252 RETROSPECTIVE ANALYSIS OF THE SEQUENTIAL USE OF SORAFENIB AND SUNITINIB IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA (RCC)

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Phase II multicentric study of sunitinib in metastatic renal cell carcinoma (MRCC) with a poor prognosis refractory to immunotherapy

Cardiovascular toxicity following sunitinib therapy in metastatic renal cell cancer: A multicenter retrospective analysis

Longo N.1, Di Lorenzo G.2, Fusco F.1, Verze P.1, Barba C.1, Arcaniolo D.1, Mirone V.1

Autorino R.1, Di Lorenzo G.2, De Nunzio C.3, Perdonà S.4, Cartenì G.5, Tudini M.6, Aieta M.7, De Placido S.2, Ewer M.8

University Federico II, Dept. of Urology, Naples, Italy, 2University Federico II, Dept. of Oncology, Naples, Italy 1

Introduction & Objectives: Sunitinib is an orally administered multi targeted tyrosine kinase inhibitor that is approved worldwide for renal cell carcinoma. Our intent was to examine the efficacy and toxicity of sunitinib in patients with MRCC refractory to immunotherapy in a Memorial SloanKettering Cancer Center (MSKCC) risk group > 3. Material & Methods: A phase II multicentric study was conducted on thirty patients with MRCC refractory to immunotherapy. Sunitinib 50 mg was administered orally and consecutively on days 1-28 of each 6-week cycle. The primary objective was to evaluate the response rate (complete and partial) in accordance with the Response Evaluation Criteria in Solid Tumors Guidelines (RECIST). The secondary objective was to evaluate the disease-related progression-free survival (PFS) rates. Results: Complete remission, partial remission, stable disease and disease progression occurred in 9 patients (30%), 2 patients (6.6%), 3 patients (10%) and 14 patients (46.6%), respectively. Patients with complete remission had an average progression-free survival of 4 months (95% CI, range: 2-10 months). The most common hematological complication was neutropenia (5 patients, 16.9%); the most common non-hematological toxicity was asthenia (7 patients, 23%) and stomatitis (6 patients, 20%).

Second University of Naples, Dept. of Urology, Naples, Italy, 2Federico I I University, Dept. of Oncology, Naples, Italy, 3Sant’ Andrea University Hospital, Dept. of Urology, Rome, Italy, 4INT Fondazione Pascale, Dept. of Urology, Naples, Italy, 5Cardarelli Hospital, Dept. of Oncology, Naples, Italy, 6Aquila University, Dept. of Oncology, L’aquila, Italy, 7Oncological Regional Hospital, Dept. of Oncology, Rionero In Vulture, Italy, 8MD Anderson Cancer Center, Dept. of Cardiology, Houston, United States of America 1

Introduction & Objectives: Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. Material & Methods: The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian Institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with pre-existing cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. Results: Grade 3 hypertension was seen in 17 patients (9.7%); in twelve of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left-ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were of classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). A significant univariate association for predictors of CHF were history of hypertension (p=0.008), history of coronary heart disease (p=0.0005) and prior treatment with an angiotensin converting enzyme inhibitor (ACE) (p= 0.04). Multivariate analysis suggested that a history of coronary artery disease (OR 18, 95% CI, 4-160 p 0.005) and hypertension (OR 3, 95% CI, 1.5-80 p 0.04) were the only significant independent predictors of CHF.

Conclusions: Sunitinib was efficacious and safe as a single therapeutic agent even in patients with pre-treated MRCC with a poor prognosis.

Conclusions: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.





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Sequential use of the tyrosin kinase inhibitors sorafenib and sunitinib Heuer R., Eichelberg C., Zacharias M., Heinzer H. University Hospital Hamburg-Eppendorf, Dept. of Urology, Hamburg, Germany Introduction & Objectives: Little data are available about sequential use of the tyrosine kinase inhibitors (TKI) sorafenib and sunitinib for treatment of metastatic renal cell carcinoma (mRCC). We recently published our experience with sequential therapy of TKI treatment. Purpose of this study was to give an update on our previously published data to confirm that an objective response could be obtained for patients progressing under treatment with sorafenib by changing medication to sunitinib. Material & Methods: Patients who had progressive mRCC under sorafenib subsequently received sunitinib. We retrospectively identified 44 patients treated with sorafenib and then sunitinib between May 2005 and Oct 2008. Radiologic evaluation of treatment was performed every 3 mo according to the criteria for Response Evaluation Criteria in Solid Tumors (RECIST). Adverse events and abnormalities (e.g. dose reduction) were documented during regular visits. Results: 84% of patients had clear cell renal carcinoma. 65% had different kinds of immunotherapy before sequential TKI therapy was initiated. 39 (88,6%) of patients responded to initial sorafenib therapy by stable disease or partial response. 24 (54,4%) benefited from the secondary use of sunitinib by new disease stabilisation or partial response. 20 patients did not respond to treatment switch and had progressive disease on first scan. Median progression free survival under treatment with sorafenib was 9,2 mo and 5,7 mo in median until second progression occurred under treatment with sunitinib. The overall treatment time until second progression under TKI treatment occurred was 19 mo. Treatment duration for sunitinib responder was significantly longer. Conclusions: This update to our previously published data supports the hypothesis that sequential TKI therapy has clinical activity for patients with mRCC. Patients suffering progressive disease under inital therapy with sorafenib may benefit from further treatment with sunitinib.

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Retrospective analysis of the sequential use of sorafenib and sunitinib in patients with advanced renal cell carcinoma (RCC) Porta C.1, Procopio G.2, Sabbatini R.3, Bearz A.4, Chiappino I.5, Imarisio I.1, Guadalupi V.2, Paglino C.1, Verzoni E.2, Ferraris E.1, Bajetta E.2 Irccs San Matteo University Hospital Foundation, Oncologia Medica, Pavia, Italy, 2National Cancer Institute, Oncologia Medica, Milan, Italy, 3Modena University Hospital, Oncologia Medica, Modena, Italy, Oncology Reference Center, Oncologia Medica, Aviano, Italy, 5San Giovanni Battista Hospital, Oncologia Medica, Turin, Italy

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4

Introduction & Objectives: Sorafenib and sunitinib are both approved for the treatment of advanced RCC. The effectiveness of these drugs has made the shift from one treatment to the other extremely frequent, despite a substantial lack of prospective data supporting the two possible sequences. The primary objective of this study was to assess the optimal clinical benefit of the two sequences (sorafenib-sunitinib; sunitinibsorafenib) in patients with advanced RCC. Material & Methods: This study was a retrospective analysis of 118 patients with advanced RCC treated at 5 centers in Italy. Patients were treated with sorafenib (400 mg bid continuous dosing) or sunitinib (50 mg qd, 4 weeks on, 2 weeks off) until disease progression, determined by radiologic assessment (RECIST criteria). Following progression, patients switched therapeutics and received the inverse treatment. Results: Baseline patient characteristics were similar between both populations in terms of age, sex, ECOG PS, and histology. However, a higher proportion of patients who received sunitinib therapy first tended to have a poorer Motzer score than patients who received sorafenib therapy first. Patients experienced a mean PFS of 9.4 or 8.6 months when sorafenib or sunitinib were administered first, respectively, whilst a slightly longer second PFS of 8.1 months vs. 4.8 months was observed when they received sorafenib as their first therapy. The overall mean PFS was 17.5 months vs. 13.4 months for patients receiving sorafenib first-line vs. sunitinib first-line. Conclusions: Despite being biased by their retrospective nature, these results clearly suggest the lack of cross-resistance between sorafenib and sunitinib. The overall PFS appears to be longer in patients who received the sorafenib-sunitinib sequence, compared with those treated with the sunitinib-sorafenib sequence. Our observations warrant further investigation to prospectively address the optimal sequence within a specifically designed trial. Sorafenib-Sunitinib (n=77) Median age, years (range) Male, % ECOG PS, % 0/1/2 Motzer score, % good/ intermediate/poor Clear cell histology, % Mean first PFS, months Mean second PFS, months Mean overall (first + second) PFS, months

Sunitinib-Sorafenib (n=41) 57.5 (30-77) 80.5 72.7/24.7/2.6 57.1/36.4/6.5

59 (34-77) 78.0 85.4/14.6/0 51.2/22.0/26.8

80.5 9.4 8.1 17.5

87.8 8.6 4.8 13.4

Eur Urol Suppl 2009;8(4):183