, 2009, and the data were locked on May 16, 2011. All 52 patients received selumetinib, and are thus all included in the safety and efficacy analyses. The characteristics of the patients are presented in table 2. Median age of the patients was 51 years (range 24–77). Most patients were white, had GOG performance status 0, and had ovarian disease. 30 (58%) of 52 patients had received three or more previous chemotherapeutic

Discussion

Our study shows that selumetinib is well tolerated, and is an active treatment in recurrent LGSC, with 15% of patients in this trial achieving a complete or partial response. Median PFS was 11·0 months, with 63% of patients having a PFS of longer than 6 months. In an exploratory analysis, response to selumetinib did not seem to be related to KRAS or BRAF mutation status (panel).

LGSCs have been increasingly recognised as more chemoresistant than HGSCs, with 88% of patients having positive

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