Pembrolizumab Plus SBRT Active in Advanced Solid Tumors

Jason J. Luke, MD, FACP

The addition of pembrolizumab (Keytruda) to stereotactic body radiotherapy (SBRT) induced an objective response rate of 13.2% among patients with advanced solid tumors, according to a phase I study published in the Journal of Clinical Oncology.

Among 68 patients who had imaging follow-up, the median overall survival (OS) was 9.6 months (95% CI, 6.5-not reached) and median progression-free survival (PFS) was 3.1 months (95% CI, 2.9-3.4). There was 1 complete response, 8 partial responses, 21 patients with stable disease, and 38 with progressive disease.

“This population was unselected for PD-L1 expression, consisted of 27 cancer types, and was enriched in histologies not associated with significant [a] response rate to pembrolizumab. Our response rate is similar to that of the multitumor basket study KEYNOTE-028 (range, 11% to 13% response rate) in which patients were selected for high PD-L1 expression,” lead study author Jason J. Luke, MD, assistant professor of medicine, University of Chicago Medicine, and coinvestigators wrote.

“These results build on initial studies that incorporated SBRT and interleukin-2—based immunotherapy. Our findings support clinical and animal models demonstrating synergistic antitumor activity of radiotherapy and immunotherapy,” added Luke et al.

Increased tumor burden correlates with decreased efficacy of PD-1 immunotherapy, so investigators hypothesized that tumor debulking with SBRT could enhance immunotherapy response. Additionally, preclinical observations noted tumor infiltration of T cells following radiation, suggesting the potential for synergy with immunotherapies.

To test that theory, Luke et al recruited 79 patients into this phase I study from January 2016 to March 2017. Eligible patients had metastatic solid tumor previously treated with standard-of-care therapy and an ECOG performance status ≤1. Measurable disease by RECIST version 1.1 was required with at least 2 tumors ranging from 0.25 mL to 65 mL that were amenable to SBRT. Metastatic tumors >65 mL were partially treated with radiation.

For tumors >65 mL, a target volume was created within the gross tumor volume to limit the treated tumor to <65 mL. SBRT dose was 45 Gy in 3 fractions for peripheral lung, liver, and abdominal/pelvic tumors; 50 Gy in 5 fractions for central lung and mediastinal/cervical tumors; and 30 Gy in 3 fractions for osseous and spinal/paraspinal tumors.

A dose of 200 mg of pembrolizumab was initiated within 7 days after the final SBRT fraction and administered intravenously every 3 weeks. Treatment continued until clinical or radiographic disease progression, dose-limiting toxicity, withdrawal from study, or death. Treatment could continue beyond progression, but patients were not allowed any additional anticancer therapeutics during enrollment.

Nearly all patients (94.5%) had 2 metastases treated with SBRT, 4.1% had 3 metastases treated, and 1.3% had 4 metastases treated. Twenty-six (35.6%) patients had irradiated metastases confined to 1 anatomic location and 47 patients (64.4%) had irradiated metastases in 2 or more locations. Overall, a total of 151 metastases were treated with SBRT (peripheral lung, n = 30; central lung, n = 23; mediastinum/thoracic, n = 15; liver, n = 24; spinal, n = 15; osseous, n = 16; abdominal/pelvic, n = 28). All 73 patients received at least 1 cycle of intravenous pembrolizumab within 7 days of finishing radiotherapy.

The primary endpoint was treatment-related dose-limiting toxicity (DLT) on the basis of anatomic cohort assignment. Median follow-up for treatment-related toxicity was 5.5 months (IQR, 3.3-8.1) for all patients and 7.1 months (IQR, 4.8-10.2) for living patients.

There were no radiation-dose reductions, but 6 patients experienced severe treatment-related toxicity, including 3 cases of grade 3 pneumonitis, 2 cases of grade 3 colitis, and 1 case of grade 3 hepatic toxicity.

Sixty-two patients had at least 3 months of follow-up, corresponding to a DLT rate of 9.7%. All patients with a DLT had 2 metastases treated with SBRT. All planning constraints (including <15% normal lung volume receiving 20 Gy) were met. Three patients had both metastases in the same anatomic location, and 3 patients had metastases in separate anatomic locations.

The mean percent change in tumor diameter was −21.7% (standard deviation[SD], 24.3%) for irradiated metastases versus 1.7% (SD, 46.3%) for nonirradiated metastases (P = .0008). When investigators compared tumor control between irradiated and nonirradiated metastases for the 52 patients with paired data, they found that neither the irradiated nor the nonirradiated metastases progressed in 36 patients. Irradiated metastases progressed but the nonirradiated did not in 1 patient. In 15 patients, the nonirradiated metastases progressed but the irradiated did not. No patient experienced progression in both types of metastases (P = .0005).

Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors [published online February 13, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.76.2229.