Jeffrey Lemons

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

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 Evolution of Radiation Therapy in Metastatic Breast Cancer: From Local Therapy to Systemic Agent

Radiation therapy is a mainstay of treatment in early and locally advanced breast cancer but is typically reserved for palliation of symptomatic lesions in patients with metastatic breast cancer. With new advances in the field of tumor biology and immunology, the role of radiation in the metastatic setting is evolving to harness its immune-enhancing properties. Through the release of tumor antigens, tumor DNA, and cytokines into the tumor microenvironment, radiation augments the antitumoral immune response to affect both the targeted lesion and distant sites of metastatic disease. The use of immunotherapeutics to promote antitumoral immunity has resulted in improved treatment responses in patients with metastatic disease and the combination of radiation therapy and immunotherapy has become an area of intense investigation. In this article, we will review the emerging role of radiation in the treatment of metastatic disease and discuss the current state of the science and clinical trials investigating the combination of radiation and immunotherapy.

SBRT and the Treatment of Oligometastatic Disease

For patients with metastatic cancer, there is significant variation in the amount of time from diagnosis to disease progression or death. For physicians, predicting the duration of this interval can be difficult. The clinical course for these patients is dependent on myriad factors including the primary histology, size, and location of metastatic lesions. Attempts have been made to model prognosis based on other factors such as response to neoadjuvant chemotherapy and volume of disease. A distinct clinical state of metastases with low volume disease and few organs affected was coined “oligometastases.” It is hypothesized this state may be amenable to local therapy to improve outcomes. After long term follow up, patients with this limited metastatic progression appear to have relatively good outcomes, with some long-term survivors, after aggressive treatment with local therapy combined with systemic therapy. In the past 20 years since the conception of the oligometastatic hypothesis, there have been advances in surgical and radiation therapy techniques resulting in reduced toxicities. Additionally, developments in systemic therapy have prolonged survival for patients with metastatic disease. Herein we discuss the history and rationale for local treatment of oligometastases and delve into the implementation of stereotactic body radiotherapy (SBRT) to this evolving treatment paradigm.