Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

Abstract

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ-induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ-associated genes from post-SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion 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.

Fig 1.

Protocol enrollment and analysis diagram. (*) A total of 12 patients had paired (both pre- and postradiation) biopsy samples, six patients had preradiation biopsy samples, and six patients had postradiation biopsy samples. Of the patients with paired samples, eight had adequate follow-up to be included in this analysis. (†) Five patients had prior PD-1–axis blockade. (‡) A total of 52 patients had at least one measurable RECIST target metastasis that was not irradiated. SBRT, stereotactic body radiotherapy.

Fig 2.

Best overall response waterfall plots. (A) Maximum percent change in the aggregate diameter of Response Evaluation Criteria in Solid Tumors (RECIST) target metastases. (B) Maximum percent change in aggregate diameter of irradiated metastases. (C) Maximum percent change in aggregate diameter of unirradiated RECIST target metastases.

Fig 3.

Kaplan-Meier curves of (A) overall and (B) progression-free survival.

Fig 4.

Posttreatment biopsy-specimen immune score correlation with unirradiated metastasis response. (A) Spearman rank analysis of poststereotactic body radiotherapy–irradiated tumor gene expression demonstrated significant correlations between the four-gene interferon-γ–related immune score and percent change in the nonirradiated Response Evaluation Criteria in Solid Tumors target metastasis size in relation to baseline measurements. (B) Of the four genes, granzyme K expression in the irradiated metastasis demonstrated the strongest correlation with unirradiated metastasis response. Each dot represents an individual patient sample.