Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial

Abstract

Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.

Keywords: chemosensitivity; individualized chemotherapy; melanoma; phase-3 trial.

Figure 1. Schematic presentation of the study flow

Figure 2. Waterfall plot depicting the best tumor response for each patient

Data regarding the best tumor response are shown for 84 patients in the sensitivity-directed combination chemotherapy arm (A) and for 94 patients in the dacarbazine monochemotherapy arm (B), who had undergone at least one tumor assessment after study treatment. Each bar represents data for an individual patient. Colors indicate the treatment regimen received by the patients. The percent change from baseline in the sum of the longest diameters of the target lesions defined at study entry is shown on the y axis. Negative values indicate tumor shrinkage; positive values indicate tumor growth. The pointed lines indicate changes in diameters corresponding to partial response (-30%) and progressive disease (+20%), respectively.

Figure 3

Kaplan Meier curves showing the probability of progression-free and overall survival of the per-protocol population (n=244) by treatment arm (A) and by ex-vivo determined tumor chemosensitivity. (B) Differences between groups were calculated using the log rank test. Censored observations are indicated by vertical bars.