Randomized phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS): Survival results after 2 years of follow-up and intratumoral B-cell receptor (BCR) correlates.
Authors: Keung Emily Zhi-Yun , Nassif Elise F , Lin Heather Y. , Lazar Alexander J. , Torres Keila E , Wang Wei-Lien , Guadagnolo Beverly Ashleigh , Bishop Andrew Justin , Hunt Kelly , Feig Barry W. , Bird Justin E. , Lewis Valerae O. , Ratan Ravin , Patel Shreyaskumar , Zelazowska Monika , Liu Bin , McBride Kevin , Wargo Jennifer Ann , Roland Christina Lynn , Somaiah Neeta 
Published: June 2022

LBA11501 Background: We conducted a randomized, phase II non-comparative trial evaluating the efficacy of neoadjuvant ICB [nivolumab or ipilimumab/nivolumab] in patients (pts) with surgically resectable retroperitoneal DDLPS or extremity/truncal UPS treated with concurrent neoadjuvant radiation therapy (XRT, UPS only). Methods: As of February 28 2022, all pts have a minimum follow-up of 2 years from the start of ICB treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan Meier method. The association of pathologic response (percent hyalinization and viable tumor at surgery) with PFS and OS was assessed using Cox univariate models. Comparison of survival curves was done by log-rank method. The intratumoral BCR repertoire was evaluated by bulk tumor RNA sequencing with TRUST4 algorithm, on biopsy specimens collected at baseline. Description of the intratumoral BCR repertoire included diversity by inverse Simpson index, and clonal distribution by Gini coefficient. High and low categories were defined by median values. Results: At a median follow-up of 31 months (interquartile range [IQR]=27-43) since start of ICB treatment, the median PFS was not reached (NR) in UPS (IQR=19-NR) and 18 months for DDLPS (IQR=8-NR), with 13 pts experiencing relapse (2 UPS, 11 DDLPS) and 2 pts who had progressive metastatic disease on treatment (1 UPS, 1 DDLPS). Five pts died of disease relapse (1 UPS, 4 DDLPS) and the median OS was NR. There was no association between percent hyalinization at surgery and PFS (Hazard Ratio [HR]=0.98, p=0.12) or OS (HR=0.99, p=0.60) nor between percent viable tumor at surgery and PFS (HR=1.00, p=0.62) or OS (HR=1.00, p=0.67). There was no association between RECIST response and PFS (p=0.67) or OS (p=0.67). The median BCR heavy chain (IgH) clonal counts detected at baseline was 2,536 per sample (IQR=82-7,680), and the median BCR light chain (IgL) clonal count was 8,870 per sample (IQR=306-30,214). Pts with higher intratumoral BCR clonality and diversity at baseline tended to have longer PFS (Table). High BCR IgH clonality was significantly associated with OS (p=0.02) with consistent trends in each histotype (DDLPS: p=0.06; UPS: p=0.25). Conclusions: Survival results demonstrate efficacy of ICB with XRT in UPS but there is a crucial need to define better predictive markers of survival after neoadjuvant therapy. Further characterization of the BCR repertoire is ongoing and will be presented at the meeting. Clinical trial information: NCT03307616. [Table: see text]