Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutation-positive metastatic melanoma (MM) patients (pts) treated with dabrafenib (D) as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib (T).

Melanoma/Skin Cancers
Session Type and Session Title: 
Poster Discussion Session, Melanoma/Skin Cancers
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 9016)
Jonathan S. Cebon, Keith Flaherty, Jeffrey S. Weber, Kevin Kim, Jeffrey R. Infante, Adil Daud, Omid Hamid, Richard Kefford, Lynn Mara Schuchter, Jeffrey Alan Sosman, Mario Sznol, William Howard Sharfman, Rene Gonzalez, Miles Cameron Andrews, Roxana Stefania Dronca, Georgina Long, Shonda M Little, Peng Sun, Kiran Patel, Robert R. McWilliams; Ludwig Institute for Cancer Research, Melbourne, Australia; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Moffitt Cancer Center, Comprehensive Melanoma Research Center, Tampa, FL; The University of Texas MD Anderson Cancer Center, Houston, TX; Drug Development Unit; Sarah Cannon Research Institute, Nashville, TN; University of California, San Francisco, San Francisco, CA; The Angeles Clinic and Research Institute, Los Angeles, CA; Westmead Hospital and Melanoma Institute Australia, Westmead, Australia; University of Pennsylvania, Philadelphia, PA; Vanderbilt University Medical Center, Nashville, TN; Yale University, New Haven, CT; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; University of Colorado Denver, Aurora, CO; Ludwig Institute for Cancer Research - Austin Branch, Heidelberg, Australia; Mayo Clinic, Department of Medical Oncology, Rochester, MN; Melanoma Institute Australia, Westmead Hospital, University of Sydney, Sydney, Australia; GlaxoSmithKline, Collegeville, PA; Mayo Clinic, Rochester, MN

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Abstract Disclosures


Background: The MAP kinase (MAPK) pathway is of critical importance for keratinocyte proliferation and maturation and is essential for epidermal homeostasis. Occurrence of hyperproliferative skin lesions including keratoacanthomas (KA) and cuSCC are considered a class effect of BRAFi [Anforth 2012, Chu 2012, Mattei 2012]. These effects, as well as promotion of pre-existing RAS-driven malignancies, may be caused by paradoxical activation of the MAPK pathway downstream of BRAF in wild-type BRAF cells. As MEK inhibition blocks downstream MAPK signaling, it was hypothesized that addition of a MEKi to a BRAFi would abrogate these effects [Su, 2012]. Methods: This 4-part phase I/II study enrolled 365 BRAFV600E/Kmutated MM pts in Parts B-D. In part C, 162 pts (BRAFi and MEKi treatment-naïve, ≥ 18 yrs; ECOG PS <2; RECIST measurable disease) were randomized to D monotherapy 150mg BID (D mono) vs. the combination of D (150 mg BID) and T (1 mg or 2 mg QD). Primary endpoints included safety and efficacy. Occurrence of cuSCC (including KA) across three arms in Part C and secondary malignancies with D+T across all Parts are provided below. Results: The difference in incidence of cuSCC between D mono and the D+T (150/1) was statistically significant, whereas the difference in incidence between D mono and D+T (150/2) was not. The median time to onset of cuSCC was 30 days in D mono compared to 282 and 152 days with D+T (150/1 and 150/2, respectively). Of 365 pts who received D+T, 2 (<1%) cases of new cancers (colorectal and gliobastoma) and 2 (<1%) cases of new primary malignant melanoma were reported. Conclusions: These data support the experimental hypothesis that the occurrence of cuSCC (including KA) can be substantially reduced and delayed by the addition of a MEKi to BRAFi therapy. Clinical trial information: NCT01072175.

Treatment groups for Part C
D 150 mg BID 150 mg BID 150 mg BID
T -- 1 mg QD 2 mg QD
N 53 54 55
Any cuSCC including KA, n (%) 10 (19) 1 (2) 4 (7)
Reduction -- 89% 63%
P value (2-sided) -- 0.0040 0.0901