A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC)
Angiogenesis and RAS/RAF/MEK/ERK pathway have been demonstrated to be relevant in hepatocellular carcinoma (HCC). Sorafenib, an oral multikinase inhibitor with activity against RAF kinase and vascular endothelial growth factor receptor-2, is approved for the treatment of advanced HCC. The therapeuti...
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| Published in: | Annals of oncology Vol. 27; no. 12; pp. 2210 - 2215 |
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| Main Authors: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
England
Elsevier Ltd
01-12-2016
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Angiogenesis and RAS/RAF/MEK/ERK pathway have been demonstrated to be relevant in hepatocellular carcinoma (HCC). Sorafenib, an oral multikinase inhibitor with activity against RAF kinase and vascular endothelial growth factor receptor-2, is approved for the treatment of advanced HCC. The therapeutic benefit however is modest. While displaying tumour growth inhibition and angiogenesis, sorafenib treatment in pre-clinical models exhibited up-regulation of pERK which may limit its anti-tumour activity. Inhibition of the MEK/ERK pathway by selumetinib enhanced the anti-tumour effect of sorafenib in pre-clinical models of HCC. In this phase I study, we investigated the maximum tolerated dose (MTD), safety and activity of combination sorafenib and selumetinib in patients with advanced HCC. The combination of selumetinib and sorafenib has manageable toxicity and showed encouraging anti-tumour activity. These findings support further evaluation in a phase II study.
Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Patients with Child–Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand–foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes.
The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation.
NCT01029418. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0923-7534 1569-8041 |
| DOI: | 10.1093/annonc/mdw415 |