Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).

Abstract

11505 Background: is a randomized, phase II non-comparative trial evaluating the efficacy of neoadjuvant checkpoint blockade [nivolumab (N) or ipilimumab/ nivolumab (I/N)] in patients (pts) with surgically resectable retroperitoneal DDLPS or extremity/truncal UPS treated with concurrent neoadjuvant radiation therapy (RT, UPS only). Methods: Primary endpoint was pathologic (path) response. Secondary endpoints were safety, RECIST response, recurrence-free survival, overall survival and patient-reported outcomes. Biospecimens (tumor, blood, fecal microbiome) at baseline, on therapy, and at time of surgery were collected and will be assessed for immune-based prognostic biomarkers. We assessed correlation between radiographic and pathologic response by linear regression. Correlative analyses includes assessment of tumor PD-L1 expression, characterization of tumor immune infiltrates by multiplex immunohistochemistry, and transcriptomic and genomic analyses. Results: Of the 25 pts enrolled; 24 are evaluable for response (14 DDLPS, 9 UPS). Clinical activity was variable by histologic subtype and treatment with RT. Median path response in the UPS cohort was 95% [95% CI 85–99] and was similar between the N/RT and I/N/RT groups (Table). Median path response in the DDLPS cohort was 22.5% [95% CI 85–99; Table]. Median change in tumor size (radiographic response) was -4% and +9% in the UPS and DDLPS cohorts, respectively. There was no correlation between path response and radiographic response (R2 0.0309; p = 0.43). Of 8 pts with path response ≥ 85%, there was 1 partial response, 5 stable disease and 2 progressive disease by RECIST criteria. There was 1 delay to surgery due to grade 3 hyperbilirubinemia (Arm B). There was no difference in toxicity between N/RT and I/N/RT. Conclusions: N/RT and I/N/RT have significant clinical activity in UPS; more than expected compared to historic controls. Toxicity profiles were as expected and the majority of patients underwent resection without delay. Larger studies evaluating N/RT in UPS are warranted given the significant path response in this cohort. RECIST was not associated with path response and better markers of on-treatment clinical activity are needed. Correlative analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT03307616 .

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma

“…Therapeutic options, however, are limited, and in a recent trial, a histology-tailored regimen was inferior to standard chemotherapy with epirubicin and ifosfamide [2]. Immunotherapy, which has been successfully introduced for several cancers, might be an option to individualise therapy of sarcoma patients [3].…”

Immunotherapy for sarcomas: new frontiers and unveiled opportunities

“… 27 Preliminary results from 24 evaluable patients (9 UPS and 14 LPS) show a median pathological response of 95% in the UPS cohort and 22.5% in the LPS cohort. 28 This study is still recruiting and will also include transcriptome, immune and microbiome profiling, which will provide much needed information about the immune response in sarcoma and the molecular mechanisms that promote/hinder the response to ICB in UPS and LPS. 26 So far, these highlighted studies show that UPS and LPS are responsive to ICB.…”

Recent advances in the understanding and management of liposarcoma

“…Two prospective trials currently underway include SARC032 54 , a RCT investigating the role of neoadjuvant pembrolizumab in addition to preoperative radiation therapy and resection for patients with DDLPS and UPS, and a phase II noncomparative randomized trial investigating the effect of neoadjuvant nivolumab and ipilimumab/nivolumab on pathologic response in patients with UPS and RP DDLPS undergoing preoperative radiation therapy and surgery 55 . Preliminary results suggest limited activity in DDLPS 56 . In the metastatic setting, nivolumab and nivolumab/ipilimumab exhibited modest activity with a median PFS of 4.6 and 5.5 months, respectively.…”