(P 143) EARLY ASSESSMENT OF DISEASE RESPONSE TO IMMUNOTHERAPY VIA CIRCULATING TUMOR DNA IN ADVANCED SOFT TISSUE SARCOMAS

Objective: It remains unclear if declines in ctDNA could be a potential biomarker for treatment response and survival outcome in advanced soft tissue sarcomas (STS).

Methods: This study includes patients who received immune checkpoint inhibitor therapy at Stanford Sarcoma Center between May 2021 and March 2024. ctDNA was tested with Natera’s CLIA lab using a personalized, tumor-informed ctDNA assay (SignateraTM, bespoke mPCR, NGS assay). We correlated longitudinal changes in ctDNA levels with radiographic imaging results (CT or MRI) and survival outcomes. ctDNA response was defined as a >50% decrease in mean tumor molecules per mL from baseline, with a second confirmatory measurement. Radiographic response was defined as stable disease or partial response. Overall survival (OS) was defined as time from initiation of immunotherapy to death or last clinical follow up; progression-free survival (PFS) was defined as time from initiation of immunotherapy to disease progression by imaging or clinical status, death, or last clinical follow up.

Results: A total of 21 patients (median age at diagnosis 53 years [range 22 – 72], 62% female, 38% Caucasian, 33% Asian, 24% Hispanic/Latino, 5% Black) were included in this study. Tumor histological subtypes consisted of leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (n = 4), dedifferentiated liposarcoma (n = 2), malignant perivascular epithelial cell tumor (n = 1), angiosarcoma (n = 1), clear cell sarcoma of soft parts (n = 1), malignant peripheral nerve sheath tumor (n = 1), chondrosarcoma (n = 1), solitary fibrous tumor (n = 1), malignant phyllodes tumor (n = 1), myxofibrosarcoma (n = 1), and uterine adenosarcoma (n = 1). Median tumor mutational burden (TMB) was 1 mutations/megabase (mut/mb) (range < 1 [not quantified] – 3 mut/mb). Before immunotherapy, patients received a median of two prior lines of therapy (range 0 – 4). Immunotherapy consisted of ipilimumab/nivolumab (n = 19), pembrolizumab (n = 4), and anti-PD-1 clinical trial drug (n = 1). Five patients received two lines of immunotherapy (pembrolizumab followed by ipilimumab/nivolumab [n = 4] and anti-PD-1 clinical trial drug followed by ipilimumab/nivolumab [n = 1]). Other systemic therapies used concurrently with immunotherapy were cabozantinib (n = 6), temozolomide (n = 2), pazopanib (n = 2), palbociclib (n = 2), gemcitabine (n = 1), ivosidenib (n = 1), and carboplatin/paclitaxel (n = 1). Median follow-up time after initiation of immunotherapy was 19 months (range 2 – 32 months) (Figure 1). Median OS and PFS were 22.8 months (95% CI 10.2 – not reached) and 2.9 months (95% CI 2.3 – 12.8), respectively. Median OS and PFS were significantly longer for ctDNA responders (n = 8) than non-responders (n = 13), p = 0.04 and p = 0.006, respectively. Substantial agreement was observed between ctDNA response and radiographic response (Cohen’s kappa, 0.617). Time on treatment was longer for ctDNA responders vs. non-responders (median 9 vs 4 months; p = 0.0473 by Wilcoxon rank sum test).

Conclusion: Decline in ctDNA demonstrates correlation with radiographic response to immunotherapy and improved survival and could be a potential early biomarker of therapeutic efficacy in advanced soft tissue sarcomas.