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Abstract: The role of the programmed death-1 (PD-1) signaling pathway in tumor immunotherapy is becoming increasingly important, and several PD-1-blocking agents have been approved by the US Food and Drug Administration. PD-1-blocking therapy alone or in combination with other therapeutic modalities has become a standard treatment for several kinds of solid tumors. However, sarcomas are not indications for anti-PD-1 therapy. Sarcomas are a group of heterogeneous diseases that can currently only be cured by surgery at the early stage. No effective treatments exist for sarcoma patients in advanced stages. Owning to the diversity of sarcomas, it is very difficult to conduct randomized controlled clinical studies on specific subtypes of sarcomas. Although clinical studies of sarcomas continue, few breakthroughs in the treatment of sarcomas have been achieved over the past decades. This review summarizes recent progress in anti-PD-1 therapy for sarcomas. Based on the published data, PD-1 blockade may be more effective in combination with other modalities for the treatment of sarcomas. In addition, biomarkers may be used to ascertain sensitivity to PD-1 blockade in sarcoma patients.
Keywords: PD-1 blockade, immunotherapy, sarcoma
INTRODUCTION
Sarcomas are a heterogeneous group of malignancies derived from mesenchymal tissue and also can arise anywhere of the body with considerably different clinical and pathological features. These malignancies are broadly classified as soft tissue sarcomas (STS) or bone sarcomas and account for about 1% of all malignancies in adults and 15% in children; sarcoma is the third leading cause of cancer-related death among children and adolescents.1 Surgical resection en bloc is the mainstay treatment for primary-localized diseases, and the 5-year recurrence-free survival rate is about 60%.2 In patients with distant metastasis, the 5-year survival rate is below 20%.3 Therefore, new treatment options for recurrent/metastatic sarcoma are urgently needed.
Immunological checkpoint inhibitors represented by anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) monoclonal antibodies (MoAb) have shown promising clinical efficacy for various malignancies and predicted the age of cancer immunotherapy. However, the rarity of sarcomas and variances in the disease, with over 50 histological subtypes, limit the performance of randomized controlled clinical studies. Therefore, data related to PD-1 blockade for the treatment of sarcomas are lacking. Herein, we summarized the latest advancements in the treatment of sarcomas with PD-1 blockade and the possible biomarkers that might predict the efficacy of anti-PD-1 therapy for sarcomas.
PD-1 BLOCKADE IN RECURRENT/METASTATIC SARCOMA
Nivolumab is an anti-PD-1 fully human immunoglobulin (Ig)G4 MoAb that has shown broad antitumor activity by binding with PD-1 specifically.4–7 A retrospective study of 10 patients with advanced sarcoma who were treated with nivolumab alone showed that partial remission was achieved in one patient, and stable disease was achieved in four patients; however, progressive disease was observed in five patients.7 Thereafter, studies on PD-1 blockade and sarcomas were reported sporadically.8–11 Alliance A091401 is a prospective study comparing the clinical efficacy of nivolumab alone or in combination with ipilimumab in patients with metastatic sarcomas. Of the 76 eligible patients (38 patients in each group), a confirmed response was achieved in two patients in the nivolumab group and six in the nivolumab plus ipilimumab group. In the nivolumab group, 29 patients had progressive disease at the first evaluation, of whom 18 were eligible for continuing nivolumab treatment. Eleven of these 18 patients were confirmed to have progressive disease after 1 month of treatment, and 7 continued nivolumab therapy for 2–8.5 months. In the nivolumab plus ipilimumab group, 18 patients had progressive disease at the first evaluation, of whom 8 were eligible for continuing combination therapy. Three of the eight patients had progressive disease at the time of confirmation, and the other five patients had a stable disease at the time of confirmation and continued to receive combined therapy for another 3–12 months. Interestingly, one patient receiving combined therapy exhibited a partial response within 3 months of initial progressive disease, which is in accordance with so-called pseudo-progression.12 The median progression-free survival (PFS) was 4.1 months and the median OS was 14.3 months, as to the patients received combination therapy, the 12-month OS rate was 54.6%. Of course, the occurrence of grade 3–4 treatment-related adverse events was higher in patients received combination therapy (14% vs 7%).12 This study indicated that the efficacy of nivolumab alone in patients with unselected sarcomas is limited but might be improved by other immunomodulatory agents. The Phase 2 study of nivolumab in patients with uterine leiomyosarcoma likewise demonstrated the limited efficacy of nivolumab monotherapy; no confirmed response was observed in the 12 patients enrolled in this study.4 However, this study indicated that the histopathological type might be a factor influencing the efficacy of PD-1 blockade, and therefore it is necessary to verify the efficacy of PD-1 blockade in different histopathological subgroups.
Pembrolizumab, another anti-PD-1 humanized IgG4 MoAb, displays antitumor activity in many kinds of solid tumors, including sarcomas.9,10,13–15 SARC028 is a multicenter Phase 2 study designed to estimate the clinical efficacy of pembrolizumab in patients with advanced sarcomas. During the 80 patients eligible for efficacy evaluation, 18% (7/40) of 40 patients with STS displayed an objective response, including 4 of 10 patients with undifferentiated pleomorphic sarcoma (UPS), 2 of 10 patients with liposarcoma, and 1 of 10 patients with synovial sarcoma. No patients with leiomyosarcoma had an objective response. Five percent (2/40) of patients with bone sarcoma had an objective response, including 1 of 22 patients with osteosarcoma and 1 of 5 patients with chondrosarcoma; none of the 13 patients with Ewing’s sarcoma had an objective response. The median PFS was 18 weeks in patients with STS and 8 weeks in patients with bone sarcomas, and severe adverse events occurred in 11% of the patients.13 The results of SARC028 demonstrated promising activity in UPS, suggesting that patients with this subtype of sarcoma might benefit more from pembrolizumab. For patients with other subtypes of sarcomas, the better choice might be PD-1 blockade-combined regimen.
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