128598-144

COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma

Subcategory: 
Category: 
Melanoma/Skin Cancers
Session Type and Session Title: 
Clinical Science Symposium, Novel Combination Therapies for Melanoma
Abstract Number: 
9011^
Citation: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 9011^)
Author(s): 
Georgina V. Long, Daniil L. Stroyakovsky, Helen Gogas, Eugeny Levchenko, Filippo de Braud, James M. G. Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Douglas James DeMarini, Jhangir G Irani, Ngocdiep Le, Michelle Casey, Kiran Patel, Keith Flaherty; Melanoma Institute Australia, Sydney, Australia; Moscow City Oncology Hospital, Chemotherapy Department, Moscow, Russia; University of Athens, Athens, Greece; Petrov Research Institute of Oncology, Saint Petersburg, Russia; Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy; Royal Marsden Hospital, London, United Kingdom; Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany; Saint André Hospital CHU de Bordeaux, Dermatology, Bordeaux, France; University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Service de Dermatologie, Centre Hospitalo-Universitaire Sainte-Marguerite, Marseille, France; IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy; APHP Hôpital Saint Louis, University Paris Diderot, Paris, France; Papa Giovanni XIII Hospital, BErgamo, Italy; Sir Charles Gairdner Hospital, Perth, Australia; GlaxoSmithKline, Research Triangle Park, NC; GlaxoSmithKline, Collegeville, PA; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Massachusetts General Hospital Cancer Center,Harvard Medical School, Boston, MA

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract: 

Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAFV600 mutant, metastatic melanoma (MM). Resistance develops in most pts, and oncogenic toxicities (e.g., cutaneous squamous carcinoma (cuSCC)) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects in the Phase I/II study of D+T v D (NCT01072175), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01584648) was conducted to confirm the superiority of D+T over D in pts with BRAFV600E/K mutant MM. Methods: Pts were randomized 1:1 to receive D (150 mg twice daily) + T (2 mg once daily) or D+ placebo (P) as first-line therapy. Eligible pts were ≥18 years and ECOG performance status ≤1, with histologically confirmed unresectable stage IIIC or IV, BRAFV600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59. Results: From May 2012 to Jan 2013, 423 pts were randomized (211 to D+T, 212 to D+P). Median follow up was 9 mo (0-16 mo). HR for investigator-assessed PFS was 0.75 (95% CI: 0.57, 0.99; p=0.035), in favor of D+T with a median PFS of 9.3 v 8.8 mo with D+P. The confirmed ORR was 67% (complete response [CR] 10%) for D+T and 51% (CR 9%) for D+P (p=0.0015). HR for interim OS was 0.63 (95% CI 0.42, 0.94; p=0.023), in favor of D+T (40 v 55 deaths). Rates of AEs were similar for both arms. More pts had AEs leading to dose modifications with D+T v D+P. Increased incidence (51% v 28%) and severity (grade 3, 6% v 2%) of pyrexia occurred with D+T v D+P. Fewer cutaneous hyperproliferative events occurred with D+T v D+P (CuSCC 2% v 9%; hyperkeratosis 3% v 32%). Conclusions: D+T demonstrated a significant improvement in PFS compared to D+P in pts with BRAFV600E/K mutant MM. Clinical trial information: NCT01072175.