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

Selma Ugurel; Carmen Loquai; Patrick Terheyden; Dirk Schadendorf; Erika Richtig; Jochen Utikal; Ralf Gutzmer; Knuth Rass; Cord Sunderkötter; Annette Stein; Michael Fluck; Martin Kaatz; Uwe Trefzer; Katharina Kähler; Rudolf Stadler; Carola Berking; Christoph Höller; Laura Kerschke; Lutz Edler; Annette Kopp-Schneider; Jürgen C Becker

doi:10.18632/oncotarget.18635

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

Oncotarget. 2017 Jun 27;8(44):76029-76043. doi: 10.18632/oncotarget.18635. eCollection 2017 Sep 29.

Authors

Selma Ugurel^{1

2}, Carmen Loquai³, Patrick Terheyden⁴, Dirk Schadendorf^{1

5}, Erika Richtig⁶, Jochen Utikal^{7

8}, Ralf Gutzmer⁹, Knuth Rass¹⁰, Cord Sunderkötter¹¹, Annette Stein¹², Michael Fluck¹³, Martin Kaatz¹⁴, Uwe Trefzer¹⁵, Katharina Kähler¹⁶, Rudolf Stadler¹⁷, Carola Berking¹⁸, Christoph Höller¹⁹, Laura Kerschke^{20

21}, Lutz Edler²⁰, Annette Kopp-Schneider²⁰, Jürgen C Becker^{1

2

5

6}

Affiliations

¹ Department of Dermatology, University Hospital of Essen, Essen, Germany.
² Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
³ Department of Dermatology, University Hospital of Mainz, Mainz, Germany.
⁴ Department of Dermatology, University Hospital of Lübeck, Lübeck, Germany.
⁵ Translational Skin Cancer Research, Deutsches Konsortium für 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 Münster, Münster, 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 Münster, Münster, Germany.

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.

Keywords: chemosensitivity; individualized chemotherapy; melanoma; phase-3 trial.