Treatment with the PD-1 inhibitor pembrolizumab plus metronomic cyclophosphamide had limited activity in patients with soft-tissue sarcomas and gastrointestinal stromal tumors.
Treatment with the PD-1 inhibitor pembrolizumab plus metronomic cyclophosphamide had limited activity in patients with soft-tissue sarcomas and gastrointestinal stromal tumors (GIST), according to the results of a phase II study published in JAMA Oncology.
Only 3 of 50 patients assessed for efficacy had any tumor shrinkage. Tumor sample analyses showed strong infiltration by M2 macrophages expressing the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO).
“Given the importance of macrophage infiltration and the IDO1/kynurenine pathway in patients with soft-tissue sarcomas, further strategies are warranted to assess the combination of [anti–PD-1/PD-L1] with colony-stimulating factor 1 receptor inhibitors and/or IDO inhibitors in patients with selected sarcoma subtypes,” wrote researcher Maud Toulmonde, MD, of the department of medical oncology, Institut BergoniÃ©, Bordeaux, France, and colleagues.
The study enrolled 57 patients with advanced soft-tissue sarcoma and assigned them treatment with 50 mg twice daily cyclophosphamide for 1 week on and 1 week off plus 200 mg of pembrolizumab every 3 weeks.
Three patients had tumor shrinkage at 6 months, including one with a partial response in a single solitary fibrous tumor. Thirty-one patients had stable disease.
Patients in the study had sarcomas including leiomyosarcoma, undifferentiated pleomorphic sarcoma, other sarcomas, and GIST. Six-month non-progression rates were 0% for leiomyosarcoma, 0% for undifferentiated pleomorphic sarcoma, 14.3% for others, and 11.1% for GIST.
PD-L1 expression of 1% or greater was observed in tumor cells of 12% of patients and in immune cells of 40% of patients. The patient with the partial response was the only patient with PD-L1 expression of 10% or greater.
“Furthermore, this patient’s tumor had mild IDO1-positive immune cells, a CD68-positive cell density below the median (0.57 cells/mm2), and a very high CD8-positive cell density (439 cells/mm2),” the researchers wrote.
They also observed that a high proportion of patients were prominently infiltrated by CD153-positive macrophages that favor the M2 phenotype known to play a role in immune suppression. In addition, these tumor-associated macrophages expressed IDO1. According to the researchers, “this suggests that this pathway could preferentially contribute to the immune-suppressive phenotype of these cells and could be an important mechanism of the primary resistance to PD-1 inhibition observed in this study.”
The most common adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. Grade 3/4 events were rare and mainly included fatigue, oral mucositis, and anemia.