Elsevier

The Lancet Oncology

Volume 18, Issue 11, November 2017, Pages 1493-1501
The Lancet Oncology

Articles
Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30624-1Get rights and content

Summary

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.

Introduction

Sarcomas, which are broadly categorised as soft-tissue sarcomas or bone sarcomas, represent a heterogeneous group of mesenchymal malignancies with more than 50 histological subtypes.1 Studies of sarcomas and therapeutic outcomes are limited by their rarity and heterogeneity. The median overall survival is around 2 years for advanced leiomyosarcoma but less than 1 year for most other advanced soft-tissue sarcomas, and only about 10% of patients are alive at 5 years.2 Similarly, adult patients with metastatic bone sarcomas have a 5-year overall survival of less than 25%.3, 4

Treatment options are few and generally palliative, while the expected benefits are tempered by a high rate of severe side-effects. Response to conventional chemotherapy and radiotherapy is dependent on the specific histology because some subtypes are chemoresistant. The past decade has seen collaborative investigation of novel drugs for the treatment of sarcoma in large randomised controlled clinical trials,5, 6, 7, 8 leading to approval of several drugs by the US Food and Drug Administration (FDA), including pazopanib, trabectedin, eribulin, and olaratumab. However, these therapies still do not have a substantial cure rate, prompting the need for development of other novel drugs.

Research in context

Evidence before this study

We searched PubMed up to May 5, 2017, with the terms “metastatic sarcoma”, “clinical trials”, “PD-1”, “PD-L1”, “immune checkpoint blockade”, “immune response”, “pembrolizumab”, and “nivolumab” for articles published in English. Patients with metastatic soft-tissue sarcoma or bone sarcoma have a poor prognosis and low survival. First-line treatment of soft-tissue sarcoma with single-agent chemotherapy remains the standard of care and leads to a response in 10–15% of patients. Combination therapies have little or no effect on overall survival in patients with soft-tissue sarcoma, while consistently increasing the incidence of adverse events. Treatment of bone sarcoma with combination chemotherapy in the neoadjuvant and adjuvant setting can be curative despite the substantial toxicity. However, in patients with advanced bone sarcomas, no existing therapeutic options offer a survival advantage. Sarcoma has not traditionally been considered an immunogenic tumour; however, several studies showed PD-L1 to be expressed in up to 30–40% of certain sarcoma subtypes. Anecdotal reports and retrospective series studies have described responses to immune checkpoint blockade in select sarcomas. One phase 2 study of nivolumab in leiomyosarcoma was stopped early for futility, but no prospective studies have been published to date in other subtypes of soft-tissue sarcoma or bone sarcoma. Treatment with antibodies targeting the PD-1/PD-L1 axis led to durable responses in several cancers.

Added value of this study

To our knowledge, this prospective, multicentre, phase 2 study is the first to investigate the use of immune checkpoint blockade with anti-PD-1 antibodies in the treatment of soft-tissue sarcoma and bone sarcoma. We considered the heterogeneity of sarcomas and limited the study to specific histological subtypes to identify potential subtype-specific efficacy signals. We observed an objective response in seven (18%) of 40 patients with soft-tissue sarcoma, and the benefit was limited to patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcomas. The characteristics of the responses were consistent with the durable benefit observed with checkpoint blockade in other cancers. We observed little to no benefit in patients with synovial sarcoma or leiomyosarcoma. Similarly, we observed infrequent responses to therapy in patients with bone sarcomas, suggesting the need for combination approaches in this population.

Implications of all the available evidence

These findings suggest that pembrolizumab is clinically active in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Expanded cohorts of these subtypes, which represent more than 30% of all soft-tissue sarcomas, are ongoing. Further investigation is required to determine the utility of predictive biomarkers for response and to understand the mechanisms of resistance in the other subtypes of soft-tissue sarcoma and bone sarcoma, in which rational combination therapies could be considered.

Immunotherapy with adjuvant mifamurtide, a non-specific immune stimulator that was shown to improve overall survival in osteosarcoma in a phase 3 trial,9 is already approved in some countries. The appeal of immunotherapy has increased as studies10, 11, 12, 13, 14 of pembrolizumab, an anti-PD-1 antibody, have shown the benefits of immune checkpoint inhibition beyond melanoma; for example, pembrolizumab has shown therapeutic benefit in non-small-cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, and Merkel cell carcinoma. However, except for mifamurtide, immunotherapy has had little therapeutic benefit in patients with soft-tissue sarcoma or bone sarcoma, with studies9, 15, 16, 17 using cytokines or immune adjuvants not achieving their primary endpoints.

Therefore, we aimed to determine the safety and activity of immune checkpoint blockade with pembrolizumab in patients with advanced soft-tissue sarcoma or bone sarcoma.

Section snippets

Study design and participants

SARC028 was a multicentre, two-cohort, open-label, phase 2 trial of pembrolizumab monotherapy, done at 12 academic medical centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC; appendix p 11). 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. Eligible patients had histological evidence of metastatic or surgically unresectable locally advanced

Results

Between March 13, 2015, and Feb 18, 2016, 86 patients were enrolled in the study and 84 patients were treated with pembrolizumab (figure 1). 40 patients with soft-tissue sarcoma were evaluable for response and assigned to one of four disease subtypes (n=10 per subtype): undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, synovial sarcoma, and leiomyosarcoma. 40 patients with bone sarcoma were evaluable for response, of whom 22 had osteosarcoma, 13 had Ewing's sarcoma, and five

Discussion

To our knowledge, SARC028 is the first multicentre, open-label, phase 2 study of immune checkpoint blockade in patients with advanced soft-tissue sarcoma or bone sarcoma. Pembrolizumab monotherapy was associated with clinically meaningful and sustained objective responses in seven (18%) of 40 patients with soft-tissue sarcoma and in two (5%) of 40 patients with bone sarcoma. Although eight or more of the 40 patients in each group had to have an objective response for treatment to be considered

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