(P 348) EVALUATING THE IMPACT OF BIOLOGICAL EFFECTIVE DOSE AND DELAYED RADIOTHERAPY ON THE SYNERGISTIC EFFICACY OF TRABECTEDIN IN METASTATIC SOFT TISSUE SARCOMA PATIENTS

Objective: Trabectedin has cytotoxic and radiosensitizing activity as demonstrated in the TRASTS study (Martin-Brodo et al. 2022). However, how could other potential determinants of radiotherapy (RT), such as biological effective dose (BED) (using an alpha/beta ratio of 10) and the interval between trabectedin and RT, influence the outcome of the combination treatment, especially those with large tumor size, remains uncertain.

Methods: A retrospective analysis selected sarcoma patients treated with trabectedin in combination with RT. Because of the real-world setting of this study, we pragmatically define “combination” as RT initiated either during the course of trabectedin treatment or within one month of the start or end of the last trabectedin administration, including patients who received “delayed” RT after few cycles of trabectedin. Tumor sizes and BED values were recorded prior to treatment. The objective response rate (ORR) of the irradiate lesion was assessed using RECIST 1.1. Overall survival was estimated from the start date of radiotherapy to either death or the last follow-up date and the impact of prognostic factors were evaluated using Cox proportional hazard model.

Results: A total of 28 lesions (22 patients, F:M 14:8, median age 51.5, range 34-66) were treated with the combination of trabectedin plus radiotherapy. Histological subtypes by lesion included leiomyosarcoma (n = 15), phyllodes tumor (n = 4), dedifferentiated liposarcoma (n = 3), myxoid round cell liposarcoma (n = 2), and others (n = 4). The most common irradiated anatomical region was the intra-abdominopelvic area (10, 36%) followed by the lungs (8, 29%). The median size of irradiated tumor was 9.29 cm (range 4.10 – 22.54 cm), 46% (13/28) of the lesions were larger than 10 cm. The details of the fractionations and total dose of radiation received for each lesion is shown in Table 1. Among the 28 irradiated lesions, progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR) was seen in 1, 14, 9, and 4 lesions, respectively (Waterfall plot, Figure 1). The overall ORR was 46.3% (95% CI 0.27-0.66). Lesions receiving a BED > 50 Gy (n = 12) had an ORR of 75% (95% CI 0.43-0.95) as compared to the ORR of 25% (95% CI 0.07- 0.52) of lesions receiving a BED ≤ 50 Gy (Odds ratio for ORR 9.0, p = 0.012). For lesions > 10 cm, BED > 50Gy and ≤50 Gy yielded an ORR of 100% (2/2) and 27% (3/11), respectively. For 10 patients, the start of radiotherapy was delayed after more than 2 cycles after trabectedin treatment (median time from trabectedin start to RT start 75 days, range 50-296 days), but 40% (4/10) of lesions showed responsiveness (CR 1, PR 3). The median OS was 9.4 months (95% CI 3.63 – NA). Having a PR or CR after the RT is associated with longer OS (Figure 2, log-rank p = 0.033). The details of the duration of control of each lesion will be reported at CTOS.

Conclusion: Our study demonstrated that the trabectedin could be combined with BED > 50 Gy RT with potent efficacy including large-sized (> 10 cm) metastatic lesions. Real-world data also supports that synergistic activity could be maintained when RT was given after patients have received trabectedin for two or more cycles.