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.
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/m(2) 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).


CONCLUSIONS
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.


BACKGROUND
F Hoffmann-La Roche.
Centre Leon Bérard, Lyon, France; EAM 4128 Santé-Individu-Société, Université Claude Bernard Lyon I, Lyon, France. isabelle.ray-coquard@lyon.unicancer.fr
Isabelle
I
Ray-Coquard
Jean-Yves
JY
Blay
Antoine
A
Italiano
Axel
A
Le Cesne
Nicolas
N
Penel
Jianguo
J
Zhi
Florian
F
Heil
Ruediger
R
Rueger
Bradford
B
Graves
Meichun
M
Ding
David
D
Geho
Steven A
SA
Middleton
Lyubomir T
LT
Vassilev
Gwen L
GL
Nichols
Binh Nguyen
BN
Bui
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D000970:Antineoplastic Agents; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2