Efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600 mutation-positive melanoma in the real-world setting: Interim results of the non-interventional COMBI-r study

Abstract

Abstract Background Despite the availability of improved treatment options in BRAFV600 mutation-positive metastatic melanoma, key questions regarding therapy sequence and duration, tumor dynamics, as well as efficacy in patient subgroups (e.g. brain metastases, concomitant diseases) that were not included in previous phase III clinical trials remain unresolved. Therefore, the objective of this non-interventional prospective study (COMBI-r) was to assess the treatment of a broad patient population in metastatic melanoma with dabrafenib and trametinib in clinical routine. Methods Between December 2015 and December 2018, 504 patients at 58 German Skin Cancer Centers were enrolled in COMBI-r. This interims analysis focuses on efficacy (OS, PFS, ORR, DOR) and safety of dabrafenib and trametinib in patients treated for at least 1 year or who have already terminated treatment (approx. 330 patients). During the first year on treatment, visits were scheduled every 3 months, followed by half-yearly visits until end of treatment (EoT), and two follow-up visits at 3 and 6 months. Results Efficacy outcomes will be correlated with patient demographics at baseline as well as clinical, laboratory and biological parameters. In addition, patients will be assigned to slow, intermediate and fast tumor dynamic subgroups based on key baseline characteristics previously shown predictive of clinical benefit including tumor stage, organ involvement, therapy line and laboratory markers (S100, LDH). Conclusions Data from the COMBI-r interims analysis can provide insights as to whether efficacy and safety demonstrated in clinical trials as well as currently acknowledged predictive factors for clinical benefit and long-term outcomes are transferable to clinical routine. Further, it remains to be evaluated whether other criteria such as tumor dynamics are potentially suitable to predict outcomes in broader and more heterogeneous patient populations in metastatic melanoma. Legal entity responsible for the study Novartis Pharma GmbH. Funding Novartis Pharma GmbH. Disclosure C. Berking: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : Amgen; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : BMS; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : Merck Serono; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, institutional grants, personal fees and non-financial support : 4SC; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Non-remunerated activity/ies, personal fees and non-financial support : Pierre Fabre; Honoraria (self), Non-remunerated activity/ies, personal fees and non-financial support : Sanofi-Aventis; Honoraria (self), Non-remunerated activity/ies, institutional grants : Array Pharma; Honoraria (self), Non-remunerated activity/ies, institutional grants : Regeneron; Honoraria (self), Non-remunerated activity/ies, institutional grant and personal fees (member of steering committee) related to the submitted work: Novartis. E. Livingstone: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Actelion; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Medac; Travel / Accommodation / Expenses: Pierre Fabre. M. Weichenthal: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sun Pharma. K. Wittmann: Full / Part-time employment: Novartis. T. Eigentler: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Leo Pharma; Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: MSD. P. Mohr: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi-Aventis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. F. Kiecker: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. C. Loquai: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sun Pharma. D. Debus: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi. R. Gutzmer: Research grant / Funding (self): Pfizer; Research grant / Funding (self): Johnson&Johnson; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): MerckSerono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Almirall-Hermal; Honoraria (self), Advisory / Consultancy: LEO; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self): 4SC; Advisory / Consultancy: Incyte; Advisory / Consultancy: SUN; Honoraria (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca. All other authors have declared no conflicts of interest.