Comprehensive molecular analysis of phase IB/II trial of durvalumab plus doxorubicin combination in patients with advanced soft-tissue sarcoma.

Abstract

11555 Background: We conducted an open-label, phase IB/II study to determine the activity and safety of the standard-of-care, doxorubicin in combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in patients with anthracycline-naïve soft tissue sarcoma (STS) and identified patients who would likely benefit from combination treatment. Methods: In this phase IB/II trial (NCT03798106), we enrolled patients with metastatic and/or recurrent STS had not received anthracycline chemotherapy and PD-L1/PD-1 inhibitor. Tumor biopsies were obtained from all patients prior to treatment for targeted sequencing, RNA sequencing, and Opal multiplexed immunofluorescence staining. Results: No DLTs were observed during the phase II and recommended phase II dose was defined at doses of 75/m 2 doxorubicin and proceed the phase II part. Of 41 evaluable patients, an objective response rate of 31.7% and the median progression free survival was 8.2 months (95% CI, 7.3-9.0) and median overall survival was 24.1 months (95% CI, 7.6-40.3). In the prespecified genomic analysis, using a multivariate Cox proportional regression model with clinical factors in combined with PD-1 cell density and signaling pathways, genetic alterations in RTK/RAS (HR 6.446, [95 % CI, 1.934-21.486]; P=0.002) and PD-1 density (HR 0.214, [95 % CI, 0.071=0.649]; P=0.006) were identified as the independent predictors of PFS . High PD-1 tumors without RTK/RAS pathway alteration had longer PFS (16.9 months) than the others (7.4 months for RTK/RAS alteration or PD-1 high, 1.0 months for RTK/RAS pathway alteration and PD-1 low group, P<0.001). In the gene set analysis, antigen processing and presentation, interferon alpha response, and interferon gamma response showed significantly higher scores in PD1 high without RTK/RAS pathway alteration. Conclusions: Durvalumab combined with doxorubicin demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. In exploratory correlative analysis, we identified potential role of RTK/RAS signaling and PD-1 expression as independent predictors for the efficacy, although further investigations are needed. Clinical trial information: NCT03798106 .