Targeting microenvironment and cellular immunity in sarcomas with trabectedin combined with metronomic cyclophosphamide: The TARMIC study

Recent pre-clinical data have suggested that the antitumor activity of trabectedin is not only related to their effects on tumor cells, but also on its ability to affect the tumor microenvironment (TME), in particular tumor associated macrophages and their pro-tumoral functions. We report results of the phase II part of the first study evaluating trabectedin in combination with metronomic chemotherapy on the TME of patients (pts) with advanced sarcomas. TARMIC is an open-label multicenter phase I/II study of trabectedin in combination with low-dose cyclophosphamide in pts with advanced STS. The RP2D was of 0.5 mg/m2. Primary endpoint was 6-month non progression rate. Secondary endpoints included efficacy and evaluation of impact on TME through mandatary tumor biopsies at baseline and after one cycle of treatment. 30 patients (17 males, 13 females) have been included. Median age was 67 years (23 – 80). The two most frequent histologies were undifferentiated pleiomorphic liposarcoma (n=9) and leiomyosarcoma (n=7). The median number of previous lines of treatment was 2 (range 1-5). The most frequent adverse events were: grade 1/2 fatigue (86.7%), nausea (66.7%) and anemia (66.7%). 24 pts were eligible and assessable for efficacy. Best objective response as per RECIST based on central review was: partial response for 2 (8.3%), stable disease for 9 (37.5%) and progressive disease for 13 pts (54.2%) respectively. 3 pts (12.5% IC95% [2.7%; 32.4%]) were progression-free at 6 months indicating that the first endpoint was not reached. Median progression-free survival and overall survival were 1.9 months (95% CI: [1.7; 4.4]) and 12.0 months (95% CI: [5.8; -]), respectively. RNA sequencing of paired biopsies indicated that patients with activation immune response and Th17 differentiation had a better outcome. Increase in CD8 T cell density was significantly associated with improved PFS. No impact of trabectedin on macrophage infiltration was observed. We report the first clinical study investigating the immunological activity of trabectedin in patients with advanced STS. Modulation of TME under trabectedin appear to be correlated with outcome.