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The multikinase inhibitor sorafenib tosylate has been shown to slow tumour growth and improve survival of kidney cancer patients. It gained FDA and EU approval for treating renal cell carcinoma in 2005-6
IRCCS San Matteo University Hospital Foundation
Adjunct Professor of Medical Oncology
University of Pavia
IRCCS San Matteo University Hospital Foundation
IRCCS San Matteo University Hospital Foundation
Sorafenib tosylate (BAY 43-9006, Nexavar, Bayer Schering Pharma; for chemical structure see Figure 1) was an originally identified screening compound able to inhibit the serine-threonine kinase Raf (with its three isoforms, A-Raf, B-Raf, and Raf1 or C-Raf). It was the first kinase along the so-called mitogen-activated protein kinase (MAPK) pathway, a key regulator of cell proliferation and survival. Furthermore, wild-type Raf1 can also prolong cell survival, independent of MAPK signalling, by direct interaction with antiapoptotic and apoptotic regulatory proteins.
Only later was the activity of sorafenib on several tyrosine kinases involved in tumour angiogenesis demonstrated. Indeed, sorafenib is able to inhibit, at pharmacological concentrations, kinases such as VEGFR-2, VEGFR-3, PDGFR-beta, c-KIT, Flt-3, FGFR1 and RET (see Table 1).
Thus, sorafenib exerts its antitumour activity by inhibiting both cell proliferation (through its activity on Raf kinase) and angiogenesis (through its activity on VEGFR-2 and -3 and PDGFR-beta), acting on tumour cells as well as on endothelial cells and pericytes (see Figure 2).[4,5]
If, on the one hand, sorafenib’s antiangiogenic properties are well evident in all the tumour models studied so far, its inhibitory activity on the MAPK pathway seems to be relatively more or less important depending on the the type of tumour considered. For example, the MAPK pathway appears to be extremely important in hepatocellular carcinoma (HCC), while its relevance in kidney cancer remains to be precisely defined.
Summary of phase I studies
Four single-agent phase I trials[7-10] evaluating different
sorafenib doses and schedules have been performed (see Table 2). Based on the results of these studies, continuous oral administration of sorafenib at 400mg twice a day emerged as the schedule recommended for the drug’s future development. Dose-limiting toxicities in these studies included grade 3 diarrhoea and fatigue at 800mg twice a day, and grade 3 skin toxicity at 600mg twice a day. Overall, Sorafenib was well tolerated, and the majority of adverse events were mild to moderate in severity and easily manageable. In these phase I trials, 11 patients with metastatic RCC were evaluated for tumour response (RECIST). Early signals of antitumour activity were detected in one patient with metastatic RCC who, having been treated with sorafenib 600mg twice a day, had a sustained (104-day) confirmed partial response (PR), as well as in two additional RCC patients who experienced sustained (â‰¥two years) stable disease.
Proof of principles of sorafenib activity in RCC: results of a randomised discontinuation trial
Sorafenib’s safety and efficacy for treating advanced cancer patients were first studied within a phase II study designed as a discontinuation randomisation trial (RDT). The aim of the RDT (or withdrawal trial) design is to assess the clinical activity of a drug while minimising use of placebo; in such a trial, all patients receive the study drug for an initial run-in period, then there is random assignment of potential responders to either the study drug or placebo.
Originally, the study focused on patients with colorectal cancer but allowed enrolment of patients with other solid-tumour types. During the course of the study, evidence of tumour regression in many patients with RCC led to a protocol amendment extending recruitment of patients with RCC and terminating enrolment of patients with colorectal cancer.
Of the 202 RCC patients treated during the run-in period, 73 had tumour shrinkage of â‰¥25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n=32) or placebo (n=33). At 24 weeks, 50% of the sorafenib-treated patients were progression-free, vs 18% of the placebo-treated patients (p=0.0077); median progression-free survival (PFS) from randomisation was significantly longer with sorafenib (24 weeks) than placebo (six weeks; p=0.0087). Median overall PFS was 29 weeks for the entire RCC population. Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib, until further progression, for a median of 24 weeks.
As far as sorafenib tolerability is concerned, common adverse events were as expected from previous phase I studies, and included skin rash/desquamation, hand-foot skin reaction and fatigue; 9% of patients discontinued therapy; and no patients died due to toxicity.
The results of this placebo-controlled phase II study clearly demonstrate that sorafenib has significant activity in metastatic RCC; additional evidence for antitumour activity was provided by the restabilisation of the disease in patients whose tumour had progressed on placebo and who were switched to sorafenib.
Furthermore, the median duration of sorafenib treatment in these patients after crossover was comparable to the median PFS for patients randomly assigned to placebo, suggesting that patients were not disadvantaged due to a brief period of placebo treatment.
Phase III registration trial of sorafenib in RCC: the TARGET study
The TARGET study was a large, registration, phase III, multicentre, randomised, placebo-controlled trial in which 903 patients with clear-cell RCC resistant to standard therapy were randomised to receive either continuous treatment with oral sorafenib (at the classic dose of 400mg twice a day) or placebo.
Even though the primary endpoint of the study was overall survival (OS), a single planned analysis of progression-free survival (PFS), performed in January 2005, showed a statistically significant benefit of sorafenib over placebo; consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. At the January 2005 cutoff the median PFS was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group: 0.44, p<0.01).[13,14]
OS analysis before crossover showed an estimated 39% improvement for sorafenib vs placebo (HR=0.71, p=0.015); a subsequent intention-to-treat (ITT) analysis, performed six months after crossover and including patients (n=216) crossed over to sorafenib, showed a 30% improvement in OS for sorafenib vs placebo (HR=0.77, p=0.015). Prespecified O’Brien-Fleming statistical boundaries were not reached by these OS differences.[15,16] Final OS at 561 deaths showed a nonsignificant improvement of 13.5% for sorafenib vs placebo (median 17.8 vs 15.2 months; HR=0.88, p=0.146). A preplanned secondary analysis, censoring placebo data to avoid the confounding effect of crossover, was then performed. A significant OS benefit for sorafenib vs placebo was seen (HR=0.78, 95% CI: 0.62, 0.97; p=0.0287).
Regarding tumour response assessment, 84% of the 451 sorafenib-treated patients had a clinical benefit (<1% had a complete response, 10% had a partial response and 74% had stable disease), while among the 452 patients randomised to receive placebo, 55% had a clinical benefit (2% had a partial response and 53% had stable disease).
Regarding tolerability, adverse events occurring during sorafenib treatment were predominantly of grade 1 or 2; however, sorafenib-induced side-effects are extremely peculiar and if not promptly recognised and adequately treated could progress to higher grades and negatively impact on patients’ everyday lives.
The commonest side-effects reported within the TARGET study included diarrhoea, skin rash, fatigue, hand-foot skin reaction, alopecia, nausea and hypertension; moreover, the most common laboratory abnormalities included lymphopenia, hypophosphataemia and elevated lipase levels.
Sorafenib in everyday clinical practice: results of the global expanded-access programmes
The antitumour activity of sorafenib as well as its safety
were confirmed by the results of the two expandedaccess
programmes (EAPs) performed in the EU and
The results of the two EAPs are extremely important, since patients treated within them are more representative of a broader range of RCC patients in the community than those enrolled into the registration TARGET study.
Notably, both response rates and toxicities observed in EAPs were similar to those reported in the phase III TARGET study;[18,19] furthermore, sorafenib proved to be active and tolerable also in very peculiar (and not previously tested) patient populations, including patients with non-clear-cell histology, patients with brain metastases (where the drug proved to be manegeable without an excess risk of cerebral hemorrhages, despite early concerns), patients previously treated with other antiangiogenic agents, and elderly
patients (>65 years of age).
Sorafenib was approved by the FDA on 20 December 2005 for treating RCC, and received EU marketing authorisation for the same indication on 19 July 2006. More recently, the European Commission granted marketing authorisation for sorafenib tablets for treating patients with HCC, following presentation of the results of the SHARP study, on 30 October 2007.
Sorafenib is one of the four new molecularly targeted agents that have reached (or are set to reach) the bedside in the once-orphan field of medical treatment of kidney cancer, and that have radically changed the natural history of this disease.
Presently it is the treatment of choice for patients refractory to cytokines, and as such it has received a grade A recommendation in European Urology Association (EAU) guidelines.
Furthermore, despite the negative results of a randomised phase II trial as a frontline treatment for advanced RCC patients, sorafenib could also be used in the first line in patients not suitable for cytokine-based treatments (for example, in Italy its registration includes this setting), or based on clinical judgement where allowed by regulatory authorities.
Sorafenib is currently under experimental evaluation in combination with cytokines or as part of a dose-escalation strategy. As a whole, its use in the EU will probably increase over the coming years, becoming even more widespread as soon as it becomes available in all countries for treating HCC.
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