BAY 43–9006 (sorafenib-BAY) alters proliferation pathways and mutant specific-PCR (MS-PCR) improves detection of BRAF mutations in metastatic melanoma (MM)

Abstract

8542 Background: Approximately 60% of melanomas carry BRAF mutations (mut). BAY is a multi-kinase inhibitor that inhibits the BRAF pathway. A phase II trial of BAY in MM is being conducted to: 1) determine if treatment (tx) with BAY can alter proliferation as measured by cyclin D1, Ki-67 and ERK, 2) assess for differential anti-tumor responses and 3) to assess a newly developed fluorescent-based PCR assay to detect mutant BRAF. Methods: Eligibility criteria: Biopsy (bx)-accessible, untreated MM. Measurable disease (RECIST). Stratification of tumor BRAF status determined by routine PCR sequencing for codon 600 mut prior to tx and fluorescent MS-PCR sequencing for confirmation. MS-PCR specifically amplified the M-BRAF allele without amplifying the wild-type (WT)allele. Tx: BAY 400 mg po BID D1–28 q4w. Repeat bx on Day 28. Bx assessed for Ki-67, cyclin-D1 and ERK. Serum collagen cryptic epitopes were measured serially. Re-imaging was done every 2 cycles and pts treated until POD. Results: 29 pts (9-M1a, 8-M1b, 12-M1c) enrolled. 26 wild type (WT) and 3 mutant (M) BRAF by routine PCR. Due to the low yield of mut on routine PCR, MS-PCR was done. 6 mutants were detected in the first 16 pts with MS-PCR compared to 2 with routine sequencing. Median age: 68 (range 22–91). 8 pts with LDH ≥ 1.5 × nl. Tox: Gr I-diarrhea(7), alopecia(4), rash(6), mucositis(4), nausea(4), pain(4), hand-foot(2); Gr II- HTN(4), fatigue(2),mucositis(1), rash(3), pain(3), hand-foot(2); Gr III-hand-foot(1), rash(1), fatigue(1) and intestinal perforation(1). Responses: 12 NE (2 WD, 8 early POD, 1 tox, 1 too early); M BRAF- 1 PR (lymph nodes and large SQ arm masses) and 2 PD; WT BRAF- 1 PR, 7 POD after 2 cycles, 6 SD. Matched paired biopsies demonstrated down regulation of tumor ki-67, erk and cyclin-D1. Collagen cryptic epitopes correlated with tumor responses. Conclusions: MM patients with tumors that were molecularly characterized for BRAF mutational status were entered on this single agent BAY trial and responses were seen in both M and WT arms. Down-regulation of Ki-67, cyclin D1 and ERK was demonstrated and MS-PCR improved the sensitivity to detect BRAF mut. Supported by NCI N01-CM17103 and TRI. No significant financial relationships to disclose.