Good Tolerability and Anti-Tumour Activity of GDC-0980
The PI3K AKT-mTOR signaling pathway (Phosphatidylinositide 3-kinase (PI3K) AKT (also known as Protein Kinase B) mammalian target of rapamycin (mTOR), is deregulated in a wide variety of cancers. A novel dual PI3K/mTOR inhibitor, GDC-0980, was successfully tested in a multi-centre phase I trial and the data presented from 113 patients with advanced solid tumours: 57 patients enrolled within the dose escalation stage, receiving once daily oral doses of 2 to 70 mg GDC-0980. Subsequently, 56 patients were treated using the recommended phase II doses of 40 mg for all tumour types and 30 mg for malignant pleural mesothelioma (MPM).
The oral, potent, dual inhibitor of PI3K/mTOR showed encouraging pharmacodynamics and anti-tumour activity: Inhibition of the PI3K/mTOR pathway was demonstrated at doses > 16 mg with 50 percent of patients having fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Four partial RECIST (Response Evaluation Criteria In Solid Tumours) responses (PR) were seen at doses of 8 (1-PIK3CA mutation R88Q), 30 (2) and 50 mg (1) in 33 MPM patients. An additional PR was detected in a PIK3CA mutant squamous cell head and neck cancer patient who received 40 mg.
Novel dual PI3K/mTOR inhibitor with persistent reponses
Dose limiting toxicities of hyperglycaemia and rash occurred at 70 mg. Doses < 50 mg GDC-0980 were well tolerated by most patients. At 2 to 70 mg, the frequency of grade 3-4 adverse events was < 15 percent; these included hyperglycaemia, rash, diarrhoea, fatigue, abnormal liver function tests and pneumonitis (the latter arose at doses > 40 mg). Most unwanted effects were managed with supportive treatment and reversed on cessation of GDC-0980 administration.
Encouraging results were demonstrated with this oral dual PI3K/mTOR inhibitor; particularly in mesothelioma and squamous cell head and neck cancer. Moreover, persistent responses were seen across many solid tumours. Biomarker analysis suggests PIK3CA mutation may enrich for anti-tumour activity. Further evaluation of GDC-0980 activity in head and neck cancer, renal cell carcinoma, and endometrial cancer is ongoing in this trial and other phase II studies.
The Royal Marsden Hospital
London, United Kingdom
Proffered Papers Session: Drug Development
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Hall: Room G104
Date: Monday, 30 September
From 10:00 to 10:12