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 language | English (US) |
|---|---|
| Pages (from-to) | 1493-1501 |
| Number of pages | 9 |
| Journal | The Lancet Oncology |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2017 |
ASJC Scopus subject areas
- Oncology
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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 H.; 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, Vol. 18, No. 11, 11.2017, p. 1493-1501.Research output: Contribution to journal › Article › peer-review
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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 H.
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
N1 - Funding Information: The study drug and partial funding was provided by Merck. The funder otherwise had no role in study design, data collection, data analysis, data interpretation, or in the writing of this report. The funder reviewed the manuscript before submission. Raw data were accessible to all authors. All authors made the decision to submit the report for publication. Funding Information: 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 a success, the 12-week progression-free survival in the soft-tissue sarcoma group was 55%, which was significantly higher than the 40% expected for an active regimen, suggesting meaningful clinical activity in this population. In the soft-tissue sarcoma group, six of seven objective responses and improvements in 12-week progression-free survival were observed in patients with undifferentiated pleomorphic sarcoma or liposarcoma. The median duration of response (49 weeks) and the median overall survival (not reached) for patients with undifferentiated pleomorphic sarcoma suggested that immune checkpoint blockade induces durable responses and has meaningful clinical activity in patients with this subtype. This cohort is being expanded to confirm and further characterise the clinical activity of pembrolizumab. PD-L1 expression has been correlated with T-cell infiltration in undifferentiated pleomorphic sarcoma. 21–23 This finding suggests that undifferentiated pleomorphic sarcoma might fit the model of an inflamed tumour and could explain the activity of single-agent anti-PD-1 antibodies in this disease. 24 PD-L1 expression was observed in only two (5%) of 40 samples in which tumour response was evaluable; both tumours were undifferentiated pleomorphic sarcoma and responded to therapy. This finding is consistent with a previous report 21 in which PD-L1 expression was found in only two (5%) of 36 non-gastrointestinal stromal soft-tissue sarcomas, both of which were undifferentiated pleomorphic sarcoma. In our study, responses were seen even in the absence of PD-L1 expression, consistent with other tumour types, including melanoma, in which PD-L1-negative tumours might respond to checkpoint blockade. 14 The role of PD-L1 expression in soft-tissue sarcoma remains unclear; 22,23,25 however, ongoing analyses with multicolour immunohistochemistry using samples collected from our study will help to elucidate the role of PD-L1 and will be reported separately. We also observed clinical activity in the absence of PD-L1 expression in patients with liposarcoma. The liposarcoma cohort included several high-grade liposarcoma subtypes. However, because of the absence of responses in patients with myxoid or round cell liposarcoma, only patients with dedifferentiated liposarcoma will be included in an expansion cohort. The results for leiomyosarcoma were consistent with a phase 2 study 26 of nivolumab that was stopped early because of futility, suggesting that single-agent anti-PD-1 therapy might not elicit an immune response in these patients. The mechanisms underlying resistance to immunotherapy in patients with leiomyosarcoma remain unclear, although a report implicated loss of PTEN expression as a potential mechanism of resistance. Such investigations could yield targetable pathways—in the case of PTEN, the PI3K-AKT pathway—that could be pursued in combination with checkpoint blockade. 27 Synovial sarcoma, which has high expression of cancer testis antigens, was anticipated to be responsive to pembrolizumab given reports of objective reponses with T-cell therapy in patients with advanced synovial sarcoma. 28 However, most patients with synovial sarcoma in this study had rapid progression. A phase 2 pilot study investigating use of ipilimumab to treat synovial sarcoma expressing the NY-ESO-1 antigen in six patients was terminated early because of poor activity and absence of immune responses. 29 In our study, only one patient with synovial sarcoma had a short-lived partial response and another had prolonged stable disease and is still deriving clinical benefit while on therapy for almost 2 years. The response of the patient still on therapy was classified as a partial response according to irRC, confirming that this pattern of response can correlate with clinical benefit. Pembrolizumab had low activity in patients with bone sarcoma, although the two responses observed (one in a patient with osteosarcoma and the other in a patient with chondrosarcoma) were substantial (>50% tumour shrinkage) and durable (>6 months). Although immunotherapy has shown promise as an adjuvant therapy for osteosarcoma, only one patient with metastatic osteosarcoma had a response to pembrolizumab. Osteosarcoma has been shown to have variable PD-L1 expression and frequent loss of MHC class I, potentially facilitating immune evasion. 30–32 Mifarmutide was shown to increase immune-cell infiltration into osteosarcoma metastases, 33 a crucial step to improve the efficacy of anti-PD-1 antibodies. Pembrolizumab had no activity in the 13 patients with Ewing's sarcoma, which could be associated with the highly immunosuppressive microenvironment of the tumour. Only one patient with Ewing's sarcoma had a partial response according to irRC, suggesting that a small subset of patients with Ewing's sarcoma could benefit from single-agent therapy. Nevertheless, combination approaches will clearly be needed for clinical activity in this rapidly growing, aggressive malignancy. In a retrospective study 34,35 high regulatory T-cell counts were seen in the tumour tissues of patients who presented with metastatic Ewing's sarcoma, which might contribute to inhibition of cytotoxic CD8-positive T lymphocytes and promotion of tumour escape. Five patients with chondrosarcoma were enrolled in this study, one of whom achieved a partial response. This finding was consistent with one retrospective series study, 36 in which one (25%) of four patients with dedifferentiated chondrosarcoma responded to nivolumab. The finding of a response to treatment is important given the few therapeutic options available for chondrosarcoma, which is refractory to most if not all anticancer therapies. 37 In a retrospective report, 38 PD-L1 expression was associated with the number of tumour-infiltrating lymphocytes and HLA class I expression in 11 (52%) of 21 dedifferentiated chondrosarcomas. These results suggest that further evaluation of immune checkpoint blockade in chondrosarcoma is warranted. The safety profile of pembrolizumab in the study population was consistent with what has been observed for other approved indications; specifically, no increase was seen in the incidence of pneumonitis despite most patients with advanced sarcomas having lung metastases. Sarcoma is generally considered a non-immunogenic tumour. However, we found sarcomas to be highly variable in their biology, suggesting that each histological subtype should be considered a separate therapeutic challenge requiring a distinct understanding of its immune and molecular biology. The role of PD-L1 and other potential biomarkers in the observed clinical differences between individual sarcoma subtypes will be explored as we continue to analyse the serial blood and tumour samples collected during this study. Our study was limited by its non-randomised design and small sample size. However, if the clinical activity of pembrolizumab can be confirmed in other, larger studies, our findings could change practice given that undifferentiated pleomorphic sarcoma and liposarcoma are two of the three most common soft-tissue sarcomas (together representing more than 30% of all soft-tissue sarcomas). The results of planned correlative analyses will hopefully improve our understanding of the immune response and mechanisms of resistance to immunotherapy in sarcoma, and help prioritise combination strategies with chemotherapy, radiotherapy, 39 targeted agents, or other immune checkpoint inhibitors. Our study was a testament to the collaborative efforts of SARC investigators, pharmaceutical companies, and philanthropic organisations, which allowed rapid accrual of patients and collection of high-quality data and biospecimens. The results of this study will lay the foundation for the future of immunotherapy in sarcoma. Contributors HAT, MB, and JC led the study design with support from Merck. The study was managed by SARC. VB, JC, HAT, and MB did the data analysis. HAT, MB, VB, BAVT, SMS, JH, SD, SA, RFR, DAP, SM, LED, SHO, DRR, and JC interpreted the data. HAT and VB wrote the manuscript. All versions of the manuscript were reviewed by HAT, MB, VB, BAVT, SMS, JH, SD'A, SA, RFR, DAP, SM, LED, SHO, DRR, JC, LHBu, RS, JR-C, AJL, IIW, LHBa, RGM, DR, and SP. All authors gave final approval of the manuscript. The investigators who contributed to recruitment, treatment, and follow-up of patients are listed in the appendix (p 2) . Declaration of interests HAT reports Bristol-Myers Squibb consulting and research support to his institution and consulting for Novartis and EMD-Serono, outside the submitted work. MB reports personal fees from Immune Design, EMD-Serono, and Eisai, and other from Eli Lilly, outside the submitted work. BAVT reports grants from Merck, outside the submitted work. SMS reports grants from SARC and non-financial support from Merck, during the conduct of the study, and personal fees from Janssen and Daiichi Sankyo, outside the submitted work. SD'A reports other from Nektar Therapeutics and Amgen, outside the submitted work. RFR reports other from AADi Bioscience, Threshold, Arog, Immune Design, Karyopharm, Merck, SARC, and Plexxlkon; personal fees and other from Daiichi Sankyo, Novartis, Eli Lilly, Tokalas, Ignyta, and Eisai; and personal fees from Janssen and EMD-Serono, outside the submitted work. LED reports grants from Novartis and personal fees from Eisai, outside the submitted work. IIW reports grants and personal fees from AstraZeneca/Mediimune, Roche/Genentech, Merck, and HTG Molecular Diagnostics; grants from Adaptimmune and EMD-Serono; and personal fees from Ariad, Pfizer, and Asuragen, outside the submitted work. RGM reports personal fees from Novartis, Eli Lilly, Gem Pharma, Karyopharm, Bayer, and Arcus; personal fees and other from Tracon, Eisai, and SARC; and other from UpToDate, Springer, GlaxoSmithKline, Tracon, and Bayer, outside the submitted work. SP reports grants and personal fees from Janssen, Eisai, and Morphotek, and personal fees from EMD-Serono, CytRx, Bayer, Eli Lilly, Epizyme, and Novartis, outside the submitted work. All other authors declare no competing interests. Acknowledgments The study was funded in part by Merck. Additional funding was obtained from the SARC, the Sarcoma Foundation of America, the QuadW Foundation, Ewan McGregor, and Pittsburgh Cure Sarcoma. We thank the patients and their families, the investigators, and participating study teams.
PY - 2017/11
Y1 - 2017/11
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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UR - http://www.scopus.com/inward/citedby.url?scp=85030654856&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(17)30624-1
DO - 10.1016/S1470-2045(17)30624-1
M3 - Article
C2 - 28988646
AN - SCOPUS:85030654856
VL - 18
SP - 1493
EP - 1501
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 11
ER -