Blockade of VEGFR and PD-L1 Inhibits Alveolar Soft-Part Sarcoma

[D.ap]

Alveolar soft-part sarcoma (ASPS) typically arises from aberrant upregulation of HIF1α and VEGF and is inherently resistant to chemotherapy. VEGF has been shown to promote tumor angiogenesis and suppress immune responses within the tumor microenvironment, limiting the efficacy of immune checkpoint inhibitors. Previous studies in melanoma and renal cell carcinoma have demonstrated the efficacy of combined inhibition of VEGF signaling and immune checkpoint inhibitors. To evaluate such an approach in sarcoma, Wilky and colleagues conducted a phase II clinical trial in 33 patients with advanced or metastatic sarcomas in which patients received the VEGF receptor tyrosine kinase inhibitor axitinib in combination with the anti–PD-1 inhibitor pembrolizumab. The primary endpoint was 3-month progression-free survival (PFS), and secondary endpoints were incidence of treatment-related adverse events, objective response, clinical benefit, time to progression, and overall survival. For all patients, 3-month progression-free survival was 65.6% (95% CI 46.6–79.3), with a median overall survival of 18.7 months; specifically, 3-month PFS was 72.7% (95% CI 37.1–90.3) in patients with ASPS (n = 12) and 61.9% (95% CI 38.1–78.8) in patients with non-ASPS sarcoma (n = 21). Grade 3 or 4 treatment-related adverse events included hypertension, autoimmune toxicities, and seizures. Serious adverse events included autoimmune colitis, pneumothorax, seizures, and hypertriglyceridemia. The median duration of response and time to achieve a partial response was 29 weeks and 19.4 weeks, respectively. Clinical benefit was observed in 53.1% (n = 17; 95% CI 35–70.5) of patients, with eight patients achieving partial response and nine patients achieving stable disease; the majority of partial responses occurred in patients with ASPS. Further, PD-L1 positivity was observed in all 9 ASPS biopsies and 6 of 20 (30%) non-ASPS sarcoma biopsies, and most ASPS exhibited high levels of tumor-infiltrating lymphocytes. Taken together, these results show that, in patients with sarcoma, axitinib plus pembrolizumab is most effective in patients with ASPS, thus warranting additional evaluation of this treatment regimen.

https://aacrjournals.org/cancerdiscover ... eolar-Soft