SBRT and Anti–PD-1 Treatment in Metastatic Solid Tumors
In a phase I study reported in the Journal of Clinical Oncology, Luke et al found that a strategy of multisite stereotactic body radiotherapy (SBRT) followed by pembrolizumab was feasible in patients with metastatic solid tumors. It was hypothesized that stimulation of immune responses by SBRT might augment the activity of anti–programmed cell death protein 1 (PD-1) treatment.
Study Details
In the single-institution study (University of Chicago), patients with progressive disease on standard treatment received SBRT to two to four metastases; not all metastases were irradiated, and metastases > 65 mL were partially irradiated. SBRT doses ranged from 30 to 50 Gy in three to five fractions with predefined dose reduction for excessive dose-limiting toxicities. Pembrolizumab was given at 200 mg every 3 weeks starting within 7 days of SBRT completion. Pre- and post-SBRT specimens were analyzed in a subgroup of patients to assess interferon-gamma–induced gene expression.
Toxicity and Tumor Response
Of 79 patients enrolled between January 2016 and March 2017, 73 received SBRT and at least one cycle of pembrolizumab. A total of 94.5% of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months. There were no radiation dose reductions, but six patients (8.2%) had severe treatment-related toxicity, consisting of grade 3 pneumonitis in three, grade 3 colitis in two, and grade 3 hepatic toxicity in one.
Among 68 patients with imaging follow-up, the overall objective response rate was 13.2%.
The mean change in tumor diameter was -21.7% for irradiated metastases vs 1.7% for nonirradiated metastases (P = .0008). Among 52 patients with paired data, tumor control (lack of progression at last follow-up) was observed in 36 patients for both irradiated and nonirradiated metastases; irradiated metastases but not nonirradiated metastases progressed in one patient and nonirradiated metastases but not irradiated metastases progressed in 15 (P = .0005). Median progression-free survival was 3.1 months, and median overall survival was 9.6 months.
In a small subgroup of patients evaluated, increased interferon-gamma gene expression in post-SBRT specimens was significantly correlated with response in nonirradiated tumors (P = .023). Elevated immune scores primarily reflected GZMK overexpression. No association was observed between pre-irradiation immune gene expression and response in irradiated or nonirradiated tumors.
The investigators concluded, “Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1–directed immunotherapy are warranted.”
The study was supported by the University of Chicago, National Institutes of Health, Merck, and others.
Steven J. Chmura, MD, PhD, of the Department of Radiation and Cellular Oncology, University of Chicago, is the corresponding author for the Journal of Clinical Oncology article.
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