Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: Results from a phase I extension trial

Abstract

Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m² IV for up to six 3-week cycles. Sorafenib 400 mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3–4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C_max (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common solid tumour¹ and the third leading cause of cancer deaths worldwide.² Eighty percent of cases occur in Asia and sub-Saharan Africa.³ Despite a relatively lower incidence in Europe and the United States (US), the rates have roughly doubled from the 1960s and 1970s to the mid 1990s.4, 5, 6, 7, 8

Current treatment options for HCC are limited. Only 15% of patients qualify for surgical intervention and/or transplantation.⁹ Systemic cytotoxic therapies have been largely unsuccessful, yielding marginal anti-tumour activity and exerting no appreciable impact on survival.10, 11, 12 Nonetheless, chemotherapy is used frequently in clinical practice, with doxorubicin as the agent of choice.¹⁰ Outcomes in patients with HCC treated with conventional chemotherapy are generally poor; 5-year survival rates are typically less than 5%.⁵ New therapeutic approaches are urgently needed to improve outcomes in this difficult-to-treat patient population.

Sorafenib (BAY 43-9006, Nexavar^®), an oral multikinase inhibitor with anti-proliferative and anti-angiogenic activities, has been shown to inhibit the activity of the serine/threonine kinases (c-Raf and B-Raf); vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3 and platelet-derived growth factor receptor (PDGFR)-α and -β as well as c-Kit, Flt-3 and RET.13, 14, 15 Preclinical studies have shown that sorafenib suppresses tumour proliferation through inhibition of the Raf/MEK/ERK pathway, and tumour angiogenesis through inhibition of VEGF receptors.15, 16, 17

Sorafenib has demonstrated potent anti-tumour activity in preclinical models of breast cancer, lung cancer, colorectal cancer, renal cell carcinoma (RCC) and HCC, all of which are known to exhibit a dysregulated Raf pathway and upregulated angiogenesis.15, 18 Analysis of HCC tumour xenografts has shown that apoptosis, angiogenesis and the Raf/MEK/ERK pathway are targeted by sorafenib.¹⁹ Activation of the Raf pathway in HCC may result from divergent underlying causes²⁰: hepatitis B virus (HBV) transcriptional activation alters the expression of growth-control genes, including Raf and Ras; hepatitis C virus (HCV) core proteins interact with Raf and other members of the MAPK pathway to modulate proliferation; and aflatoxin B₁ is associated with a specific p53 mutation and Ras oncogene activation.²¹ Sorafenib has been shown to reduce MEK and ERK phosphorylations, decrease microvessel density and to increase apoptosis in HCC cells in vivo.¹⁶

In a phase II study of 137 patients with advanced HCC who received single-agent sorafenib, the overall best response of stable disease (SD) or better was 41.6%.²² Recently, the phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial demonstrated increased overall survival in patients with advanced HCC who were treated with single-agent sorafenib 400 mg bid, compared with those who received placebo.²³ This was the first trial to show such an increase with a systemic therapy in the HCC patient population. This result led to approvals of sorafenib for the treatment of HCC by the US Food and Drug Administration and by the European Medicines Agency.

The combination of sorafenib and chemotherapeutic agents such as doxorubicin has demonstrated additive anti-tumour activity in vitro.²⁴ In a phase I dose-escalation study, combining sorafenib and doxorubicin in 34 patients with refractory solid tumours, 15 patients (48%)—four of whom had a diagnosis of HCC—achieved SD for ⩾12 weeks.²⁵ Sorafenib (400 mg bid) and doxorubicin (60 mg/m²) were well tolerated, without reaching the toxic dose level.

Long-term safety has not been evaluated in patients receiving the combination of sorafenib plus doxorubicin, for up to the maximum lifetime cumulative dose of doxorubicin, and followed by single-agent sorafenib therapy. To better characterise the long-term safety and efficacy of this drug combination, an extension study of a phase I trial in patients with inoperable HCC was performed. The primary objective of the extension study was to determine the long-term safety of continuously administered sorafenib combined with doxorubicin every 21 days for up to six cycles or up to the maximum lifetime cumulative dose of doxorubicin, and followed by single-agent sorafenib. Secondary objectives included determining the effect of doxorubicin on the pharmacokinetics of sorafenib (and vice versa), as well as tumour response to this combination therapy.