PGX7608: PGx evaluation of efficacy of dabrafenib and trametinib by meta-analysis of melanoma subjects from BRF113710, BRF113929, BRF113683, MEK114267, MEK115306 and MEK116513

Trial description: Dabrafenib (GSK2118436) is a potent, ATP-competitive and selective inhibitor of mutant BRAF kinase (V600E/K) and trametinib (GSK1120212) is a selective, non-ATP competitive, allosteric inhibitor of MEK1 and MEK2 kinases. The U.S. Food and Drug Administration recently approved dabrafenib and trametinib as single-agent therapies as well as in combination for the treatment of unresectable melanoma or metastatic melanoma in adult subjects with the most common type of BRAF mutations: BRAF V600E (dabrafenib) and BRAF V600E/K (trametinib). The BRAF V600E/K mutation is found in 40-60% of melanomas causing constitutive activation of BRAF and, in turn, the MAP kinase pathway. Both dabrafenib and trametinib prolong median survival of BRAF V600E/K mutant melanoma subjects compared to chemotherapy, however, similar to other kinase inhibitors, secondary resistance typically develops after an initial robust response to these drugs. Multiple resistance mechanisms have been identified (mostly somatic), but there are no validated biomarkers that could predict the response. Germline genetic variations may help explain the variation in treatment response (in addition to the somatic changes in the tumor).Prior PGx investigations of PFS (200632, 200633 and 201568) in various dabrafenib/ trametinib melanoma studies (BRF113710, BRF113929, BRF113683, MEK114267 and MEK115306) identified no significant association of functional candidate or genome wide variants with PFS. The primary objective of this study is to test association between genetic variants and PFS by meta-analysis of Caucasian melanoma subjects treated with dabrafenib, trametinib or a combination of dabrafenib and trametinib from studies BRF113710, BRF113929, BRF113683, MEK114267, MEK115306 (mono and combi arms) and MEK116513-combi arm. The secondary objective is to test association between genetic variants and PFS in Caucasian melanoma subjects treated with 1) a BRAF inhibitor (dabrafenib or vemurafenib (Roche BRAF inhibitor) in studies BRF113710, BRF113929, BRF113683, MEK115306 and MEK116513 or 2) a combination of dabrafenib and trametinib (combi arms of MEK115306 and MEK116513). Genome wide genotype data generated for previous PGx evaluations using either the Illumina Human Omni Express plus Exome (OEE) BeadChip array (BRF116604 and 200632) or Affymetrix Axiom Biobank Plus GSK Custom array (200633, 200997 and 201568) will be reused in this PGx investigation. Genome wide data for MEK116513 will be generated using Affymetrix Axiom Biobank Plus GSK Custom array. Genome wide imputation will be carried out to obtain missing genotype data for variants typed on the 2 genotyping platforms. A total of 6 million genetic variants (directly genotyped or imputed) across two different genotyping platforms will be tested for associations with PFS. The association study for the primary objective will be conducted in subjects from MEK116513-combination armfirst and then the results will be meta-analyzed along with summary statistics from the other clinical studies (BRF113710, BRF113929, BRF113683, MEK114267 and MEK115306 (mono and combi arms)) which were analyzed in the previous PGx investigation (201568). The association study for the first secondary objective will be conducted separately for subjects from MEK116513-vemurafenib arm first and then the results will be meta-analyzed along with summary statistics from subjects who received dabrafenib monotherapy from BRF113710, BRF113929, BRF113683 and MEK115306 monotherapy arm. The results for subjects receiving the combination of dabrafenib and trametinib (MEK115306 – combi and MEK116513 – combi) will be meta-analyzed for the other secondary objective. Genotype association tests will be performed using Cox proportional hazards model with covariates selected by evaluation and the first top 10 principal components. Additive genetic effect will be assumed in these analyses.All other trademarks identified herein are the intellectual property rights of their respective owners.