Abstract
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.
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.
| Original language | English |
|---|---|
| Article number | 8552 |
| Journal | Journal of Clinical Oncology |
| Volume | 28 |
| Issue number | 15_Supplement |
| DOIs | |
| Publication status | Published - 20 May 2010 |