256 “COMPASSIONATE USE”-PROGRAM (CUP) “TEMSIROLIMUS” IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA IN GERMANY

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A patient-focused approach: optimizing sorafenib treatment outcomes in renal cell carcinoma (RCC) Mulders P.F.A.1, Bellmunt J.2, Eisen T.3, Porta C.4, Szczylik C.5 Radboud University Nijmegen Medical Centre, Dept. of Urology, Nijmegen, The Netherlands, Autonomous University of Barcelona, Medical Oncology Service, Barcelona, Spain, Cambridge Research Institute, University of Cambridge, Dept. of Oncology, Cambridge, United Kingdom, 4Istituto Di Ricovero E Cura A Carattere Scientifico, San Matteo University Hospital, Medical Oncology, Pavia, Italy, 5Wojskowski Instytut Medyczny, Dept. of Oncology, Warsaw, Poland 1

2 3

Introduction & Objectives: Sorafenib is one of 5 targeted agents that has shown efficacy in phase III trials for advanced RCC. As no one agent is likely to benefit all patients, selecting the most appropriate therapy for individual patients is challenging, particularly since patients in routine clinical practise have heterogeneous characteristics not always represented in phase III trials. We have developed a patient-focused approach to treatment selection that considers disease (MSKCC risk category, tumor histology, number/sites of metastases), patient (age, performance status [PS], comorbidities) and treatment-related factors (Bellmunt J, et al. ESMO, 2008, 612P). Using this approach we analyzed the most recent data available to identify subgroups of patients who may benefit most from treatment with sorafenib. Material & Methods: A panel of experts reviewed the latest available safety and efficacy data for sorafenib (phase II and III clinical trials, expanded access programs [EAPs], sub-analyses and single-center studies). A consensus on the strength of recommendation for the use of sorafenib in each ‘patient population’ was recorded. Results: There are strong data and clinical experience to support the use of sorafenib for a range of patient subgroups, including: elderly and non-elderly patients and patients with renal insufficiency or cirrhosis, with lung, liver, bone or lymph metastases in up to 3 different organs, with good and intermediate MSKCC scores, with controlled hypertension or haematological comorbidities, or with a PS of 0–2. For example, in a subgroup analysis of phase III data median progression-free survival (PFS) was similar for patients aged ≥70 and <70 (23.9 vs. 26.3 weeks, respectively). Furthermore, while phase III data supports the use of sorafenib in patients unsuitable for/or refractory to cytokine therapy, there is also evidence to suggest that sorafenib is beneficial to patients who failed previous targeted therapies. Additionally, data from EAPs shows that patients with brain metastases may benefit from sorafenib (e.g. EU-EAP, median PFS in patients with brain metastases 7.4 months vs. 6.9 months for the overall population).



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A subanalysis of patients with and without prior nephrectomy in a large open-label, non-comparative phase 3 European Advanced Renal Cell Carcinoma (RCC) Sorafenib Study (EU-ARCCS) Staehler M.1, Procopio G.2, Keilholz U.3, Negrier S.4, Szczylik C.5, Beck J.6, Strauss U.P.7, Burock K.8, Mersmann S.7, Escudier B.9 1 Grosshadern Clinics, University of Munich, Dept. of Urology, Munich, Germany, 2Istituto Nazionale Dei Tumori, Divisione Di Oncologia Medica B, Milan, Italy, 3Charité Universitätsmedizin Berlin, Tumorzentrum Benjamin Franklin, Dept. of Oncology, Berlin, Germany, 4Centre Leon Berard, Service De Cancérologie Médicale, Lyon, France, 5Wojskowy Instytut Medyczny, Klinika Onkologii, Warsaw, Poland, 6Johannes-Gutenberg-Universität Iii. Medizinische Klinik, Iii. Med. Klinik, Mainz, Germany, 7Bayer Schering Pharma, Dept. of Clinical Development, Leverkusen, Germany, 8Bayer Schering Pharma, Dept. of Statistics, Wuppertal, Germany, 9Institut Gustave Roussy, Unité Immunothérapie, Villejuif, France

Introduction & Objectives: The phase 3 TARGET trial demonstrated that sorafenib, a multikinase inhibitor, doubled progression-free survival (PFS) and improved overall survival vs. placebo in patients with advanced RCC. The EU-ARCCS study, a single-arm, open-label, phase 3b study of sorafenib was conducted to collect safety and limited efficacy data from a large and broad study population reflecting clinical practice. The role of prior nephrectomy in the treatment paradigm for patients receiving targeted therapies such as sorafenib has not yet been determined; This subanalysis evaluated the safety and efficacy of sorafenib in patients with and without prior nephrectomy. Material & Methods: Adult patients with advanced RCC who were eligible for EU-ARCCS (≥1 prior systemic therapy failed or unsuitable for cytokine therapy, ECOG PS 0-2) received sorafenib 400 mg bid until disease progression, intolerable toxicity, or withdrawal of consent. Endpoints included PFS, clinical benefit rate (patients who achieved a complete response, partial response, or stable disease by radiologic or clinical assessment for ≥8 wks), and safety. Endpoints were compared for patients with and without prior nephrectomy and the entire EU-ARCCS study population. Results: Baseline patient characteristics were similar across all patient populations. Efficacy and safety results are summarized in the table. Prior nephrectomy (n=1018) No prior nephrectomy(n=130) Male, % 75 Median age, years (range) 62.0 (18-84) ECOG status, % 0/1/2 41/45/13 Clear cell only histology, % 76 Median PFS, months (95% CI) 7.0 (6.3-7.8) PFS rate, % at 6 months (95% CI) 55.9 (52.6-59.1) PFS rate, % at 12 months (95% CI) 31.0 (27.8-34.2) Evaluable for benefit response n=939 Clinical benefit rate, % (95% CI) 84.5(82.0-86.7) Evaluable for safety (n=862) Drug-related adverse events Grades 3/4* All categories 43.6 Hand-foot skin reaction 12.9 Diarrhea 5.6 Rash/desquamation 5.1 Mucositis, oral 2.4 Anorexia 2.8 * Selected by most common adverse events by prior nephrectomy status.

All patients(N=1148) 72 61.0 (18-84) 30/42/27 72 5.3 (4.0-7.1) 42.2 (32.8-51.3) 19.2 (12.0-27.8) n=105 79.1(70.0-86.4) (n=116)

75 62.0 (18-84) 40/45/15 76 6.9 (6.2-7.5) 54.4 (51.3-57.4) 29.7 (26.8-32.7) n=1044 83.9 (81.5-86.1) (n=978)

43.1 10.3 6.9 5.2 2.6 3.4

43.6 12.6 5.7 5.1 2.5 2.9

Conclusions: This approach demonstrates the suitability of sorafenib for a broad range of patients with RCC, including patient types that are not typically represented in phase III studies.

Conclusions: As previously demonstrated, EU-ARCCS confirmed the safety findings of the TARGET study in a clinically relevant population. Patients with prior nephrectomy had a more favorable response and longer PFS than patients without prior nephrectomy. Sorafenib had a generally acceptable toxicity profile regardless of prior nephrectomy. A prospective, randomized, placebo-controlled trial with prior nephrectomy status as a stratification factor is needed to validate these results.





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Menstruations were altered by Sorafenib in female patients with advanced renal cell carcinoma: The possible mechanism

“Compassionate Use”- Program (CUP) “Temsirolimus” in patients with advanced renal cell carcinoma in Germany

Zhang H.L., Ye D.W., Shi G.H., Yao X.D., Zhang S.L., Dai B., Shen Y.J., Zhu Y., Yang B.S.

Pelz H.F.1, Baierl T.2, Wiesmann K.3, Kosch M.4

Fudan University Cancer Hospital, Dept. of Urology, Shanghai, China Introduction & Objectives: Changes in the menstruations of female patients were noticed during the treatment of advanced renal cell carcinoma with Sorafenib. In this study, our purpose was to investigate the alterations in hormones associated with menstruation, such as estrogen (E2), Luteinizing hormone (LH), and follicle stimulating hormone (FSH) and to discuss the possible mechanism of this special side effect of Sorafenib. Material & Methods: From March 2006 to May 2008, Totally 73 patients with advanced renal cell carcinoma were treated with Sorafenib. In which, 9 were female and less than 45 years old with regular menstruations. The dosage of Sorafenib in these patients was 400mg twice daily. Levels of serum E2, LH, and FSH were tested before and 4 weeks, 8 weeks, and 16 weeks after administration of Sorafenib. At the same time, the period and amount of menstruations before and after treatment were recorded in detail. Paired-Samples T Test was used in statistics. Results: After 16 weeks treatment, four patients showed complete halt in their menses, another four patients have their period of menses prolonged and amount of menses increased, and just one patient had no change in her menstruation. The level of E2 significantly decreased after treatment (p=0.017), but the level of FSH increased (p=0.032). No obvious change was seen in the level of LH (P=0.219). This might indicate that the function of ovaries were inhibited by the application of this molecular targeted agent. Conclusions: Routine dosage of Sorafenib could interrupt the menstruations of female patients with normal menses in the treatment of advanced renal cell carcinoma. Levels of E2 and FSH were significantly changed after drug administration. Inhibition of ovarian function by Sorafenib might be the most important reason.

Eur Urol Suppl 2009;8(4):184

1 Wyeth Pharmaceuticals, Dept. of Medicine - Oncology, Muenster, Germany, 2Wyeth Pharmaceuticals, Regulatory Affairs, Muenster, Germany, 3Wyeth Pharmaceuticals, Dep. of Pharmacovigilance, Muenster, Germany, 4Wyeth Pharmaceuticals, Dept. of Medicine, Muenster, Germany

Introduction & Objectives: Temsirolimus (TEMS) was licensed in the EU for the firstline treatment of patients with advanced renal cell cancer (aRCC) who have at least 3 of 6 prognostic risk factors in November 2007. In 2006 data from the pivotal study became available demonstrating that TEMS significantly increased overall survival (OS) in poor risk aRCC vs. the former standard Interferon (10.9 months vs. 7.3 months). With these data and TEMS´s approval in the EU expected in late 2007, Wyeth received an increasing number of requests for the preregistration availability of TEMS. Material & Methods: In this highly ethical situation Wyeth set up a “Compassionate Use” – Program (CUP) for patients with aRCC. Due to varying legal situation throughout Europe and pending legislation in Germany we followed the EU Regulation 726/2004 and AMG §21.2 (German medicinal product law). TEMS was supplied free of charge on an individual request only in aRCC. As this has not been a clinical study the follow up through Wyeth was restricted to pharmacovigilance aspects. The involved physicians had to acknowledge the unlicensed status of the drug, the indication (aRCC), the information provided (draft SmPC) and the pharmacovigilance obligations. Results: With regulatory and ethic committees notification CUP started in Germany in December 2006 and was closed after TEMS approval and availability on November, 26th 2007. During 12 months we received 289 TEMS-requests for 200 patients. Altogether, we supplied about 2200 single doses TEMS. Our pharmacovigilance department received 8 reports of serious adverse events (SAE). Two included events possibly related to TEMS (mucosal inflammation, stomatitis, increased LDH, bone pain, increased CRP, pyrexia), one (increased LDH) was without statement regarding relationship and the other five (disease progression (2x), paralytic ileus, pneumonia, respiratory failure) were considered not related by the treating physician. Conclusions: Following EU Regulation 726/2004 and German AMG TEMS was offered to aRCC-patients lacking other treatment options via CUP. The program was well received and experiences were shared with regulatory authorities. The reported SAEs confirmed the known safety profile of TEMS. The low incidence of reported SAEs reflects the low level of spontaneous SAE reporting and supports the need of additional tools to identify the true safety profile of newly approved drugs when used outside of clinical trials. These tools could be non-interventional trials, e.g. pharmacovigilance studies and registries.