BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM).

Melanoma/Skin Cancers
Session Type and Session Title: 
Oral Abstract Session, Melanoma/Skin Cancers
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 9005)
Jeffrey Alan Sosman, Adil Daud, Jeffrey S. Weber, Kevin Kim, Richard Kefford, Keith Flaherty, Jeffrey R. Infante, Omid Hamid, Jonathan S. Cebon, Lynn Mara Schuchter, Robert R. McWilliams, Mario Sznol, William Howard Sharfman, Alain Patrick Algazi, Karl D. Lewis, Shonda M Little, Peng Sun, Georgina Long, Kiran Patel, Rene Gonzalez; Vanderbilt University Medical Center, Nashville, TN; University of California, San Francisco, San Francisco, CA; Moffitt Cancer Center, Comprehensive Melanoma Research Center, Tampa, FL; The University of Texas MD Anderson Cancer Center, Houston, TX; Westmead Hospital and Melanoma Institute Australia, Westmead, Australia; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; The Angeles Clinic and Research Institute, Los Angeles, CA; Ludwig Institute for Cancer Research, Melbourne, Australia; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Mayo Clinic, Rochester, MN; Yale University, New Haven, CT; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; University of Colorado Cancer Center, Aurora, CO; GlaxoSmithKline, Collegeville, PA; University of Sydney, Sydney, Australia; UCHSC, Anschultz Cancer Pavilion, Aurora, CO

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Abstract Disclosures


Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D + T after BRAFi resistance has been acquired. This analysis evaluates the ability of D + T combination to treat acquired resistance compared to the D + T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D+T in Part B (n=26) and Part C (n=43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D+T in Part B (n=24) and Part C (n=54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D+T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D+T was lower than initial D+T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D+T combination. Conclusions: The clinical activity for 150/2 D+T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi + MEKi is far less effective. Clinical trial information: NCT01072175.

BRAFi resistant BRAFi naive
Cohort Part B Part C Part B Part C
Treatment group 150/2
Mono X-over
150/2 combination
PFS, median, months 3.6 3.6 10.8 9.4
ORR, % 15% 9% 63% 76%