- Email: [email protected]
New Perspectives: An Oral Multikinase Inhibitor in Patients with Advanced RCC
european urology supplements 6 (2007) 499–504
available at www.sciencedirect.com journal homepage: www.europeanurology.com
New Perspectives: An Oral Multikinase Inhibitor in Patients with Advanced RCC Bernard Escudier * Institut Gustave-Roussy, Villejuif Cedex, Paris, France
Article info
Abstract
Keywords: Advanced renal cell cancer Clinical benefit Overall survival Phase 3 trial Progression-free survival Sorafenib
Sorafenib (Nexavar1; Bayer Healthcare, West Haven, CT, USA) is an oral multikinase inhibitor that may provide dual action by inhibiting tumour cell proliferation and angiogenesis. Sorafenib was recently evaluated in the largest phase 3, randomised trial ever conducted in renal cell carcinoma (RCC): Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). In TARGET, sorafenib significantly increased progression-free survival versus placebo, which led to a change in the study protocol allowing patients in the placebo arm of the trial to cross over to receive sorafenib. At the time of crossover, sorafenib improved overall survival by 39% compared with placebo (hazard ratio = 0.72; 95% confidence interval 0.54–0.94; p = 0.02, not significant as per O’Brien–Fleming threshold for statistical significance: p = 0.0005). Sorafenib continued to show a trend towards improved overall survival at a subsequent analysis 6 mo post-crossover. Importantly, 84% of sorafenib-treated patients achieved investigator-assessed stable disease or better compared with 55% of placebo recipients. Sorafenib was well tolerated, had a manageable side-effect profile, and offered benefit with no compromise in quality of life. The data from the phase 3 TARGET study provided further evidence that sorafenib may be effective in a wide range of patients with advanced RCC. Clinical trials are planned to assess the potential of sorafenib as combination therapy and in the adjuvant setting. # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. * Institut Gustave-Roussy, 39 Rue Camille Desmoulins, Villejuif Cedex, Paris 94805, France. Tel. +33 1 4211 4211; Fax: +33 1 4211 5411. E-mail address: [email protected].
1.
Introduction
Renal cell carcinoma (RCC) is the most common primary cancer of the kidney and accounts for 80–85% of all malignant kidney cancers [1]. Although nephrectomy may be curative, 50% of patients with localised RCC who have undergone such surgery will
develop advanced metastatic disease [2]. Long-term survival for these patients is extremely poor and the 5-yr survival rate of patients with metastatic kidney cancer is only 9.5% [3]. In addition, many patients fail to respond to standard therapy such as interleukin-2 or interferon-a (IFN-a) [4]. Furthermore, a high proportion of patients with RCC are not suitable
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology.
doi:10.1016/j.eursup.2007.01.020
500
european urology supplements 6 (2007) 499–504
Fig. 1 – Sorafenib is active against both tumour cell and tumour vasculature. (MEK = mitogen extracellular kinase; ERK = extracellular signal-regulated kinase; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; PLC = phospholipase C; PI3K = phosphatidylinositol 3-kinase.)
for such therapies or relapse following cytokine therapy (as described in the article by Professor Patard in this supplement). Since only a limited subset of patients are likely to achieve clinical benefit with current cytokine therapies, new therapeutic approaches are urgently needed to improve outcomes in patients with metastatic RCC. Over the last decade, increased understanding of the molecular pathways involved in oncogenesis has generated therapies that target signalling pathways involved in tumour angiogenesis and tumour cell proliferation [5,6]. A key therapeutic advance in patients with RCC is the multikinase inhibitor, sorafenib (Nexavar1; Bayer Healthcare, West Haven, CT, USA). Sorafenib is an orally active bi-aryl urea that was originally identified through its inhibitory effects on the serine/threonine kinase Raf-1 (C-Raf: IC50 6 nmol)
[7]. Raf was the first mammalian effector of Ras to be characterised [8] and is an essential component of the Raf/MEK/ERK–signalling pathway downstream of the membrane-bound G-protein Ras. Components of the Ras/Raf–signalling pathways are known to play a pivotal role in cell-cycle progression and inhibition of apoptosis in both tumour cells and endothelial cells [9,10] (Fig. 1). In biochemical and cellular assays, sorafenib was found to have potent activity against several serine/ threonine kinases and receptor tyrosine kinases, including C-Raf, B-Raf, vascular endothelial growth factor receptor (VEGFR)-2 and platelet-derived growth factor receptor (PDGFR)-b [11]. The VEGFR and Raf/MEK/ERK signalling pathways have been strongly implicated in tumour angiogenesis and tumour cell proliferation, respectively [12]. In addition, sorafenib has demonstrated a broad-spectrum, antitumour activity in a number of tumour models, including human breast, lung, and colon xenografts [11]. Importantly, sorafenib also showed antitumour activity in a murine renal carcinoma model [13]. These promising preclinical data led to the evaluation of sorafenib in the clinical setting. Most notably, sorafenib was investigated recently in the largest phase 3, randomised trial ever conducted in RCC: the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET).
2. Treatment Approaches in Renal Cancer Global Evaluation Trial 2.1.
Objectives and study design
This phase 3, multicentre, randomised, doubleblind, placebo-controlled trial was conducted to
Fig. 2 – TARGET study design. (RCC = renal cell carcinoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; MSKCC = Memorial Sloan-Kettering Cancer Centre; b.i.d. = twice daily; OS = overall survival; PFS = progression-free survival.)
european urology supplements 6 (2007) 499–504
evaluate the efficacy and safety of sorafenib in patients with advanced RCC (Fig. 2). The primary objective was overall survival (OS). Secondary objectives were progression-free survival (PFS), best overall response rate (RR) using Response Evaluation Criteria In Solid Tumors (RECIST), safety, and tolerability [14]. Patients with RCC were eligible if they had metastatic clear cell histology, failed one prior systemic therapy in the last 8 mo, and had Eastern Cooperative Oncology Group (ECOG) Performance Status 1. To add homogeneity, patients were stratified by Memorial Sloan-Kettering Cancer Center (MSKCC; Motzer) criteria and country. A total of 903 patients were randomised (1:1) to receive either sorafenib (400 mg twice daily [b.i.d.] orally) or placebo in this trial. Response rates were measured by independent investigator assessment. The age range of patients enrolled in TARGET was 19–86 yr; 73% of patients were male. No differences were observed between the groups at baseline in age, gender, performance status, number of metastases, and presence of lung or liver metastases. In addition, pretreatment regimens and prognostic factors (MSKCC) were similar between the two groups. Approximately half of the patients enrolled had low MSKCC scores, with the remainder having intermediate scores. 2.2.
Sorafenib significantly increased PFS
Following a first planned analysis, sorafenib demonstrated a statistically significant increase of median PFS compared with placebo: 5.5 versus 2.8 mo (hazard ratio [HR] = 0.44; 95% confidence interval [95%CI], 0.35–0.55; p < 0.001; Fig. 3) [14]. This PFS benefit was evident across all patient subgroups, independent of age, MSKCC prognostic group, prior cytokine therapy, presence of lung or liver metastases, or time since diagnosis (<1.5 or >1.5 yr). This
Fig. 4 – Change in tumour size from baseline in patients treated with sorafenib and placebo.
striking improvement in PFS led to a modification of the protocol in April 2005 to allow patients receiving placebo to cross over to receive sorafenib. 2.3.
Sorafenib induced clinical benefit in 84% of patients
Following investigator assessment, clinical benefit (defined as a complete response + partial response + stable disease) was achieved in 84% of patients receiving sorafenib versus 55% of patients receiving placebo. Partial responses according to RECIST were 10% (43 of 451) versus 2% (8 of 452) for sorafenib and placebo, respectively, whereas stable disease was achieved in 74% (333 of 451) versus 53% (239 of 452) of patients. Disease progression was observed in only 12% (56 of 451) of sorafenib-treated patients compared with 37% (167 of 452) of patients receiving placebo. Moreover, three times more patients had some degree of tumour shrinkage in the sorafenib group than in the placebo group (76% vs. 25%; respectively; Fig. 4). The disparity between the tumour shrinkage rate and objective RR suggests that RR measured by RECIST may underestimate the clinical benefit induced by sorafenib. 2.4. in OS
Fig. 3 – Sorafenib significantly doubled progression-free survival compared with placebo.
501
Sorafenib showed a trend towards an improvement
In the first planned interim analysis in May 2005, sorafenib showed a trend towards improved OS, with a 39% improvement over placebo (Fig. 5; HR = 0.72; p = 0.02; 95%CI, 0.54–0.94); however, data from this analysis did not meet the prespecified O’Brien–Fleming stopping boundary for statistical significance ( p < 0.0005) [14]. The OS curves for sorafenib and placebo separated early, and remained separated for the duration of the study. Notably, at the time of the interim analysis, median OS for sorafenib-treated patients had not yet been reached, and the median OS for placebo-treated patients was 14.7 mo.
502
european urology supplements 6 (2007) 499–504
Institute, Villejuif, France. Fifteen (83%) of these 18 patients had tumour stabilisation or tumour shrinkage. 2.6.
Fig. 5 – At the time of crossover, a trend towards improved median overall survival was observed in patients treated with sorafenib compared with placebo.
Following the protocol modification allowing patients from the placebo arm to cross over to the sorafenib arm, a total of 216 of the original cohort of 452 patients (48%) crossed over to receive sorafenib. Thus, the results from the second planned interim analysis of OS data (data cut off 30 November 2005) included a large subset of patients in the placebo group who had at least some exposure to sorafenib. At that time there were 367 deaths (171 in the sorafenib arm and 196 in the placebo arm). Analyses of these data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2006 [15]. In the first analysis, the median OS was performed on an intent-to-treat basis, revealing a 19.3-mo OS for sorafenib versus a 15.9-mo OS for placebo (HR = 0.77; 95%CI, 0.63–0.95; p = 0.02). Although this finding did not attain the level of significance specified by the O’Brien–Fleming stopping rule for the interim analysis, these data demonstrate a continued favourable trend in survival benefit despite the crossover of 48% of placebo patients [15]. To examine the crossover effect, a post hoc analysis of OS was performed on these 6-mo postcrossover data. For this analysis, the placebo arm was censored (30 June 2005 cutoff) to exclude the effect of sorafenib crossover on OS; the sorafenib arm was not censored. Median OS was 19.3 mo for sorafenib versus 14.3 mo for placebo (HR = 0.74; 95%CI, 0.58–0.93; p = 0.010). However, this analysis did not meet the prespecified O’Brien–Fleming threshold for statistical significance ( p < 0.0094). Final analysis will be performed after 540 deaths. 2.5.
Crossover experience at the Gustave-Roussy Institute
Of the 216 patients crossing over to sorafenib across all centres, 18 were from the Gustave-Roussy
Sorafenib was well tolerated
Sorafenib was generally well tolerated and was associated with a low incidence of discontinuations, dose interruptions, and dose reductions. The rate of discontinuations due to adverse events was similar between the treatment arms (10% with sorafenib vs. 8% with placebo). Twenty-one percent of sorafenibtreated patients had a dose interruption (mainly related to hand–foot skin reaction [HFSR]) versus 6% with placebo. Thirteen percent of sorafenib-treated patients had dose reductions (mainly due to HFSR and diarrhoea) compared with 3% of patients receiving placebo. Clinical experience suggests that early intervention to manage side-effects may reduce the need for treatment modification. For example, various strategies are available to manage HFSR, which is often reported with targeted therapies such as sorafenib. A pedicure before receiving sorafenib therapy may help to prevent the development of HFSR, whereas use of shock absorbers, wearing of sandals, and application of topical therapies for symptomatic relief may alleviate many of the symptoms of HFSR during treatment [16,17]. Hypertension that may be associated with sorafenib therapy can also be successfully managed in accordance with standard medical practice. Patients with high blood pressure or those at risk of developing hypertension should be monitored during the first 6 wk of sorafenib therapy and thereafter, if required [17]. Sorafenib demonstrated a manageable side-effect profile, with the majority of adverse events being reversible following discontinuation of treatment. In TARGET, the most frequent treatment-emergent adverse events (any grade; sorafenib vs. placebo) were diarrhoea (43% vs. 13%), rash/desquamation (40% vs. 16%), fatigue (37% vs. 28%), HFSR (30% vs. 7%), alopecia (27% vs. 3%), nausea (23% vs. 19%), pruritis (18% vs. 6%), and hypertension (17% vs. 2%). Similar drug-related toxicities have also been reported with other targeted agents, such as sunitinib (Sutent1; Pfizer Inc, New York, NY, USA; a multikinase inhibitor with activity against VEGFR and PDGFR) and bevacizumab (Avastin1; Genentech Inc, South San Francisco, CA, USA; an anti-VEGF antibody). In a recent phase 3 trial of sunitinib versus IFN-a, the most frequently reported treatmentrelated adverse events (any grade) with sunitinib were diarrhoea (53%), fatigue (51%), and nausea (44%) [18]. Fatigue is also a common toxicity of
european urology supplements 6 (2007) 499–504
bevacizumab. In a randomised trial, 33% of patients (13 of 39) treated with high-dose bevacizumab (10 mg/ kg) experienced fatigue compared with 15% of patients (6 of 40) receiving placebo [19]. In contrast, in TARGET, the incidence of fatigue was similar in patients receiving sorafenib and placebo (37% vs. 28%); grade 3–4 fatigue was rarely (5%) reported in sorafenib-treated patients. Thus, sorafenib was well tolerated with a safety profile that compared favourably with those of other targeted agents. 2.7.
Sorafenib and patients’ quality of life
Treatment benefit on health-related quality of life was assessed with the use of the Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index (FKSI) [20]. This system consists of a multipleitem questionnaire; each item is scored on a fivepoint scale on which a high score indicates fewer symptoms and a smaller impact on health-related quality of life. Likelihood methods (random coefficient model) were used to evaluate treatment differences in mean FKSI (15-item) total score over time, and a random coefficient model was used to further investigate individual items of the FKSI. On analysis, no significant changes were observed in mean FKSI total scores between the patients receiving sorafenib or placebo, which indicated that sorafenib had no overall negative impact on health-related quality of life. Notably, sorafenibtreated patients showed improvements in respiratory symptoms (coughing and shortness of breath) and ability to enjoy life compared with placebo. The positive data from TARGET suggest that the improvement in patients’ quality of life following treatment with sorafenib may reduce the burden of their disease and also allow them to continue with their normal daily lives.
3. Future clinical studies with sorafenib in RCC The potential of sorafenib as a first-line treatment for advanced RCC is currently being investigated in comparison with IFN-a 2a in a phase 2 trial of 190 patients with RCC. In this study, the primary end point is PFS at 99 events; the secondary end points include disease control rate, overall best RR, PFS, and pharmacokinetic analysis. Initially, patients will be randomised to receive sorafenib (400 mg b.i.d orally) or IFN-a 2a (9 million international units three times weekly). On progression, sorafenib-treated patients will receive a higher dose of sorafenib (600 mg b.i.d.), and patients treated
503
with IFN-a 2a will receive sorafenib (400 mg b.i.d.). Preliminary safety results of this study were presented at ASCO 2006 [21]. Sorafenib was generally well tolerated with an incidence of serious drugrelated adverse events (any grade) of just 11% in the sorafenib group compared with 13% in the IFN-a 2a group. In addition, more patients withdrew from treatment because of serious adverse events in the IFN group than in the sorafenib group (nine vs. four patients). Since only 87 PFS events of 99 events (primary end point) had been reported at the data cutoff, the data for PFS are not yet available. Furthermore, the Data Monitoring Committee has recently increased the number of PFS events needed to report PFS to 140. The data from preclinical studies and clinical trials showing the favourable safety profile of sorafenib suggest that it is suitable for combination therapy with other chemotherapeutic agents. Clinical trials of sorafenib as combination therapy for the treatment of RCC are currently under way. In addition, studies are planned to evaluate the efficacy of sorafenib in adjuvant (described in the article by Professor Eisen in this supplement) and neoadjuvant settings.
4.
Conclusions
In TARGET, sorafenib was efficacious and improved OS, PFS, and clinical benefit compared with placebo. Sorafenib was also generally well tolerated with a manageable and predictable sideeffect profile, which included a low incidence of grade 3–4 toxicities. Moreover, unlike some chemotherapeutic and immunotherapeutic agents, sorafenib did not cause patients with RCC to experience debilitating side-effects and, importantly, did not increase the incidence of fatigue compared with placebo. Although sorafenib treatment was associated with diarrhoea and HFSR, these conditions are easily managed; early treatment can reduce the requirement for dose interruption or discontinuation. The positive impact of sorafenib on certain RCC symptoms and the lack of an adverse effect on patients’ health-related quality of life is consistent with the positive efficacy data and the low incidence of treatment-limiting toxicities. Overall, the favourable safety profile, positive impact on quality of life, and broad efficacy of sorafenib means that it is expected to play an important role in the future treatment of RCC. In addition, sorafenib has the potential to treat patients with RCC in a range of settings, including neoadjuvant and adjuvant settings. Future clinical
504
european urology supplements 6 (2007) 499–504
trials will help to determine the broad-spectrum use of sorafenib and its place in clinical practice.
Conflicts of interest Dr Escudier has received honoraria from Bayer.
Acknowledgements The author kindly acknowledges the contribution of Susan Thorp (GeoMed) for professional medical writing support and Karen Middleton (GeoMed) for editorial assistance, with funding for professional writing services from Bayer Healthcare Pharmaceuticals. References [1] Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865–75. [2] Janzen NK, Kim HL, Figlin RA, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003;30:843–52. [3] National Cancer Institute, Surveillance Epidemiology and End Results. SEER Cancer Statistics Review 1975–2003. Available at http://www.seer.cancer.gov/csr/1975_2003/. Accessed 5 December 2006. [4] Mickisch GH, Roehrich K, Koessig J, et al. Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma. J Urol 1990;144:755–9. [5] McKillop C. Interview with Professor Per-Anders Abrahamson: angiogenesis and renal cell carcinoma. Eur Urol 2006;50:609–11. [6] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49:633–43. [7] Wilhelm S. Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002;8:2255–7. [8] Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11–22. [9] Alavi A, Hood JD, Frausto R, et al. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301:94–6.
[10] Slater EP, Stubig T, Lau QC, et al. C-Raf controlled pathways in the protection of tumor cells from apoptosis. Int J Cancer 2003;104:425–32. [11] Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109. [12] Gollob JA, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ ERK signal transduction pathway. Semin Oncol 2006;33:392–406. [13] Chang YS, Henderson A, Xue D, et al. BAY 43-9006 (sorafenib) inhibits ectopic and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis. Poster presented at AACR 2005, Anaheim, Orange County, CA, USA 2006. [14] Escudier B, Eisen T, Stadler WM, et al. Sorafenib for advanced clear-cell renal cell carcinoma. N Engl J Med 2007;356:125–34. [15] Eisen T, Bukowski RM, Staehler M, et al. Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): impact of crossover on survival. J Clin Oncol 2006;24(Suppl):223s (abstract no. 4524). [16] Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500. [17] Sorafenib prescribing information. Available at http:// www.nexavar.com. Accessed 20 October 2006. [18] Motzer RJ, Hutson TE, Tomczac P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferonalfa (IFN-a) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006;24(Suppl):2s (abstract no. LBA3). [19] Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34. [20] Cella D, Yount S, Du H, et al. Development and validation of the Functional Assessment of Cancer TherapyKidney Symptom Index (FKSI). J Support Oncol 2006;4: 191–9. [21] Escudier B, Szczylik C, Demkow T, et al. Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment naive patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006;24(Suppl):18s (abstract no. 4501).
available at www.sciencedirect.com journal homepage: www.europeanurology.com
New Perspectives: An Oral Multikinase Inhibitor in Patients with Advanced RCC Bernard Escudier * Institut Gustave-Roussy, Villejuif Cedex, Paris, France
Article info
Abstract
Keywords: Advanced renal cell cancer Clinical benefit Overall survival Phase 3 trial Progression-free survival Sorafenib
Sorafenib (Nexavar1; Bayer Healthcare, West Haven, CT, USA) is an oral multikinase inhibitor that may provide dual action by inhibiting tumour cell proliferation and angiogenesis. Sorafenib was recently evaluated in the largest phase 3, randomised trial ever conducted in renal cell carcinoma (RCC): Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). In TARGET, sorafenib significantly increased progression-free survival versus placebo, which led to a change in the study protocol allowing patients in the placebo arm of the trial to cross over to receive sorafenib. At the time of crossover, sorafenib improved overall survival by 39% compared with placebo (hazard ratio = 0.72; 95% confidence interval 0.54–0.94; p = 0.02, not significant as per O’Brien–Fleming threshold for statistical significance: p = 0.0005). Sorafenib continued to show a trend towards improved overall survival at a subsequent analysis 6 mo post-crossover. Importantly, 84% of sorafenib-treated patients achieved investigator-assessed stable disease or better compared with 55% of placebo recipients. Sorafenib was well tolerated, had a manageable side-effect profile, and offered benefit with no compromise in quality of life. The data from the phase 3 TARGET study provided further evidence that sorafenib may be effective in a wide range of patients with advanced RCC. Clinical trials are planned to assess the potential of sorafenib as combination therapy and in the adjuvant setting. # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. * Institut Gustave-Roussy, 39 Rue Camille Desmoulins, Villejuif Cedex, Paris 94805, France. Tel. +33 1 4211 4211; Fax: +33 1 4211 5411. E-mail address: [email protected].
1.
Introduction
Renal cell carcinoma (RCC) is the most common primary cancer of the kidney and accounts for 80–85% of all malignant kidney cancers [1]. Although nephrectomy may be curative, 50% of patients with localised RCC who have undergone such surgery will
develop advanced metastatic disease [2]. Long-term survival for these patients is extremely poor and the 5-yr survival rate of patients with metastatic kidney cancer is only 9.5% [3]. In addition, many patients fail to respond to standard therapy such as interleukin-2 or interferon-a (IFN-a) [4]. Furthermore, a high proportion of patients with RCC are not suitable
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology.
doi:10.1016/j.eursup.2007.01.020
500
european urology supplements 6 (2007) 499–504
Fig. 1 – Sorafenib is active against both tumour cell and tumour vasculature. (MEK = mitogen extracellular kinase; ERK = extracellular signal-regulated kinase; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; PLC = phospholipase C; PI3K = phosphatidylinositol 3-kinase.)
for such therapies or relapse following cytokine therapy (as described in the article by Professor Patard in this supplement). Since only a limited subset of patients are likely to achieve clinical benefit with current cytokine therapies, new therapeutic approaches are urgently needed to improve outcomes in patients with metastatic RCC. Over the last decade, increased understanding of the molecular pathways involved in oncogenesis has generated therapies that target signalling pathways involved in tumour angiogenesis and tumour cell proliferation [5,6]. A key therapeutic advance in patients with RCC is the multikinase inhibitor, sorafenib (Nexavar1; Bayer Healthcare, West Haven, CT, USA). Sorafenib is an orally active bi-aryl urea that was originally identified through its inhibitory effects on the serine/threonine kinase Raf-1 (C-Raf: IC50 6 nmol)
[7]. Raf was the first mammalian effector of Ras to be characterised [8] and is an essential component of the Raf/MEK/ERK–signalling pathway downstream of the membrane-bound G-protein Ras. Components of the Ras/Raf–signalling pathways are known to play a pivotal role in cell-cycle progression and inhibition of apoptosis in both tumour cells and endothelial cells [9,10] (Fig. 1). In biochemical and cellular assays, sorafenib was found to have potent activity against several serine/ threonine kinases and receptor tyrosine kinases, including C-Raf, B-Raf, vascular endothelial growth factor receptor (VEGFR)-2 and platelet-derived growth factor receptor (PDGFR)-b [11]. The VEGFR and Raf/MEK/ERK signalling pathways have been strongly implicated in tumour angiogenesis and tumour cell proliferation, respectively [12]. In addition, sorafenib has demonstrated a broad-spectrum, antitumour activity in a number of tumour models, including human breast, lung, and colon xenografts [11]. Importantly, sorafenib also showed antitumour activity in a murine renal carcinoma model [13]. These promising preclinical data led to the evaluation of sorafenib in the clinical setting. Most notably, sorafenib was investigated recently in the largest phase 3, randomised trial ever conducted in RCC: the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET).
2. Treatment Approaches in Renal Cancer Global Evaluation Trial 2.1.
Objectives and study design
This phase 3, multicentre, randomised, doubleblind, placebo-controlled trial was conducted to
Fig. 2 – TARGET study design. (RCC = renal cell carcinoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; MSKCC = Memorial Sloan-Kettering Cancer Centre; b.i.d. = twice daily; OS = overall survival; PFS = progression-free survival.)
european urology supplements 6 (2007) 499–504
evaluate the efficacy and safety of sorafenib in patients with advanced RCC (Fig. 2). The primary objective was overall survival (OS). Secondary objectives were progression-free survival (PFS), best overall response rate (RR) using Response Evaluation Criteria In Solid Tumors (RECIST), safety, and tolerability [14]. Patients with RCC were eligible if they had metastatic clear cell histology, failed one prior systemic therapy in the last 8 mo, and had Eastern Cooperative Oncology Group (ECOG) Performance Status 1. To add homogeneity, patients were stratified by Memorial Sloan-Kettering Cancer Center (MSKCC; Motzer) criteria and country. A total of 903 patients were randomised (1:1) to receive either sorafenib (400 mg twice daily [b.i.d.] orally) or placebo in this trial. Response rates were measured by independent investigator assessment. The age range of patients enrolled in TARGET was 19–86 yr; 73% of patients were male. No differences were observed between the groups at baseline in age, gender, performance status, number of metastases, and presence of lung or liver metastases. In addition, pretreatment regimens and prognostic factors (MSKCC) were similar between the two groups. Approximately half of the patients enrolled had low MSKCC scores, with the remainder having intermediate scores. 2.2.
Sorafenib significantly increased PFS
Following a first planned analysis, sorafenib demonstrated a statistically significant increase of median PFS compared with placebo: 5.5 versus 2.8 mo (hazard ratio [HR] = 0.44; 95% confidence interval [95%CI], 0.35–0.55; p < 0.001; Fig. 3) [14]. This PFS benefit was evident across all patient subgroups, independent of age, MSKCC prognostic group, prior cytokine therapy, presence of lung or liver metastases, or time since diagnosis (<1.5 or >1.5 yr). This
Fig. 4 – Change in tumour size from baseline in patients treated with sorafenib and placebo.
striking improvement in PFS led to a modification of the protocol in April 2005 to allow patients receiving placebo to cross over to receive sorafenib. 2.3.
Sorafenib induced clinical benefit in 84% of patients
Following investigator assessment, clinical benefit (defined as a complete response + partial response + stable disease) was achieved in 84% of patients receiving sorafenib versus 55% of patients receiving placebo. Partial responses according to RECIST were 10% (43 of 451) versus 2% (8 of 452) for sorafenib and placebo, respectively, whereas stable disease was achieved in 74% (333 of 451) versus 53% (239 of 452) of patients. Disease progression was observed in only 12% (56 of 451) of sorafenib-treated patients compared with 37% (167 of 452) of patients receiving placebo. Moreover, three times more patients had some degree of tumour shrinkage in the sorafenib group than in the placebo group (76% vs. 25%; respectively; Fig. 4). The disparity between the tumour shrinkage rate and objective RR suggests that RR measured by RECIST may underestimate the clinical benefit induced by sorafenib. 2.4. in OS
Fig. 3 – Sorafenib significantly doubled progression-free survival compared with placebo.
501
Sorafenib showed a trend towards an improvement
In the first planned interim analysis in May 2005, sorafenib showed a trend towards improved OS, with a 39% improvement over placebo (Fig. 5; HR = 0.72; p = 0.02; 95%CI, 0.54–0.94); however, data from this analysis did not meet the prespecified O’Brien–Fleming stopping boundary for statistical significance ( p < 0.0005) [14]. The OS curves for sorafenib and placebo separated early, and remained separated for the duration of the study. Notably, at the time of the interim analysis, median OS for sorafenib-treated patients had not yet been reached, and the median OS for placebo-treated patients was 14.7 mo.
502
european urology supplements 6 (2007) 499–504
Institute, Villejuif, France. Fifteen (83%) of these 18 patients had tumour stabilisation or tumour shrinkage. 2.6.
Fig. 5 – At the time of crossover, a trend towards improved median overall survival was observed in patients treated with sorafenib compared with placebo.
Following the protocol modification allowing patients from the placebo arm to cross over to the sorafenib arm, a total of 216 of the original cohort of 452 patients (48%) crossed over to receive sorafenib. Thus, the results from the second planned interim analysis of OS data (data cut off 30 November 2005) included a large subset of patients in the placebo group who had at least some exposure to sorafenib. At that time there were 367 deaths (171 in the sorafenib arm and 196 in the placebo arm). Analyses of these data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2006 [15]. In the first analysis, the median OS was performed on an intent-to-treat basis, revealing a 19.3-mo OS for sorafenib versus a 15.9-mo OS for placebo (HR = 0.77; 95%CI, 0.63–0.95; p = 0.02). Although this finding did not attain the level of significance specified by the O’Brien–Fleming stopping rule for the interim analysis, these data demonstrate a continued favourable trend in survival benefit despite the crossover of 48% of placebo patients [15]. To examine the crossover effect, a post hoc analysis of OS was performed on these 6-mo postcrossover data. For this analysis, the placebo arm was censored (30 June 2005 cutoff) to exclude the effect of sorafenib crossover on OS; the sorafenib arm was not censored. Median OS was 19.3 mo for sorafenib versus 14.3 mo for placebo (HR = 0.74; 95%CI, 0.58–0.93; p = 0.010). However, this analysis did not meet the prespecified O’Brien–Fleming threshold for statistical significance ( p < 0.0094). Final analysis will be performed after 540 deaths. 2.5.
Crossover experience at the Gustave-Roussy Institute
Of the 216 patients crossing over to sorafenib across all centres, 18 were from the Gustave-Roussy
Sorafenib was well tolerated
Sorafenib was generally well tolerated and was associated with a low incidence of discontinuations, dose interruptions, and dose reductions. The rate of discontinuations due to adverse events was similar between the treatment arms (10% with sorafenib vs. 8% with placebo). Twenty-one percent of sorafenibtreated patients had a dose interruption (mainly related to hand–foot skin reaction [HFSR]) versus 6% with placebo. Thirteen percent of sorafenib-treated patients had dose reductions (mainly due to HFSR and diarrhoea) compared with 3% of patients receiving placebo. Clinical experience suggests that early intervention to manage side-effects may reduce the need for treatment modification. For example, various strategies are available to manage HFSR, which is often reported with targeted therapies such as sorafenib. A pedicure before receiving sorafenib therapy may help to prevent the development of HFSR, whereas use of shock absorbers, wearing of sandals, and application of topical therapies for symptomatic relief may alleviate many of the symptoms of HFSR during treatment [16,17]. Hypertension that may be associated with sorafenib therapy can also be successfully managed in accordance with standard medical practice. Patients with high blood pressure or those at risk of developing hypertension should be monitored during the first 6 wk of sorafenib therapy and thereafter, if required [17]. Sorafenib demonstrated a manageable side-effect profile, with the majority of adverse events being reversible following discontinuation of treatment. In TARGET, the most frequent treatment-emergent adverse events (any grade; sorafenib vs. placebo) were diarrhoea (43% vs. 13%), rash/desquamation (40% vs. 16%), fatigue (37% vs. 28%), HFSR (30% vs. 7%), alopecia (27% vs. 3%), nausea (23% vs. 19%), pruritis (18% vs. 6%), and hypertension (17% vs. 2%). Similar drug-related toxicities have also been reported with other targeted agents, such as sunitinib (Sutent1; Pfizer Inc, New York, NY, USA; a multikinase inhibitor with activity against VEGFR and PDGFR) and bevacizumab (Avastin1; Genentech Inc, South San Francisco, CA, USA; an anti-VEGF antibody). In a recent phase 3 trial of sunitinib versus IFN-a, the most frequently reported treatmentrelated adverse events (any grade) with sunitinib were diarrhoea (53%), fatigue (51%), and nausea (44%) [18]. Fatigue is also a common toxicity of
european urology supplements 6 (2007) 499–504
bevacizumab. In a randomised trial, 33% of patients (13 of 39) treated with high-dose bevacizumab (10 mg/ kg) experienced fatigue compared with 15% of patients (6 of 40) receiving placebo [19]. In contrast, in TARGET, the incidence of fatigue was similar in patients receiving sorafenib and placebo (37% vs. 28%); grade 3–4 fatigue was rarely (5%) reported in sorafenib-treated patients. Thus, sorafenib was well tolerated with a safety profile that compared favourably with those of other targeted agents. 2.7.
Sorafenib and patients’ quality of life
Treatment benefit on health-related quality of life was assessed with the use of the Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index (FKSI) [20]. This system consists of a multipleitem questionnaire; each item is scored on a fivepoint scale on which a high score indicates fewer symptoms and a smaller impact on health-related quality of life. Likelihood methods (random coefficient model) were used to evaluate treatment differences in mean FKSI (15-item) total score over time, and a random coefficient model was used to further investigate individual items of the FKSI. On analysis, no significant changes were observed in mean FKSI total scores between the patients receiving sorafenib or placebo, which indicated that sorafenib had no overall negative impact on health-related quality of life. Notably, sorafenibtreated patients showed improvements in respiratory symptoms (coughing and shortness of breath) and ability to enjoy life compared with placebo. The positive data from TARGET suggest that the improvement in patients’ quality of life following treatment with sorafenib may reduce the burden of their disease and also allow them to continue with their normal daily lives.
3. Future clinical studies with sorafenib in RCC The potential of sorafenib as a first-line treatment for advanced RCC is currently being investigated in comparison with IFN-a 2a in a phase 2 trial of 190 patients with RCC. In this study, the primary end point is PFS at 99 events; the secondary end points include disease control rate, overall best RR, PFS, and pharmacokinetic analysis. Initially, patients will be randomised to receive sorafenib (400 mg b.i.d orally) or IFN-a 2a (9 million international units three times weekly). On progression, sorafenib-treated patients will receive a higher dose of sorafenib (600 mg b.i.d.), and patients treated
503
with IFN-a 2a will receive sorafenib (400 mg b.i.d.). Preliminary safety results of this study were presented at ASCO 2006 [21]. Sorafenib was generally well tolerated with an incidence of serious drugrelated adverse events (any grade) of just 11% in the sorafenib group compared with 13% in the IFN-a 2a group. In addition, more patients withdrew from treatment because of serious adverse events in the IFN group than in the sorafenib group (nine vs. four patients). Since only 87 PFS events of 99 events (primary end point) had been reported at the data cutoff, the data for PFS are not yet available. Furthermore, the Data Monitoring Committee has recently increased the number of PFS events needed to report PFS to 140. The data from preclinical studies and clinical trials showing the favourable safety profile of sorafenib suggest that it is suitable for combination therapy with other chemotherapeutic agents. Clinical trials of sorafenib as combination therapy for the treatment of RCC are currently under way. In addition, studies are planned to evaluate the efficacy of sorafenib in adjuvant (described in the article by Professor Eisen in this supplement) and neoadjuvant settings.
4.
Conclusions
In TARGET, sorafenib was efficacious and improved OS, PFS, and clinical benefit compared with placebo. Sorafenib was also generally well tolerated with a manageable and predictable sideeffect profile, which included a low incidence of grade 3–4 toxicities. Moreover, unlike some chemotherapeutic and immunotherapeutic agents, sorafenib did not cause patients with RCC to experience debilitating side-effects and, importantly, did not increase the incidence of fatigue compared with placebo. Although sorafenib treatment was associated with diarrhoea and HFSR, these conditions are easily managed; early treatment can reduce the requirement for dose interruption or discontinuation. The positive impact of sorafenib on certain RCC symptoms and the lack of an adverse effect on patients’ health-related quality of life is consistent with the positive efficacy data and the low incidence of treatment-limiting toxicities. Overall, the favourable safety profile, positive impact on quality of life, and broad efficacy of sorafenib means that it is expected to play an important role in the future treatment of RCC. In addition, sorafenib has the potential to treat patients with RCC in a range of settings, including neoadjuvant and adjuvant settings. Future clinical
504
european urology supplements 6 (2007) 499–504
trials will help to determine the broad-spectrum use of sorafenib and its place in clinical practice.
Conflicts of interest Dr Escudier has received honoraria from Bayer.
Acknowledgements The author kindly acknowledges the contribution of Susan Thorp (GeoMed) for professional medical writing support and Karen Middleton (GeoMed) for editorial assistance, with funding for professional writing services from Bayer Healthcare Pharmaceuticals. References [1] Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865–75. [2] Janzen NK, Kim HL, Figlin RA, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003;30:843–52. [3] National Cancer Institute, Surveillance Epidemiology and End Results. SEER Cancer Statistics Review 1975–2003. Available at http://www.seer.cancer.gov/csr/1975_2003/. Accessed 5 December 2006. [4] Mickisch GH, Roehrich K, Koessig J, et al. Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma. J Urol 1990;144:755–9. [5] McKillop C. Interview with Professor Per-Anders Abrahamson: angiogenesis and renal cell carcinoma. Eur Urol 2006;50:609–11. [6] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49:633–43. [7] Wilhelm S. Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002;8:2255–7. [8] Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11–22. [9] Alavi A, Hood JD, Frausto R, et al. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301:94–6.
[10] Slater EP, Stubig T, Lau QC, et al. C-Raf controlled pathways in the protection of tumor cells from apoptosis. Int J Cancer 2003;104:425–32. [11] Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109. [12] Gollob JA, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ ERK signal transduction pathway. Semin Oncol 2006;33:392–406. [13] Chang YS, Henderson A, Xue D, et al. BAY 43-9006 (sorafenib) inhibits ectopic and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis. Poster presented at AACR 2005, Anaheim, Orange County, CA, USA 2006. [14] Escudier B, Eisen T, Stadler WM, et al. Sorafenib for advanced clear-cell renal cell carcinoma. N Engl J Med 2007;356:125–34. [15] Eisen T, Bukowski RM, Staehler M, et al. Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): impact of crossover on survival. J Clin Oncol 2006;24(Suppl):223s (abstract no. 4524). [16] Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500. [17] Sorafenib prescribing information. Available at http:// www.nexavar.com. Accessed 20 October 2006. [18] Motzer RJ, Hutson TE, Tomczac P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferonalfa (IFN-a) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006;24(Suppl):2s (abstract no. LBA3). [19] Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34. [20] Cella D, Yount S, Du H, et al. Development and validation of the Functional Assessment of Cancer TherapyKidney Symptom Index (FKSI). J Support Oncol 2006;4: 191–9. [21] Escudier B, Szczylik C, Demkow T, et al. Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment naive patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006;24(Suppl):18s (abstract no. 4501).