SBRT Then Pembrolizumab: Well Tolerated in Metastatic Tumors

February 23, 2018

The significant tumor shrinkage and immunologic changes observed support a complementary role of SBRT and PD-1 immunotherapy, investigators concluded.

Treatment with the immune checkpoint inhibitor pembrolizumab after administration of multisite stereotactic body radiation therapy (SBRT) was well tolerated in an early-phase trial of patients with metastatic solid tumors. Some patients also experienced responses to the treatment.

“An approach to expand the benefit of PD-1 immunotherapy may involve combinations with treatments that induce IFN-associated T-cell inflammation, such as ionizing radiation,” wrote study authors led by Steven J. Chmura, MD, PhD, of the University of Chicago. “Mechanisms facilitating the augmentation of immunotherapy by radiation include increased tumor antigen release, activation of innate immune pathways, increased T-cell infiltration, augment antigen presentation, and modulation of immunosuppressive cells.”

The new study examined the tolerability of following multisite SBRT, which delivers high radiation doses to a small target, with pembrolizumab. Investigators enrolled 79 patients, although 3 of them received no therapy and 3 others received SBRT but not pembrolizumab; the analysis includes 73 patients who were treated with both therapies. The results of the study were published online ahead of print on February 13 in the Journal of Clinical Oncology.

A variety of primary cancer types were represented, including ovarian/fallopian tube cancer (12.3%), non–small-cell lung cancer (9.6%), breast cancer (8.2%), and others; 60.3% of the cohort were female. These were heavily pretreated patients, who had received a median of five prior therapies. Almost all patients (94.5%) had two metastases treated with SBRT; 3 patients (4.1%) had three sites treated and 1 patient (1.3%) had four.

Over a follow-up of 5.5 months for all patients and 7.1 months for living patients, 6 patients experienced severe treatment-related toxicity. This included 3 patients with grade 3 pneumonitis, 2 patients with grade 3 colitis, and 1 patient with grade 3 hepatic toxicity. The dose-limiting toxicity rate was 9.7%, though no patients required a radiation-dose reduction.

Response was evaluable in 68 patients in the study. There was one complete response, along with eight partial responses, for an objective response rate of 13.2%. Another 21 patients had stable disease, and 38 had progressive disease. There was a mean change in tumor diameter of −21.7% for irradiated metastases, and 1.7% for nonirradiated metastases (P = .0008). There were some out-of-field responses as well; when using a response defined as 30% reduction in any single nonirradiated metastasis, the nonirradiated response rate was 26.9%.

The researchers also assessed whether SBRT resulted in favorable immunologic changes based on expression of four interferon gamma–associated genes. They found that increased gene expression was correlated with responses in nonirradiated tumors (P = .023).

“The treatment paradigm was well tolerated, with clinical activity supporting a complementary role of SBRT and PD-1 immunotherapy,” the authors concluded. “Randomized studies are needed to determine whether combining pembrolizumab and SBRT potentiates efficacy.” They added that expansion cohorts including patients with large, partially irradiated tumors are now planned.