Immunotherapy: Immune Checkpoint Inhibitors
Immunotherapy has been one of the major breakthroughs in oncology. As for STS, the efficacy remains controversial. Of all the pathway discovered, PD-1/PD-L1 axis seems to attract the most attentions. Tumor PD-L1 expression has been reported in up to 65% of different subtypes of sarcomas and the degree of PD-1 positivity in tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor specimens from 105 cases of STS, has been correlated with a poorer prognosis and more aggressive disease.[69,70] Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody which has been found that it could exert an antitumor effect in metastatic sarcomas. In a retrospective study, a total of 28 patients with a metastatic or unresectable soft tissue or bone sarcoma received nivolumab 3 mg/kg IV every 2 weeks alone (N=10) or in combination with pazopanib (N=18). Among 24 evaluable patients, 12 patients had clinical benefit (PR + SD), 12 had progressive disease (PD). They observed three PR: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had SD including three LMS; 12 patients had progression of disease including 4 LMS.
Ipilimumab is a monoclonal antibody targeting CTLA-4 which seemed to have a very minimal effect when used alone against sarcomas. A multicenter, open-label, randomised, phase 2 study of nivolumab with or without ipilimumab aimed to investigate its activity and safety for the treatment of sarcoma. Enrolled patients were assigned (1:1) to nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. The primary endpoint was the proportion of patients achieving a confirmed objective response. Eight-five eligible patients were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done in the first 76 eligible patients (38 patients per group). The number of confirmed responses was 2 (5%) in the nivolumab group and 6 (16%) in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in 8 (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy. There were no treatment-related deaths. This trial indicated that the efficacy is much limited for nivolumab alone in an unselected sarcoma population, while nivolumab combined with ipilimumab demonstrated promising efficacy with a manageable toxicity in certain sarcoma subtypes, such as UPS, myxofibrosarcoma as well as LMS and angiosarcoma.
In the SARC028 phase 2 study, 40 patients with high grade, metastatic STS and 40 patients with bone sarcomas (osteosarcoma, Ewing's sarcoma, and dedifferentiated chondrosarcoma) were enrolled to receive pembrolizumab alone every three weeks until progression. Overall 11 of the 40 patients with STS had their tumors shrink while only three patients with bone sarcomas had tumor shrinkage. Eleven responding patients in the STS arm included four patients with UPS, 5 dedifferentiated liposarcoma (dLPS), 1 with synovial sarcoma and 1 with LMS. The patients with response in bone tumors included one patient with Ewing's sarcoma, one with osteosarcoma, and one with dedifferentiated chondrosarcoma. Pembrolizumab as a single agent showed activity in unselected sarcoma subtypes with an ORR of 17.5% and a 55% 3-month PFS; UPS and DDLS were the histologies that seemed to benefit the most.
Compared with SARC028 study, another investigation enrolled 57advanced STS patients [15 LMS, 16 UPS, 10 gastrointestinal stromal tumors (GIST) and 16 others] who received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of IV pembrolizumab every 3 weeks. The exploration indicated that 31 patients (10, LMS; 7, UPS; 8, others; and 6, GIST) with PD and 16 patients (3, LMS; 5, UPS; 5, others; and 3, GIST) with SD, 3 patients (1 patient with a STF, 1 with an endometrial stromal sarcoma, and 1 with a GIST) with progression free for 6 months. One objective response was observed in a patient with initially progressive SFT. The 6-months non-progression rate was 0%, 0%, 14.3% and 11.1% for LMS, UPS, other and GIST, respectively. Further study found that the unique PR patient with SFT bearing more than 10% PD-L1-positive immune cells and the tumor had mild IDO-1 (indoleamine 2,3-dioxygenase 1) positive immune cells, a lower CD68 positive cell density and a higher CD8-positive cell density. These findings may help us to further explore the mechanism of checkpoint inhibitors in STS.
The value of immunotherapy in STS is still largely unexplored. Further research focus on better patient selection and to investigate new combinatorial strategies.
Chin Clin Oncol. 2018;7(4) © 2018 AME Publishing Company