Elsevier

The Lancet Oncology

Volume 13, Issue 11, November 2012, Pages 1133-1140
The Lancet Oncology

Articles
Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study

https://doi.org/10.1016/S1470-2045(12)70474-6Get rights and content

Summary

Background

We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection.

Methods

Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m2 per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10.

Results

Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38–7·97; p=0·0001) and 3·48 times (2·05–4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23–4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was −5·05% (IQR −12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients).

Discussion

MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2-amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma.

Funding

F Hoffmann-La Roche.

Introduction

The P53 tumour suppressor is a potent transcription factor that is frequently inactivated in human cancer.1 It is activated after cellular stress and regulates several downstream pathways implicated in cell-cycle control, apoptosis, DNA repair, and senescence.2 MDM2 is an E3 ligase that binds P53 and regulates P53 protein concentrations through a negative feedback loop in which raised nuclear P53 concentrations activate MDM2 transcription while MDM2 blocks the P53 transactivation domain, targeting P53 for degradation.3, 4 In cells that overexpress MDM2, P53 is inactivated, leading to inefficient growth arrest and apoptosis. Blocking the P53–MDM2 interaction might restore P53 function and could be a novel approach to cancer treatment.5

A class of imidazoline compounds, termed nutlins, have been identified as potent and selective small-molecule MDM2 inhibitors.6 Treatment of cancer cell lines expressing wild-type P53 with nutlins stabilises and activates P53, leading to cell cycle arrest and apoptosis.6, 7 RG7112 is a member of the nutlin family and is the first MDM2 antagonist to be assessed clinically (appendix).6 RG7112 is a potent inhibitor of P53–MDM2 binding that effectively stabilises P53 protein, activates P53 signalling, and inhibits cancer cell growth.8 RG7112 was assessed in a phase 1 multiple-ascending-dose trial in patients with solid tumours with doses ranging from 20 mg/m2 to 1800 mg/m2.8

Tumours with MDM2 gene amplification produce high concentrations of MDM2 and typically express wild-type P53, making them an ideal target to assess the clinical potential of MDM2 antagonists.9 MDM2 amplification occurs across many tumour types but is particularly common in sarcomas.9, 10, 11 Liposarcoma is the most frequent histological type of soft-tissue sarcoma, and well-differentiated and dedifferentiated liposarcomas are the most frequent subtypes (incidence about one per 100 000 people per year).12, 13, 14 Well-differentiated and dedifferentiated liposarcomas have simple genomic profiles characterised by a molecular and diagnostic hallmark (MDM2 12q14-15 amplification).9 Surgery is the main method of management of primary well-differentiated or dedifferentiated liposarcoma. Resection with R0 margin status is an achievable goal for well-differentiated or dedifferentiated tumours located in the limbs but is more challenging for retroperitoneal tumours. Therefore, retroperitoneal tumours are associated with a higher recurrence rate than limb sarcomas.9 Systemic treatment is the most suitable approach for patients with advanced or unresectable dedifferentiated liposarcoma; however, cytotoxic drugs provide limited response rates (about 10%) and result in short median progression-free survival (PFS), usually of 2–6 months.15, 16, 17

As a preliminary step in assessing the clinical potential of RG7112, in this proof-of-mechanism study we assessed biomarker-based evidence of RG7112 clinical activity in a population of patients with liposarcoma before surgery.

Section snippets

Patients

We undertook a neoadjuvant biomarker study in patients with well-differentiated or dedifferentiated liposarcoma that was amenable to surgery with curative intent at four centres in France. Standard inclusion criteria were applied, including age at least 18 years, performance status score of 0 or 1, no previous cytotoxic or radiotherapy treatment, and normal end organ function. Patients with bone marrow dysfunction and those needing anticoagulation treatment were excluded.

The study was approved

Results

Between June 3, and Dec 14, 2010, 20 patients, (12 men and eight women) were enrolled and completed pretreatment and cycle 1, day 8 (give or take 2 days) biopsies. Patients were a median of 62 years old (range 22–79) and had a median of one previous surgery (range 0–7). All patients were chemotherapy naive; 11 were in relapse. 11 patients had well-differentiated liposarcoma (one was reclassified as a lipoma upon review) and nine patients had dedifferentiated liposarcoma. Initial localisation

Discussion

The objective of this study was to investigate the pharmacodynamic response to RG7112 in patients with MDM2-amplified liposarcoma. Although this study was done on a small set of patients, and is therefore exploratory by nature, the results suggest that RG7112 enables reactivation of the P53 pathway in most tested patients and that pharmacodynamic markers of P53 activation are correlated with RG7112 pharmacokinetics and pharmacodynamic markers (panel).

Even though some of the changes noted in

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