LBA27_PR - Phase II three-arm randomised study of the BRAF inhibitor (BRAFi) dabrafenib alone vs combination with MEK1/2 inhibitor (MEKi) trametinib in pts wit...

Date 29 September 2012
Event ESMO Congress 2012
Session Melanoma
Topics Anti-Cancer Agents & Biologic Therapy
Melanoma and other Skin Tumours
Presenter Georgina Long
Authors G.V. Long1, J.A. Sosman2, A. Daud3, J.S. Weber4, K.T. Flaherty5, J.R. Infante6, O. Hamid7, L. Schuchter8, J.S. Cebon9, I. Puzanov10, A.P. Algazi11, R. Kudchakar12, K. Lewis13, W. Hwu14, R. Kefford15, P. Sun16, S.M. Little17, R. Gonzalez18, K. Patel19, K. Kim14
  • 1Melanoma Institute Australia and Westmead Hospital, University of Sydney, 2060 - North Sydney/AU
  • 2Department Of Medicine, Vanderbilt-Ingram Cancer Center, 37232 - Nashville/US
  • 3Department Of Hematology/oncology, University of California, San Francisco, San Francisco/US
  • 4Department Of Cutaneous Oncology, Moffitt Cancer Center, Tampa/US
  • 5Cancer Center, Massachusetts General Hospital, Boston/US
  • 6Drug Development, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 7Department Of Medical Oncology, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 8Department Of Medicine, Division Of Hematology/oncology, University of Pennsylvania Abramson Cancer Center, Philadelphia/US
  • 9Department Of Medical Oncology, Ludwig Institute for Cancer Research, Austin Hospital, Melbourne/AU
  • 10Department Of Hematology/oncology, Vanderbilt University Cancer Center, 37232-6307 - Nashville/US
  • 11Department Of Cutaneous Oncology, University of California, San Francisco, San Francisco/US
  • 12Department Of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa/US
  • 13Department Of Medicine, Division Of Medical Oncology, University of Colorado Denver, Aurora/US
  • 14Department Of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston/US
  • 15Department Of Medicine, Westmead Hospital, Westmead/AU
  • 16Research And Development, GlaxoSmithKline, 19426 - Collegeville/US
  • 17Oncology R&d, GlaxoSmithKline, 19426 - Collegeville/US
  • 18Department Of Medicine/medical Oncology, University of Colorado Denver, 80045 - Aurora/US
  • 19Oncology, GlaxoSmithKline, 19426 - Collegeville/US

Abstract

Introduction: Dabrafenib (D) combined with trametinib (T) shows enhanced activity in BRAF V600-mutated cancer cell lines and xenograft models compared with either drug alone. Preclinically, D+T delays resistance and prevents BRAFi-induced proliferative skin lesions. Safety and efficacy of D+T, were evaluated in a four-part Phase 1–2 study. Safety and efficacy from Part C, the randomised study of D+T vs D are presented.

Methods: BRAFV600E/K mutation-positive, MM, BRAFi and MEKi treatment-naive pts (= 18 yrs; ECOG PS <2) with RECIST measurable disease were randomised 1:1:1 to D-150 mg BID (D mono), D-150 mg BID + T-1 mg QD (150/1), D-150 mg BID + T-2 mg QD (150/2). Crossover from D mono to 150/2 was allowed after progression. Primary endpoints were progression free survival (PFS), response rate (RR) and duration of response (DoR); secondary endpoints included overall survival (OS) and safety.

Results: Pt (n=162) baseline characteristics were balanced across the three arms. Investigator assessed median PFS for 150/2 was 9.4 mo v 5.8 for D mono (HR 0.39, 95% CI 0.25–0.62; p<0.0001). Confirmed RR was 76% for 150/2 vs 54% for D mono (p=0.03). Median DoR was 10.5 mo for 150/2 vs 5.6 mo for D mono. 12-mo OS rate was 79% for 150/2 vs 70% for D mono despite crossover of 43 (80%) pts to 150/2; median OS has not been reached. Pyrexia (71% vs 26%) and chills (58% vs 17%) were the most common adverse events (AEs) leading to dose reduction (35% vs 4%) and interruption (42% vs 6%) in 150/2 vs D mono, respectively. Most common gr 3+ AEs in 150/2 were neutropenia (11%) and hyponatremia (7%) compared to D mono. Lower incidence of hyperproliferative skin lesions was observed in 150/2 vs D mono including cuSCC (7% vs 19%), skin papilloma (4% vs 15%) and hyperkeratosis (9% vs 30%).

Conclusions: D+T provided a statistically significant and clinically meaningful improvement in PFS, RR and DoR compared to D mono in pts with BRAF V600 mutation-positive MM. The data is consistent to Part B reported with D+T. Increased incidence and severity of pyrexia and lower incidence of hyperproliferative skin lesions are observed with D+T compared to D mono. Phase 3 studies are ongoing.