Data from Monitoring sarcoma response to immune checkpoint inhibition and local cryotherapy with circulating tumor DNA analysis

Abstract

<div>Abstract<p>Purpose: Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STSs), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STSs. Experimental Design: We enrolled 30 patients with unresectable or metastatic STS to a phase 2 clinical trial. Patients received ipilimumab and nivolumab for 4 doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle. Results: ctDNA was detected in at least one sample for 96% of patients. Pre-treatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pre-treatment to post-cryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed. Conclusions: ctDNA represents a promising biomarker for monitoring response to treatment in advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STSs to immunotherapy.</p></div>