Phase I/II trial of association of sorafenib in combination with temozolomide in patients with metastatic melanoma: Looking for predictive markers of efficacy.

Abstract

8552 Background: The poor activity of treatments (tt) against metastatic melanoma (MM) mainly relies in the absence of predictive markers of efficacy that could allow selection of responsive pts. This phase I/II clinical trial of sorafenib (S) + temozolomide (T) was done with an intense translational research program in order to evaluate both safety and efficacy and to identify early markers of treatment benefit. Methods: 63 pts with MM were included in the dose-escalating phase I (n = 15) and the phase II (n = 48). Sequential blood and tumor samples were harvested to study baseline parameters and intra-individual variations of biomarkers during the treatment. Tumor sequencing of 44 exons in 12 genes were done in 37 pts. CGH arrays, RNA expression profiling, immunostaining (P-ERK, P-MEK and Ki67) were performed at d0 and 21. Functional imaging using dynamic contrast enhanced ultrasonography (DCE-US) was performed at days 0, 7, 15, and every month. Results: 54 pts weretreated at the MTD: 400 mg of S bid and 150 mg/m2 of T every other week. Half of them had received ≥ 2 lines of prior chemotherapies and 37% had high LDH. Median number of cycles was 4 (1-22). Toxicity was manageable and required tt interruption for only 3 pts. On 49 evaluable pts, 4 had PR (8%), 19 SD (39%) and 26 PD (53%) for a treatment benefit in 47%. Six months PFS and overall survival rates were respectively 15.2% and 60.6%. DCE-US functional imaging parameters before treatment, at day 7 or day 15 were significantly associated with tt efficacy (OR or SD vs. PD) at 2, 4 or 6 months (p < 0.05). NKG2D ligand, soluble MICA, was found in 80% of pts with PR or SD vs. 3% of PD pts and was also significantly associated with clinical benefit (p < 0.05). On 37 tumors tested, mutations were found in BRAF (62%), STK11 (25%), NRAS (8%), TP53 (6%) CDKN2A (3%), CTNNB1 (3%) without correlation to clinical response. CGH array and RNA expression profiling results are pending. Conclusions: This study confirms the safety and efficacy of the association of S and T in pts with MM. Translational research identified early markers associated with treatment benefit that could allow selection of patients for more personalized and efficient treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer