Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis

Abstract

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS).Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria.Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups.Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.

Efficacy and safety of angiogenesis inhibitors plus immune checkpoint inhibitors in advanced soft tissue sarcoma: a real-world, single-center study

“…The SARC028 study reported 20% (2/10) ORR to pembrolizumab monotherapy in patients with DDLPS 4 . Correlative analyses of the SARC028 trial revealed an association between immune infiltrate and response to pembrolizumab in DDLPS 18 . In a retrospective study from China, 36.3% (4/11) of patients with DDLPS showed an objective response to AIs plus ICIs combination therapy 19 .…”

Retrospective Review of Efficacy and Safety of Anlotinib in Advanced Leiomyosarcoma: A Real-World Study

“… 26 Anlotinib combined with pd-1 antibody also reported in STSs recently. In a single-center retrospective analysis, 27 61 advanced STS patients were treated with ICIs alone or combined with TKIs, the median PFS was significantly prolonged after ICI treatment in combination with TKIs (11.74 months) compared to ICI treatment alone (6.81 months), with a 12-month PFS rate of 42.9% and overall response rate of 30% in ICI-TKI combination group. We speculate that anlotinib combined with pd-1 inhibitors can play a synergistic role in the treatment of LMS, which still needs to be confirmed by relevant clinical and basic studies.…”

Efficacy of PD-1 inhibitors combined with pegylated liposomal doxorubicin and dacarbazine compared with liposomal doxorubicin and dacarbazine in advanced leiomyosarcoma patients: a retrospective, single-institutional cohort study

“…Only 1 PR and 1 minor response (decrease in the size of the target lesion of less than 30%) were observed in these 6 patients ( 15 ). A retrospective study, which included 20 LMS patients among 61 who received PD-1 and TKIs, suggested that LMS patients had the lowest response rate compared with other subtypes, and rapid progression could occur if PD-1 monotherapy was administered ( 16 ). As for PD-1 combination chemotherapy, a phase II study recruiting 15 LMS patients among 57 patients who received intravenous pembrolizumab and oral cyclophosphamide reported that the 6-month non-progression rate was 0% for LMS, but we considered the efficacy of this result limited as oral cyclophosphamide is not a standard regimen for LMS ( 17 ).…”