Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

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Abstract

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) – a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature – pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without ⩾grade 2 skin toxicity/diarrhoea. Grade 3 hand–foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400 mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for ⩾6 months in 12% of patients (6% stabilized for ⩾1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Introduction

Eukaryotic cell function is regulated by complex and coordinated arrays of growth-regulatory genes, including those for cytokines and growth factors. The GTPase Ras relays cytokine and growth factor signals from the cell surface to the nucleus via the Raf/MEK/ERK pathway.1 Raf has an important role in regulating normal cellular growth, differentiation and apoptosis, and is implicated in tumourigenesis.2, 3 B-Raf knockout mice die mid-gestation due to increased endothelial cell apoptosis and vascular defects,2 while blocking C-Raf (Raf-1 or c-Raf-1) inhibits cellular proliferation and VEGF-mediated angiogenesis.2, 4 The b-raf V599E mutation is present in 63% of malignant melanomas;4 40% of sporadic colorectal tumours with high microsatellite instability;5 38% of papillary thyroid carcinomas;6 and some non-small-cell lung carcinomas (NSCLCs).4 Activating ras mutations result in aberrant signalling via Raf, and are common in human solid tumours of the pancreas (90%), colorectum (45%), lung (NSCLC: 35%), liver (30%), skin (melanoma: 15%) and kidney (10%).1, 2, 7, 8, 9 Aberrant signalling via Ras and Raf can also result from overexpression, amplification or mutational activation of upstream vascular endothelial (VEGFR), platelet-derived (PDGFR-β), and epidermal (EGFR) growth factor receptors.2, 10, 11

The management of advanced solid tumours is limited by the fact that they are often refractory to current treatments, including radiotherapy and chemotherapy, and have a generally poor prognosis. Therefore, there is an urgent need to develop more effective drugs to stabilize/slow the progression of advanced solid tumours. Novel targeted agents that interfere with either EGF/VEGF–receptor interactions or Raf/MEK/ERK signalling downstream of EGFR/VEGFR have shown promising clinical activity against several advanced solid tumour types.1, 12, 13 In contrast to standard chemotherapies, targeted agents are also generally well tolerated.14, 15 Interestingly, the improved clinical activity of novel agents targeting the EGF pathway may correlate with the appearance of skin rash.16, 17 If confirmed, this relationship may be useful in predicting treatment response and/or ensuring optimal dose titration.

BAY 43-9006 (sorafenib) is a novel, orally administered multi-kinase inhibitor with effects on the tumour and vasculature. In biochemical assays, it is a potent inhibitor of Raf-1, wild-type B-Raf and V599E b-raf kinases, and proangiogenic VEGFR-2, VEGFR-3, and PDGFR-β tyrosine kinases.18, 19 Sorafenib also inhibits phosphorylation of Flt3, c-KIT, and p38α – a member of the MAPK family.18, 19 In xenograft models, sorafenib inhibited the growth of human colon, pancreatic and NSCLC tumours carrying b-raf or k-ras mutations.20 It also significantly inhibited neovascularization in human xenograft models of colon (HT-29 and Colo205) and breast cancer (MDA-MB-231).19 Furthermore, sorafenib monotherapy demonstrated promising efficacy (e.g., advanced refractory renal and hepatocellular carcinoma), particularly at doses ⩾200 mg bid, and favourable safety in four phase I dose-escalation trials, in which different dosing schedules were evaluated.21, 22, 23, 24, 25, 26

In the present analysis, data were pooled from these trials to provide an overview of the safety and efficacy of sorafenib monotherapy in patients with advanced cancer. Since Raf, a target for sorafenib, is a downstream effector of EGFR, we also investigated the relationship between skin toxicity/diarrhoea and time to progression (TTP).

Section snippets

Patient selection

Patients recruited into the four phase I sorafenib trials (A–D) utilized in this pooled analysis were aged ⩾16 years and had histologically documented advanced and/or metastatic solid tumours that were refractory to standard curative therapies. These patients also had an Eastern Co-operative Oncology Group (ECOG) performance status ⩽2, and life expectancy ⩾12 weeks. Recruited patients had clinically and/or radiologically evaluable disease; adequate bone marrow, hepatic, and renal function; and

Patients’ characteristics

The median age of the 179 patients was 57 years (range 18–79 years). Most participants were male (56%) with advanced refractory colorectal (38%) or gastrointestinal (13%) solid tumours, and an ECOG performance status of 0–1 at baseline. Almost all patients had received surgery (92%) and chemotherapy (98%) prior to study entry, and 39% had received radiotherapy (Table 1).

Dose escalation

The sorafenib doses administered were <100, 100, 200, 400, 600 and 800 mg bid. In addition, a dose of 300 mg bid was

Discussion

In this pooled analysis, the majority of drug-related toxicities associated with oral sorafenib administration were mild to moderate in severity, easily manageable, of gastrointestinal or dermatological nature, and unrelated to the dosing schedule. Diarrhoea was the most common gastrointestinal toxicity and was dose limiting in patients receiving the highest sorafenib dose (800 mg bid continuous). Skin toxicity (i.e., HFS and rash) was dose limiting and occurred with mild diarrhoea at sorafenib

Conflict of interest statement

Drs. Strumberg, Awada, Hirte, Clark, Seeber, Piccart and Hofstra have all received funding for undertaking phase I trials and/or have acted as consultants/received honoraria from Bayer AG, Wuppertal, Germany/Bayer Pharmaceuticals Corporation, West Haven, CT, USA. Drs. Voliotis, Christensen, Brueckner and Schwartz are all employees of Bayer AG, Wuppertal, Germany/Bayer Pharmaceuticals Corporation, West Haven, CT, USA.

Acknowledgement

The phase I trials utilized in this pooled analysis were all funded by Bayer Pharmaceuticals Corporation, West Haven, CT, USA.

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