Activity of PD-1 Inhibitor Limited in Soft-Tissue Sarcomas

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 Bergonié, 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.