Jean Jacques Grob1, Mayur M Amonkar2, Boguslawa Karaszewska3, Jacob Schachter4, Reinhard Dummer5, Andrzej Mackiewicz6, Daniil Stroyakovskiy7, Kamil Drucis8, Florent Grange9, Vanna Chiarion-Sileni10, Piotr Rutkowski11, Mikhail Lichinitser12, Evgeny Levchenko13, Pascal Wolter14, Axel Hauschild15, Georgina V Long16, Paul Nathan17, Antoni Ribas18, Keith Flaherty19, Peng Sun2, Jeffrey J Legos2, Diane Opatt McDowell2, Bijoyesh Mookerjee2, Dirk Schadendorf20, Caroline Robert21. 1. Service de Dermatologie, Aix Marseille University, and Assistance Publique Hôpitaux de Marseille (APHM), University Hospital Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. 2. GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA. 3. Przychodnia Lekarska Komed, Konin, Poland. 4. Sheba Medical Center, Ramat Gan, Ramat, Israel. 5. Department of Dermatology, Universität Zürich, Zurich, Switzerland. 6. Oncology Division, Poznan University of Medical Sciences, Med-Polonia, Poznan, Poland. 7. Moscow City Oncology Hospital #62, Stepanovskoye, Moscow, Russia. 8. Swissmed Centrum Zdrowia and Gdansk Medical University, Gdansk, Poland. 9. Centre Hospitalier Universitairede Reims-Hôpital Robert Debré, Reims, France. 10. Istituto Oncologico Veneto Istituto Di Ricovero e Cura a Carattere Scientifico, Padua, Italy. 11. Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. 12. N N Blokhin Russian Cancer Research Center, Moscow, Russia. 13. Petrov Research Institute of Oncology, Saint Petersburg, Russia. 14. University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. 15. Universitätsklinikum Schleswig-Holstein (UKSH), Department of Dermatology, Kiel, Germany. 16. Melanoma Institute Australia, The University of Sydney and The Mater Hospital, Sydney, Australia. 17. Mount Vernon Cancer Centre, Northwood, UK. 18. University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. 19. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 20. Department of Dermatology, University Hospital Essen, Essen, Germany. 21. Gustave Roussy, Département de Médecine oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France.
Abstract
BACKGROUND: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. METHODS: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. FINDINGS:From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). INTERPRETATION: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.
RCT Entities:
BACKGROUND: In the COMBI-v trial, patients with previously untreated BRAFVal600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. METHODS:COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. FINDINGS: From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). INTERPRETATION: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.
Authors: Thomas M Atkinson; Jennifer L Hay; Alexander Shoushtari; Yuelin Li; Daniel J Paucar; Sloane C Smith; Ragini R Kudchadkar; Austin Doyle; Jeffrey A Sosman; Jorge Fernando Quevedo; Mohammed M Milhem; Anthony M Joshua; Gerald P Linette; Thomas F Gajewski; Jose Lutzky; David H Lawson; Christopher D Lao; Patrick J Flynn; Mark R Albertini; Takami Sato; Karl Lewis; Brian Marr; David H Abramson; Mark Andrew Dickson; Gary K Schwartz; Richard D Carvajal Journal: J Cancer Res Clin Oncol Date: 2016-12-05 Impact factor: 4.553