Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis

Transcription

1 available at journal homepage: Kidney Cancer Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis Christian Eichelberg a, *,1, Roman Heuer a,1, Felix K. Chun a, Kristin Hinrichs a, Mario Zacharias a, Hartwig Huland a,b, Hans Heinzer a,b a Department of Urology, University Medical Centre Hamburg-Eppendorf, Germany b Martini-Clinic Prostate Cancer Centre, University Medical Centre Hamburg-Eppendorf, Germany Article info Article history: Accepted July 17, 2008 Published online ahead of print on August 8, 2008 Keywords: Therapy sequence Tyrosine kinase inhibitor Sorafenib Sunitinib Renal carcinoma Second line Abstract Background: To date, few data are available about the sequential use of the tyrosine kinase inhibitors (TKI) sorafenib and sunitinib in metastatic renal cell carcinoma (mrcc). Objective: To investigate the effectiveness of the use of sunitinib after progression under sorafenib in mrcc. Design, setting, and participants: A retrospective analysis of 30 patients with progressive mrcc, treated with sorafenib between May 2005 and February When radiologic progression was diagnosed, treatment was switched to sunitinib and continued until a further tumour progression occurred. Measurements: Radiologic evaluation of the treatment results was performed every 3 mo according to the criteria for Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects and therapeutic abnormalities (eg, dose reduction) were documented during regular visits. Results and limitations: Of the patients, 50% benefited from the secondary use of sunitinib. In detail, a radiologically confirmed new disease stabilisation or partial response was observed in seven and eight patients, respectively. Median progression-free survival was 8.7 mo and 10.3 mo under sorafenib and sunitinib, respectively. Overall, the median time from the initialisation of the first TKI until progression under therapy with the second TKI was 17.3 mo. To our knowledge, this is the second largest study reporting results of sequential therapy from sorafenib followed by sunitinib. However, the number of patients is still not extensive enough to settle this important question conclusively. Conclusions: This study supports the hypothesis that sequential TKI therapy with the sorafenib followed by sunitinib has clinical validity in some patients with advanced renal cell carcinoma when progressive disease occurs under the initial TKI therapy. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, University Medical Centre Hamburg- Eppendorf, Martinistr. 52, Hamburg, Germany. Tel. +49 (0) ; Fax: +49 (0) address: c.eichelberg@uke.uni-hamburg.de (C. Eichelberg). 1 Both authors contributed equally to the manuscript /$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 Introduction With the introduction of tyrosine kinase inhibitors (TKI), standards of treatment for metastatic renal cell carcinoma (mrcc) have been dramatically altered. In large, phase 3 trials, sunitinib (Sutent) [1] and sorafenib (Nexavar) [2] have proven their effectiveness in a first-line and a second-line setting, respectively. Consequently, they have become therapy of choice for patients with good or moderate risk (Motzer risk grouping [3]) who either are therapy-naive or have cytokine refractory renal carcinoma [4]. Few data exist about the value of a second TKI treatment in sequence in case of a progression during therapy with the first TKI. We are aware of only two abstracts, presented to the American Society for Clinical Oncology (ASCO) [5,6], and one very recent publication [7] that addressed this important topic. Since both drugs encounter very similar targets and pathways [8 10], one might suspect a kind of cross-resistance, in case of progression under TKI therapy. Further clinical importance of this topic arises from the major drawbacks of TKI therapy, which could be spared if sequential use of TKIs were to be demonstrably ineffective: Despite being orally available drugs, both agents inherit substantial sideeffects [1,2], and therapy costs are relatively high. We therefore investigated the therapeutic outcome of patients with mrcc, who we have treated in sequence with sunitinib after progression under sorafenib therapy. 2. Methods 2.1. Patient selection and treatment modalities We performed a retrospective database and chart search and identified 30 patients with progressive mrcc, which we have treated in sequence with sorafenib followed by sunitinib between May 2005 and February 2008 at our institution. Sorafenib was administered to 21 of the 30 patients as participants of three clinical trials (3 patients, after crossover [11]; 16 patients [12]; and 2 patients, arm 2, after crossover [13]). However, the data reported here originate from the authors own patient charts and database. Daily dosage of sorafenib was 400 mg bid and was reduced to 400 mg qd or 400 mg qod, depending on severity and patients tolerance of side-effects and toxicities. During treatment, patients were followed on an outpatient basis every 4 6 wk in our policlinic. Adverse effects (AE) and therapeutic abnormalities (eg, dose reduction) were additionally self-reported in each patient s treatment diary between the visits. Radiologic evaluation of the treatment results was performed approximately every 3 mo by computed tomography (CT), magnetic resonance imaging (MRI), or, in case of bone metastasis, conventional x-ray or bone scan and evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [14]. Once a radiologic progression was diagnosed, treatment was switched to sunitinib with a dosage of 50 mg per day for 4 wk, followed by a 2-wk off-treatment period. When necessary, dosage was reduced to 37.5 mg or 25 mg per day on the same schedule. Treatment with sunitinib was continued until a further tumour progression occurred (see Table 1) Statistics The patient cohort was characterised by descriptive statistics and frequency counts. The progression-free time for each single agent as well as the overall treatment duration, measured from the initialisation of sorafenib therapy, consecutive progression under sorafenib, and switch to sunitinib therapy until second progression occurred, were calculated using Kaplan-Meier analysis. Patients were censored in the Kaplan-Meier analysis for the sunitinib treatment and the overall treatment duration if progression under sunitinib had not yet occurred. Descriptive statistics, frequencies as well as Kaplan-Meier and Cox regression analysis were performed with Statistical Package for the Social Sciences (SPSS) v.12.0 (SPSS Inc, Chicago, IL, USA) Patient characteristics and disease status prior to therapy The median patient age was 60.4 yr (range: 21 77); male female ratio was 4:1. All patients had undergone a prior Table 1 Results of sequential tyrosene kinase inhibitor (TKI) therapy TKI sequence 1) Sorafenib 2) Sunitinib Best radiologic result SD or PR 83.3% (25/30) 50% (15/30) Median progression-free survival (months; range) 8.7 ( ) 10.3 ( ) a Median treatment duration (months; range) 4.4 ( ) Percentage of patients who tolerated standard dosage 53.3 (800 mg) 93.3 (50 mg) Toxicities grade 1 or 2 (%) Toxicities grade 3 (%) PR, partial response; SD, stable disease. a 11 patients censored, having not yet experienced progression.

3 1375 tumour nephrectomy; histologic classification had revealed a clear-cell subtype in 87% (26/30). Each patient had a papillary or an anaplastic or a ductus Bellini or an unknown histologic subtype diagnosed in the primary tumour. Of the identified 30 patients, 20 (67%) had been previously treated with various cytokine-based therapies. In 10 patients, sorafenib was initialised as first-line therapy due to contraindications to interleukin-2 or interferon-a treatment (eg, brain metastases). 3. Results 3.1. Adverse effects and treatment response to initial sorafenib therapy According to National Cancer Institute s Common Terminology Criteria for Adverse Events (CTCAE) [15], no grade 4 or 5 AEs were observed. However, 96.7% of patients at least transiently demonstrated typical TKI-therapy-associated grade 1 or 2 toxicities (eg, diarrhoea, hand foot syndrome, hair loss, and mucositis). In one patient, a grade 3 hand foot syndrome occurred. For the larger part of the individual treatment durations, 53.3% of the patients tolerated daily standard dosage of 800 mg sorafenib. The median treatment duration was 8.7 mo until progression occurred. The best observed radiologic response (BRR) during sorafenib therapy was partial response (PR) in 6 patients (20%), stable disease (SD) in 19 patients (63.3%), and progressive disease (PD) in 5 patients (16.7%) patients. After progression, treatment of all 30 patients was switched to sunitinib. Table 2 Best radiologic results and best clinical response for three patients without radiologic evaluation under sunitinib (two with rapidly progressive disease and one who refuses further radiologic evaluation) Sunitinib Total Progress SD/PR Sorafenib Progress 1 (+1) 3 4 (+1) SD/PR 11 (+1) 12 (+1) 23 (+2) Total 12 (+2) 15 (+1) 30 PR, partial response; SD, stable disease. common were mucositis or stomatitis, hair loss, dysphagia, dysgeusia, hypothyroidism, and fatigue. Again, no grade 4 or 5 AEs were observed, but one case of a grade 3 leucopenia and one grade 3 thrombocytopenia were observed. A total of 28 patients tolerated the standard dosage of 50 mg (4 wk on, 2 wk off) for the larger part of the treatment duration. The median treatment duration with sunitinib was 4.4 mo. At the time of analysis, 11 patients were free of progression under this therapy and consequently still received sunitinib. Accordingly, these patients are censored in the Kaplan-Meier survival analyses, resulting in a median progression-free survival (MPFS) of 10.3 mo (see Table 1). BRR during sunitinib therapy was PR in 8 patients (26.7%), SD in 7 patients (23.3%), and PD in 12 patients (40%). Two patients did not undergo radiologic evaluation due to rapidly progressive disease; one patient refused further evaluation but remains clinically stable and works in his own company Adverse effects and treatment response to second tyrosine kinase inhibitor therapy with sunitinib As for sunitinib, 80% of patients transiently demonstrated typical grade 1 or 2 toxicities. Among the most 3.3. Combined results of sequential tyrosine kinase inhibitor therapy Overall, the median time from the initialisation of sorafenib therapy to the second tumour progression, Fig. 1 Kaplan-Meier function: Total treatment duration (sorafenib plus sunitinib) until second progression; all patients (n = 30).

4 1376 Fig. 2 Kaplan-Meier function: Total treatment duration (sorafenib plus sunitinib) until second progression; separate lines for sunitinib responders (orange, n = 15) versus nonresponders (blue, n = 14). Fig. 3 Treatment diagram and patient numbers (SD = stable disease; PR = partial response; * clinically SD, no radiological evaluation). equalling the end of the sunitinib therapy, was 17.3 mo (range: mo), with 11 patients still treated with sunitinib. Table 2 shows the cross-tabulation of the best radiologic or clinical (for the three patients not evaluated by CT or magnetic resonance tomography [MRT]) outcome of sorafenib and sunitinib therapy. Fig. 1 shows Kaplan-Meier function of the total treatment duration of sorafenib and sunitinib combined until second progression occurred. The median time to second progression for the five patients, initially progressive under sorafenib therapy, was not significantly shorter than for the sorafenib responders (SD or PR) (15.83 mo vs mo; p =0.164; curves not shown) (Figs. 2 and 3). 4. Discussion The prognosis for advanced renal cell carcinoma (RCC) is generally poor: The 5-yr survival rate is <10% [16]. Tumours depend on angiogenesis to provide the substrates needed for growth and specific targets for therapeutic intervention have been identified. This has led to molecularly targeted therapies for treatment of patients with advanced RCC not eligible for surgery or other standard therapy as immunotherapy. The dominant growth factor controlling tumour angiogenesis is vascular endothelial growth factor (VEGF) [17 19], and inhibiting its receptor (VEGFR) is one therapeutic approach for mrcc. Both sunitinib and sorafenib are small-molecule TKIs, which block the intracellular domain of the VEGF receptor. Sunitinib was evaluated in a phase 3 trial of 750 patients without prior systemic treatment and compared to interferon-a. The sunitinib group showed a prolonged MPFS (11 mo vs 5 mo) [1,20]. Sorafenib was evaluated against placebo in a phase 3 trial of 903 patients who failed prior therapy. Therapy with sorafenib also showed a prolonged progression-free survival (5.5 mo vs 2.8 mo) [2]. Sorafenib and sunitinib affect similar but not identical targets: Sorafenib was initially identified as a Raf kinase inhibitor [8] and also inhibits VEGFR 1, 2, and 3; platelet-derived growth factor receptor beta (PDGFR); FMS-like tyrosine kinase 3 (Flt-3); c-kit

5 1377 protein (c-kit); and RET receptor tyrosine kinases [8,9]. Sunitinib exhibits direct activity against signalling through PDGFR, c-kit, Flt-3, and the VEGFRs [10]. Recently presented meeting abstracts suggest that the similar molecular mechanisms of sunitinib and sorafenib are probably not cross-resistant. Sablin et al showed a benefit of sequential therapy in their retrospective analysis of 90 patients [6]. Of the investigated patients, 68 received the same sequence that we report here (initial treatment with sorafenib followed by sunitinib). MPFS was 26 wk under sorafenib and 25 wk under sunitinib. PR was noted in 16% (SD in 66%) of patients under sorafenib and still is 15% (SD in 51%) under sequential sunitinib therapy. For the other 22 patients receiving sunitinib first and then sorafenib, MPFS was 22 wk versus 17 wk, and PR was seen in 23% (SD in 54%) under sunitinib and 9% (SD in 55%) under sorafenib [6]. Dham et al also showed promising data suggesting that a sequential therapy of TKIs might be of benefit for patients [5]. They evaluated 23 patients receiving sorafenib followed by sunitinib and found a MPFS of 32 wk after starting sunitinib. In this group, overall median duration of disease control was 42 wk, compared to 30.5 wk in the 13-patient group receiving sunitinib followed by sorafenib. Dham et al [5] and Sablin et al [6] reported a trend towards longer duration of response in patients receiving sorafenib followed by sunitinib, although data were very limited. To summarise, although molecular mechanisms of both TKIs are very similar, both abstracts reported a clinical benefit of sequential therapy which is comparable to our findings, with a MPFS of approximately 19 wk (4.4 mo) under sunitinib as second TKI treatment. In a very recent publication, Tamaskar et al evaluated the second line application of either sorafenib or sunitinib in patients who received prior antiangiogenic agents, such as thalidomide, lenalidomide, bevacizumab, volociximab, AG13736, sorafenib, or sunitinib [7]. Of 16 patients treated with sunitinib after failure of other antiangiogenic therapy, 9 showed PR. As for the 14 patients receiving sorafenib after other antiangiogenic therapy, 1 had a partial response. For the entire cohort, MPFS was 10.4 mo. The tumour shrinkage with sunitinib was significantly greater than that observed with sorafenib ( p = 0.02). Interestingly, the best response to a prior antiangiogenic agent did not predict the response to subsequent sunitinib or sorafenib [7]. This data also seem to underline the benefit of sequential therapy and are close to our findings, with 50% of patients (15/30) having SD or PR under sunitinib treatment after failure of sorafenib. The types and frequencies of the observed AEs in our cohort of patients are comparable to those reported in a systematic review of by Bhojani et al [21]. Dermal, gastrointestinal, and haematopoietic/ laboratory affections are particularly frequently observed. However, with an occurrence of maximum 13 16% of grade 3 AEs in the literature, the sideeffect profile of both drugs is significant but tolerable. The study we performed has several limitations. We performed a retrospective analysis of a small number of patients who were treated at a single institution. The majority of the patients analysed received an immunotherapy prior to treatment with antiangiogenic therapy. Despite the mentioned similar, but not identical, targets that both compounds inhibit in the signalling pathways, we can only speculate about further explanations for the absence of a cross-resistance. A described substantial variety of the binding specificity among drugs targeting the same kinase [22] could be a further rationale for the observed positive effect of a second TKI in some tumours. To our knowledge, this is the second largest study reporting results of sequential therapy from sorafenib followed by sunitinib which supports the hypothesis that sequential therapy is applicable for patients under prior antiangiogenic therapy. Further prospective randomised trials are required to define the optimal sequence and treatment when PD under one of the available TKIs appears. Molecular markers for predicting the resistance to either treatment should be identified to allow individual and cost-effective treatment and to prevent nonresponders from undergoing treatment at the risk of developing side-effects from treatment. 5. Conclusions Our retrospective analysis supports the hypothesis that sequential therapy of sorafenib followed by sunitinib has clinical activity in some patients with advanced renal cell carcinoma who suffered PD under sorafenib. Further, under second TKI therapy, toxicities were tolerable with a trend towards a slightly lowered prevalence. Nevertheless, additional large randomised trials are needed to settle this important question conclusively and especially to explore the question of the optimal drug sequence. Author contributions: Christian Eichelberg had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

6 1378 Study concept and design: Eichelberg, Heuer, Heinzer. Acquisition of data: Eichelberg, Heuer, Heinzer, Hinrichs. Analysis and interpretation of data: Eichelberg, Heuer, Heinzer, Chun. Drafting of the manuscript: Eichelberg, Heuer, Heinzer. Critical revision of the manuscript for important intellectual content: Heinzer, Zacharias, Huland, Chun. Statistical analysis: Eichelberg, Chun. Obtaining funding: None. Administrative, technical, or material support: Huland. Supervision: Heinzer, Huland. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr. Eichelberg has been a subinvestigator for clinical trials initiated by Bayer, Pfizer, Roche, Wilex, Novartis and an invited speaker for Bayer and Pfizer. Dr. Heuer has been a subinvestigator for clinical trials initiated by Bayer, Pfizer, Roche, Wilex, and Novartis. Dr. Chun has been a subinvestigator for a clinical trial initiated by Novartis. Dr. Huland has been primary investigator for a clinical trial initiated by Sanofi-Aventis and an investigator for a clinical trial initiated by Novartis. Dr. Heinzer has been a subinvestigator for clinical trials initiated by Bayer, Pfizer, Roche, Wilex, and Novartis and an invited speaker for Bayer, Pfizer, Roche, and Wilex. Funding/Support and role of the sponsor: None. Acknowledgment statement: The authors acknowledge our study nurses, Barbara Kherad and Christine Heinzer, for their excellent and dedicated technical and administrative support. References [1] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356: [2] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: [3] Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Onco 1999;17: [4] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51: [5] Dham A, Dudek AZ. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. J Clin Oncol 2007;25:5106. [6] Sablin MP, Bouaita L, Balleyguier C, et al. Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients. J Clin Oncol 2007;25:5038. [7] Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol 2008;179:81 6. [8] Wilhelm SM, Carter C, Tang L, et al. BAY 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: [9] Carlomagno F, Anaganti S, Guida T, et al. BAY inhibition of oncogenic RET mutants. J Natl Cancer Ins 2006;98: [10] Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9: [11] Study of BAY in patients with unresectable and/or metastatic renal cell cancer [clinical trial, identifier NCT ]. Available at: ClinicalTrials.gov. [12] An open-label, non-comparative, phase III study of the Raf-kinase inhibitor BAY as a subsequent to firstline therapy in patients with advanced renal cell carcinoma [clinical trial, identifier NCT ]. Available at: ClinicalTrials.gov. [13] BAY (sorafenib) versus interferon Alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma [clinical trial, identifier NCT ]. Available at: ClinicalTrials.gov. [14] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92: [15] National Cancer Institute. Cancer Therapy Evaluation Program: CTC v2.0 and common terminology criteria for adverse events v 3.0 (CTCAE). Available at: ctep.cancer.gov/reporting/ctc.html. [16] Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335: [17] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9: [18] Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23: [19] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49: [20] Motzer RJ, Figlin RA, Hutson TE, et al. sunitinib versus interferon-alfa (IFN-{alpha}) as first-line treatment of metastatic renal cell carcinoma (mrcc): Updated results and analysis of prognostic factors. J Clin Oncol 2007; 25:5024. [21] Bhojani N, Jeldres C, Patard J-J, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur Urol 2008;53: [22] Vogelzang NJ, Sternberg CN. Signal-transduction inhibitors in renal cell carcinoma. BJU Int 2007;99: