BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few 
treatment options that improve overall survival. Chemotherapy and targeted 
therapies offer short-lived disease control. We assessed pembrolizumab, an 
anti-PD-1 antibody, for safety and activity in patients with advanced 
soft-tissue sarcoma or bone sarcoma.
METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled 
patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in 
the USA that were members of the Sarcoma Alliance for Research through 
Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years 
or older to enrol; patients with bone sarcoma could enrol if they were aged 12 
years or older. Patients had histological evidence of metastatic or surgically 
unresectable locally advanced sarcoma, had received up to three previous lines 
of systemic anticancer therapy, had at least one measurable lesion according to 
the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least 
one lesion accessible for biopsy. All patients were treated with 200 mg 
intravenous pembrolizumab every 3 weeks. The primary endpoint was 
investigator-assessed objective response. Patients who received at least one 
dose of pembrolizumab were included in the safety analysis and patients who 
progressed or reached at least one scan assessment were included in the activity 
analysis. Accrual is ongoing in some disease cohorts. This trial is registered 
with ClinicalTrials.gov, number NCT02301039.
FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 
of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were 
evaluable for response (40 in each disease cohort). Median follow-up was 17·8 
months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had 
an objective response, including four (40%) of ten patients with 
undifferentiated pleomorphic sarcoma, two (20%) of ten patients with 
liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients 
with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients 
with bone sarcoma had an objective response, including one (5%) of 22 patients 
with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of 
the 13 patients with Ewing's sarcoma had an objective response. The most 
frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased 
lymphocyte count (five [12%]), prolonged activated partial thromboplastin time 
(four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma 
group, and anaemia, decreased lymphocyte count, and prolonged activated partial 
thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine 
(11%) patients (five [12%] in the bone sarcoma group and four [10%] in the 
soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), 
five of whom had immune-related SAEs, including two with adrenal insufficiency, 
two with pneumonitis, and one with nephritis.
INTERPRETATION: The primary endpoint of overall response was not met for either 
cohort. However, pembrolizumab showed encouraging activity in patients with 
undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment 
to expanded cohorts of those subtypes is ongoing to confirm and characterise the 
activity of pembrolizumab.
FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, 
Pittsburgh Cure Sarcoma, and Ewan McGregor.