Abstract 288: B-Raf, c-KIT, VEGFR and MGMT expression analysis in advanced melanoma (MM) patients (pts) treated with dacarbazine (DTIC) + bevacizumab (B): Correlation with response and survival
Authors: di Pietro Alessandra , Barberis Massimo , Manzotti Michela , Martinoli Chiara , Passoni Claudia , Pari Chiara , Mosconi Massimo , Cataldo Francesco , Gandini Sara , Testori Alessandro , Ferrucci Pier Francesco 
Published: June 2012

Background: Advanced MM pts’ prognosis remains poor and is not improved by the neither DTIC nor IL-2 [median survival-time &lt;9 month (mo); 5-yr survival-rate &lt;5%], nor as single-agent, nor in poly-CTh. To improve such sober results, different DTIC-combinations have been proposed. MM in vitro models showed VEGF transcription up-regulation upon DTIC treatment, suggesting DTIC/anti-VEGF combination as an intriguing exploiting path.

B-Raf is a MAPK tyrosin-kinase mutated in about 62% of cutaneous melanomas. c-Kit is a RTK mainly mutated in mucosal (39%), acral (36%) and sun damaged cutaneous (28%) melanomas. MGMT is a gene encoding for 06-metylguanine-DNA-metyltransferase, which is mutated in about 15% of melanomas. Using available tissue samples from a phase 2 study on advanced melanoma pts treated with DTIC + B combination, we looked at these molecular markers on tissues samples, in order to test whether any of them could correlate with therapy response.

Patients & Methods: Between July 2006-May 2010, 40 CTh-naïve advanced MM pts underwent CTh with DTIC (800mg/mq q4w) + B (10mg/kg q2w), being disease evaluated at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to RECIST criteria. Response rate and median TTP were analyzed. Secondly we tried to explore any combination between the molecular markers and therapy response.

Results: 36/40 pts were evaluated at the analysis-time, with 4 screening failures (3 pts: brain metastasis detection at the pre-study wb CT-scan; 1pts: bleeding risk). Male/Female=23/13; median age was 57yr. PS 0/1 = 32/4. 3 pts (8.3%) developed complete response, 4 pts (11.1%) partial response (PR), 11 (30.5%) stable disease (SD ≫24w = 6 pts, 16.6%); 17 (50%) progressive disease (PD; 8pts: RECIST-criteria PD at the first CT-scan evaluation; 9 pts: early clinical PD). On the available tissue samples from the patients in the study, B-Raf and c-Kit mutation analysis as well as methylation analysis for MGMT were performed. Secondly, VEGF-A and VEGFR were tested on the same tissues by immune-staining. Median TTP was 6 mo (Interquartile range: 2.5-10). Exploratory data analysis interestingly shows 50% clinical benefit (defined as CR+PR+SD≫24w) and 16.5 mo (95% CI 12.7-31.5) median survival.

Conclusions: Data analysis is ongoing; furthermore, to state a correlation between molecular markers expressions and response to therapy or survival the most pts enrolled in the study are retrieving material from previous surgery and from the primary tumour.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2011-288