cad a22 4500 569303524 20191002045213.0 cr unu---uuuuu 190726e201905 xx s 000 0 eng 10.5167/uzh-171777 doi 10.1016/S1470-2045(18)30940-9 doi (ZORA)oai:www.zora.uzh.ch:171777 610 ddc 30928620 pmid Patient-reported outcomes in patients with resected, high-risk melanoma with BRAF or BRAF mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial [Elektronische Daten] [Dirk Schadendorf, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Thierry Lesimple, Ruth Plummer, Jacob Schachter, Kohinoor Dasgupta, Stephanie Manson, Roy Koruth, Bijoyesh Mookerjee, Richard Kefford, Reinhard Dummer, John M Kirkwood, Georgina V Long] closedAccess eu-repo BACKGROUND In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF or BRAF mutations received adjuvant dabrafenib plus trametinib or placebo. The primary analysis showed that dabrafenib plus trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF or BRAF mutations. Here, we report the patient-reported outcomes from COMBI-AD. METHODS COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF or BRAF mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. FINDINGS Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001). INTERPRETATION These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. FUNDING Novartis. Dermatology Clinic zora Schadendorf Dirk joint author Hauschild Axel joint author Santinami Mario joint author Atkinson Victoria joint author Mandalà Mario joint author Chiarion-Sileni Vanna joint author Larkin James joint author Nyakas Marta joint author Dutriaux Caroline joint author Haydon Andrew joint author Robert Caroline joint author Mortier Laurent joint author Lesimple Thierry joint author Plummer Ruth joint author Schachter Jacob joint author Dasgupta Kohinoor joint author Manson Stephanie joint author Koruth Roy joint author Mookerjee Bijoyesh joint author Kefford Richard joint author Dummer Reinhard joint author Kirkwood John M. joint author Long Georgina V. joint author Lancet Oncology 20(5):701-710 https://www.zora.uzh.ch/id/eprint/171777/1/795_Schadendorf_D._et_al._Patient-reported_outcomes_in_patients_with_resected%2C_high-risk_melanoma_with_BRAF_V600_E_etc._Lancet_Oncol_2019.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/id/eprint/171777/1/795_Schadendorf_D._et_al._Patient-reported_outcomes_in_patients_with_resected%2C_high-risk_melanoma_with_BRAF_V600_E_etc._Lancet_Oncol_2019.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Schadendorf Dirk joint author ZORA 700 1- Hauschild Axel joint author ZORA 700 1- Santinami Mario joint author ZORA 700 1- Atkinson Victoria joint author ZORA 700 1- Mandalà Mario joint author ZORA 700 1- Chiarion-Sileni Vanna joint author ZORA 700 1- Larkin James joint author ZORA 700 1- Nyakas Marta joint author ZORA 700 1- Dutriaux Caroline joint author ZORA 700 1- Haydon Andrew joint author ZORA 700 1- Robert Caroline joint author ZORA 700 1- Mortier Laurent joint author ZORA 700 1- Lesimple Thierry joint author ZORA 700 1- Plummer Ruth joint author ZORA 700 1- Schachter Jacob joint author ZORA 700 1- Dasgupta Kohinoor joint author ZORA 700 1- Manson Stephanie joint author ZORA 700 1- Koruth Roy joint author ZORA 700 1- Mookerjee Bijoyesh joint author ZORA 700 1- Kefford Richard joint author ZORA 700 1- Dummer Reinhard joint author ZORA 700 1- Kirkwood John M. joint author ZORA 700 1- Long Georgina V. joint author ZORA 773 0- Lancet Oncology 20(5):701-710 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article closedAccess