Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis

Background: Soft-tissue sarcomas (STSs) are rare malignancies, accounting for approximately 1% of adult cancer. Metastatic disease carries a poor prognosis, and various efforts have been made to improve the prognosis of advanced STS, to date with little success. Immune checkpoint inhibitors (ICPIs) have substantially improved prognosis for many cancer types. Their role in the treatment of STS, however, remains unravelled.

Objective: The objective of the study is to assess the activity of ICPIs in the treatment of STS.

Methods: We performed a systematic review using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Furthermore, abstracts from European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and Connective Tissue Society Oncology (CTOS) congress were searched from 2017 until 2020. Prospective clinical trials investigating ICPIs, either monotherapy or combination therapy, in STS were available for inclusion. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and major toxicity. Cut-off for clinical activity was defined as an ORR of ≥0.15. Subgroup analysis was carried out as per treatment category, disease setting and histologic subtype, using a random effects model.

Results: We identified 27 studies, including a total of 1012 patients (range 6-85) with more than 25 histologic subtypes. The pooled ORR was 0.14 (95% confidence interval [CI] 0.09-0.18), DCR was 0.55 (95% CI 0.43-0.66), mean PFS range was 1.8-11.5 months and mean OS was 6.1-34.7 months. The pooled ORR as per treatment category was 0.14 for anti-programmed cell death 1 (anti-PD1) monotherapy (95% CI 0.07-0.23), 0.16 for anti-PD1 + anti-cytotoxic T-lymphocyte-associated protein 4 (95% CI 0.06-0.29), 0.20 for anti-PD1 + tyrosine kinase inhibitor (95% CI 0.06-0.38), 0.20 for anti-PD1 + chemo (95% CI 0.06-0.38) and 0.08 for anti-PD1 + immunomodulator (95% CI 0.01-0.19). The pooled ORR as per disease setting was as follows: neoadjuvant treatment, 0.09 (0.00-0.25); advanced disease first line, 0.23 (0.15-0.32) and advanced pretreated, 0.13 (0.09-0.19). High response rates were seen in classic Kaposi sarcoma (CKS), alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (UPS) with ORR of 0.69 (95% CI 0.51-0.82), 0.35 (95% CI 0.27-0.44) and 0.20 (95% CI 0.15-0.27), respectively. Activity was limited in gastrointestinal stromal tumour (ORR 0.01 [95% CI 0.0-0.08]), uterine leiomyosarcoma (ORR 0.06 [95% CI 0.02-0.18]), leiomyosarcoma (ORR 0.10 [95% CI 0.06-0.17]) and liposarcoma (ORR 0.11 [95% CI 0.07-0.17]).

Conclusion: Clinical activity of ICPIs in STS is highly variable and depends on histologic subtype, disease setting and concomitant treatment strategy. Activity was high in CKS, ASPS and UPS. Early incorporation of ICPIs in combination with chemotherapy seems a promising strategy that warrants further interest. Translational research integrating molecular profile, biological behaviour and response to ICPIs should determine their role in treatment of STS.