1527MO - Biomarkers of response and hyperprogression in patients with sarcoma treated with checkpoint blockade

Background

Checkpoint blockade with antibodies against PD-1 can mediate objective responses in selected sarcomas. There are few established predictors of response, and the incidence of hyperprogressive disease (HPD) is unknown.

Methods

We reviewed our experience treating sarcoma patients on prospective trials (RECIST v1.1) with nivolumab or pembrolizumab as monotherapy or combined with bempegaldesleukin, epacadostat, ipilimumab or Talimogene laherparepvec. HPD was an increased tumor growth rate of 50% or more post-treatment relative to pre-treatment (Ferrara et al. 2018 JAMA Oncol.) We evaluated clinical and biological predictors of response and HPD including whole exome and RNA sequencing from baseline tumor biopsies to measure tumor mutational burden (TMB), fraction genome altered (FGA) and gene set enrichment analysis (GSEA).

Results

134 patients with sarcoma received treatment from 2015 – 2019. Follow-up was 33 months, outcomes are in the table. One (3%) of 31 patients with liver metastases responded vs 8 (42%) of 19 with lymph node metastases (P < 0.001). ORR in lung, bone or other sites was 12-15%. Disease burden before CR/PR, SD, PD and HPD was 62 mm, 110 mm, 104 mm and 59 mm, respectively (CR/PR vs SD, P < 0.01; PD vs HPD, P = 0.035). Demographics, subtype, and outcomes of patients with PD and HPD were similar. TMB was similar across response groups; FGA was higher in responders. No genomic alterations associated with HPD and no relevant GSEA pathways were upregulated in HPD vs PD. Table: 1527MO

Conclusions

This study of patients with sarcoma treated with PD-1 blockade demonstrates an ORR of 16%. Low disease burden was associated with response. Patients with liver metastases were less likely to respond while those with nodal metastases were more likely. The incidence of HPD in sarcoma is comparable to other solid tumors, but we did not detect clinical or biological differences between PD and HPD tumors except disease burden at baseline. HPD does occur in sarcoma but its clinical significance remains uncertain.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C.M. Kelly: Financial Interests, Personal, Funding: Amgen; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Agios; Financial Interests, Personal, Funding: Exicure; Financial Interests, Personal, Funding: Kartos; Financial Interests, Personal, Funding: Xencor; Financial Interests, Personal, Advisory Role: Exicure; Non-Financial Interests, Personal, Other, Family member employed: Daiichi Sankyo. S. Movva: Financial Interests, Institutional, Funding: Hutchinson Medipharma; Financial Interests, Institutional, Funding: Ascentage Pharma. B. Nacev: Non-Financial Interests, Personal, Other, Uncompensated provision of services: Delphi Diagnostics; Non-Financial Interests, Personal, Other, Uncompensated provision of services: QuadW Foundation; Non-Financial Interests, Personal, Other, Uncompensated provision of services: Rapafusyn Pharmaceuticals. J.E. Chan: Financial Interests, Personal, Royalties: WebMD; Financial Interests, Personal, Research Grant: Cytek Biosciences. S.P. D'Angelo: Financial Interests, Personal, Advisory Role, Also, travel/accommodations and research funding for MSKCC: EMD Serono; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Amgen; Financial Interests, Personal, Advisory Role, Also, travel/accommodations and research funding for MSKCC: Nektar; Financial Interests, Personal, Advisory Role: Immune design; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Incyte; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Merck; Financial Interests, Personal, Advisory Role, Also, travel and accommodations: Adaptimmune; Financial Interests, Personal, Advisory Role: Immunocore; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: Deciphera. All other authors have declared no conflicts of interest.