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

Hussein A. Tawbi, Melissa Burgess, Vanessa Bolejack, Brian A. Van Tine, Scott M. Schuetze, James Hu, Sandra D'Angelo, Steven Attia, Richard F. Riedel, Dennis A. Priebat, Sujana Movva, Lara E. Davis, Scott Heitaka Okuno, Damon R. Reed, John Crowley, Lisa H. Butterfield, Ruth Salazar, Jaime Rodriguez-Canales, Alexander J. Lazar, Ignacio I. WistubaLaurence H. Baker, Robert G. Maki, Denise Reinke, Shreyaskumar Patel

Research output: Contribution to journalArticle

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Abstract

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: Pembrolizumab has meaningful clinical 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.

Original languageEnglish (US)
JournalThe Lancet Oncology
DOIs
StateAccepted/In press - 2017

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Sarcoma
Bone and Bones
Liposarcoma
pembrolizumab
Partial Thromboplastin Time
Lymphocyte Count
Anemia
Synovial Sarcoma
Adrenal Insufficiency
Chondrosarcoma
Ewing's Sarcoma
Leiomyosarcoma
Nephritis
Osteosarcoma
Therapeutics
Patient Safety
Platelet Count
Research

ASJC Scopus subject areas

  • Oncology

Cite this

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028) : A multicentre, two-cohort, single-arm, open-label, phase 2 trial. / Tawbi, Hussein A.; Burgess, Melissa; Bolejack, Vanessa; Van Tine, Brian A.; Schuetze, Scott M.; Hu, James; D'Angelo, Sandra; Attia, Steven; Riedel, Richard F.; Priebat, Dennis A.; Movva, Sujana; Davis, Lara E.; Okuno, Scott Heitaka; Reed, Damon R.; Crowley, John; Butterfield, Lisa H.; Salazar, Ruth; Rodriguez-Canales, Jaime; Lazar, Alexander J.; Wistuba, Ignacio I.; Baker, Laurence H.; Maki, Robert G.; Reinke, Denise; Patel, Shreyaskumar.

In: The Lancet Oncology, 2017.

Research output: Contribution to journalArticle

Tawbi, HA, Burgess, M, Bolejack, V, Van Tine, BA, Schuetze, SM, Hu, J, D'Angelo, S, Attia, S, Riedel, RF, Priebat, DA, Movva, S, Davis, LE, Okuno, SH, Reed, DR, Crowley, J, Butterfield, LH, Salazar, R, Rodriguez-Canales, J, Lazar, AJ, Wistuba, II, Baker, LH, Maki, RG, Reinke, D & Patel, S 2017, 'Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial', The Lancet Oncology. https://doi.org/10.1016/S1470-2045(17)30624-1
Tawbi, Hussein A. ; Burgess, Melissa ; Bolejack, Vanessa ; Van Tine, Brian A. ; Schuetze, Scott M. ; Hu, James ; D'Angelo, Sandra ; Attia, Steven ; Riedel, Richard F. ; Priebat, Dennis A. ; Movva, Sujana ; Davis, Lara E. ; Okuno, Scott Heitaka ; Reed, Damon R. ; Crowley, John ; Butterfield, Lisa H. ; Salazar, Ruth ; Rodriguez-Canales, Jaime ; Lazar, Alexander J. ; Wistuba, Ignacio I. ; Baker, Laurence H. ; Maki, Robert G. ; Reinke, Denise ; Patel, Shreyaskumar. / Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028) : A multicentre, two-cohort, single-arm, open-label, phase 2 trial. In: The Lancet Oncology. 2017.
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title = "Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial",
abstract = "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: Pembrolizumab has meaningful clinical 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.",
author = "Tawbi, {Hussein A.} and Melissa Burgess and Vanessa Bolejack and {Van Tine}, {Brian A.} and Schuetze, {Scott M.} and James Hu and Sandra D'Angelo and Steven Attia and Riedel, {Richard F.} and Priebat, {Dennis A.} and Sujana Movva and Davis, {Lara E.} and Okuno, {Scott Heitaka} and Reed, {Damon R.} and John Crowley and Butterfield, {Lisa H.} and Ruth Salazar and Jaime Rodriguez-Canales and Lazar, {Alexander J.} and Wistuba, {Ignacio I.} and Baker, {Laurence H.} and Maki, {Robert G.} and Denise Reinke and Shreyaskumar Patel",
year = "2017",
doi = "10.1016/S1470-2045(17)30624-1",
language = "English (US)",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",

}

TY - JOUR

T1 - Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028)

T2 - A multicentre, two-cohort, single-arm, open-label, phase 2 trial

AU - Tawbi, Hussein A.

AU - Burgess, Melissa

AU - Bolejack, Vanessa

AU - Van Tine, Brian A.

AU - Schuetze, Scott M.

AU - Hu, James

AU - D'Angelo, Sandra

AU - Attia, Steven

AU - Riedel, Richard F.

AU - Priebat, Dennis A.

AU - Movva, Sujana

AU - Davis, Lara E.

AU - Okuno, Scott Heitaka

AU - Reed, Damon R.

AU - Crowley, John

AU - Butterfield, Lisa H.

AU - Salazar, Ruth

AU - Rodriguez-Canales, Jaime

AU - Lazar, Alexander J.

AU - Wistuba, Ignacio I.

AU - Baker, Laurence H.

AU - Maki, Robert G.

AU - Reinke, Denise

AU - Patel, Shreyaskumar

PY - 2017

Y1 - 2017

N2 - 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: Pembrolizumab has meaningful clinical 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.

AB - 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: Pembrolizumab has meaningful clinical 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.

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