Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial

// Selma Ugurel 1, 2 , Carmen Loquai 3 , Patrick Terheyden 4 , Dirk Schadendorf 1, 5 , Erika Richtig 6 , Jochen Utikal 7, 8 , Ralf Gutzmer 9 , Knuth Rass 10 , Cord Sunderkotter 11 , Annette Stein 12 , Michael Fluck 13 , Martin Kaatz 14 , Uwe Trefzer 15 , Katharina Kahler 16 , Rudolf Stadler 17 , Carola Berking 18 , Christoph Holler 19 , Laura Kerschke 20, 21 , Lutz Edler 20 , Annette Kopp-Schneider 20 and Jurgen C. Becker 1, 2, 5, 6 1 Department of Dermatology, University Hospital of Essen, Essen, Germany 2 Department of Dermatology, University Hospital of Wurzburg, Wurzburg, Germany 3 Department of Dermatology, University Hospital of Mainz, Mainz, Germany 4 Department of Dermatology, University Hospital of Lubeck, Lubeck, Germany 5 Translational Skin Cancer Research, Deutsches Konsortium fur Translationale Krebsforschung (DKTK), Essen, Germany 6 Department of Dermatology, Medical University of Graz, Graz, Austria 7 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany 9 Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany 10 Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany 11 Department of Dermatology, University Hospital of Munster, Munster, Germany 12 Department of Dermatology, University Hospital of Dresden, Dresden, Germany 13 Department of Internal Medicine, Fachklinik Hornheide, Hornheide, Germany 14 Department of Dermatology, University Hospital of Jena, Jena, Germany 15 Department of Dermatology, University Hospital Charite, Berlin, Germany 16 Department of Dermatology, University Hospital of Kiel, Kiel, Germany 17 Department of Dermatology, Johannes Wesling Klinikum, Minden, Germany 18 Department of Dermatology, University Hospital of Munich, Munich, Germany 19 Department of Dermatology, Medical University of Vienna, Vienna, Austria 20 Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany 21 Institute of Biostatistics and Clinical Research, University of Munster, Munster, Germany Correspondence to: Selma Ugurel, email: selma.ugurel@uk-essen.de Keywords: melanoma, chemosensitivity, individualized chemotherapy, phase-3 trial Received: March 06, 2017      Accepted: May 10, 2017      Published: June 27, 2017 ABSTRACT Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.