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.

The Role of Radiation Oncology in Immuno-Oncology

“…Median gross tumor volume for partial tumor irradiation was 116.6 ml versus 7.2 ml for the metastases treated with complete tumor irradiation ( p = .0001). Control at 3 months was not significantly statistically different between patients with at least one tumor partially irradiated and patients with tumors that were completely irradiated .…”

“…So it is interesting to make clear the role of target volume in the combination therapy. A phase I study was carried out to evaluate the safety of pembrolizumab combing with multisite SBRT treating 68 patients with metastatic solid tumors . Seventeen (25%) of the 68 patients with at least one metastasis >65 ml were partially treated with SBRT.…”

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer

“…15 The ORR for the entire cohort was 13.2% and was not reported specifically in the patients with breast cancer, thereby constraining the ability to compare results across studies. In what to the best of our knowledge are the few reports of RT and immunotherapy including patients with breast cancer published to date, various dose regimens have been used with mixed results.…”

“…Pembrolizumab monotherapy has demonstrated a response rate of 4.7% in previously treated patients with mTNBC regardless of PD-L1 status. [13][14][15][16][17] RT is believed to augment the immune response through the promotion of proimmunogenic cell death and apoptosis, as well as the priming and activation of cytotoxic T cells. [8][9][10][11][12] The immunomodulatory effects of RT combined with immune checkpoint inhibitors has been reported in numerous preclinical and clinical studies that included women with metastatic breast cancer.…”

Is immune checkpoint inhibition part of standard therapy for stage III non‐small cell lung cancer?

“…In addition, preclinical and early clinical evidence suggests that chemotherapy and radiotherapy may work synergistically with anti–PD‐1/PD‐L1 therapy to promote antitumor immunity . Murine models of lung cancer as well as recent clinical data suggest a potential synergy of radiotherapy and immunotherapy for both improved local control of tumor and increased systemic control . Postulated mechanisms for the intensification of immune response by radiation include tumor antigen release, antigen presentation, and modulation of immunosuppressive cells, such as regulatory T cells and myeloid‐derived suppressor cells .…”