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 H Okuno, Damon R Reed, John Crowley, Lisa H Butterfield, Ruth Salazar, Jaime Rodriguez-Canales, Alexander J Lazar, Ignacio I Wistuba, Laurence H Baker, Robert G Maki, Denise Reinke, Shreyaskumar Patel, 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 H Okuno, Damon R Reed, John Crowley, Lisa H Butterfield, Ruth Salazar, Jaime Rodriguez-Canales, Alexander J Lazar, Ignacio I Wistuba, Laurence H Baker, Robert G Maki, Denise Reinke, Shreyaskumar Patel

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: 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.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figures 1a:
Figures 1a:
Waterfall plot of best percent change from baseline in size of Target Lesions (sum of diameters)- STS
Figure 1b:
Figure 1b:
Spider plots of % of baseline tumor size (sum of target lesion diameters) at each assessment-STS
Figure 1c:
Figure 1c:
Waterfall plot of best percent change from baseline in size of Target Lesions (sum of diameters)- BS
Figure 1d:
Figure 1d:
Spider plots of % of baseline tumor size at each assessment- Bone Sarcomas * Study day for 1 patient was truncated at 250 days to better show the earlier part of the graph.

References

    1. Goldblum JR, Folpe AL, Weiss SW, Enzinger FM, Weiss SW. Enzinger and Weiss’s soft tissue tumors. 6th ed. Philadelphia, PA: Saunders/Elsevier; 2014. xiv, 1155 p. p.
    1. Savina M, Le Cesne A, Blay JY, Ray-Coquard I, Mir O, Toulmonde M, et al. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med. 2017;15(1):78.
    1. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016;34(8):786–93.
    1. Schoffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629–37.
    1. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488–97.
    1. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.
    1. Verma V, Denniston KA, Lin CJ, Lin C. A Comparison of Pediatric vs. Adult Patients with the Ewing Sarcoma Family of Tumors. Front Oncol. 2017;7:82.
    1. Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010;8(10):705–18.
    1. Chou AJ, Kleinerman ES, Krailo MD, Chen Z, Betcher DL, Healey JH, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2009;115(22):5339–48.
    1. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.
    1. Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017;18(2):212–20.
    1. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016;374(26):2542–52.
    1. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017:JCO2016721316.
    1. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.
    1. Carvajal R, Agulnik M, Ryan CW, et al. Trivalent ganglioside vaccine and immunologic adjuvant versus adjuvant alone in metastatic sarcoma patients rendered disease-free by surgery: A randomized phase 2 trial. J Clin Oncol. 2014;32:5s(supplement; abstract 10520).
    1. Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210(4):474–84; discussion 84–5.
    1. Bielack SS, Smeland S, Whelan JS, Marina N, Jovic G, Hook JM, et al. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol. 2015;33(20):2279–87.
    1. Van Glabbeke M, Verweij J, Judson I, Nielsen OS, Tissue ES, Bone Sarcoma G. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer. 2002;38(4):543–9.
    1. Kaplan EL, Meier P. Nonparametric-Estimation from Incomplete Observations. J Am Stat Assoc. 1958;53(282):457–81.
    1. Brookmeyer R, Crowley J. A Confidence-Interval for the Median Survival-Time. Biometrics. 1982;38(1):29–41.
    1. Gajewski TF. The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol. 2015;42(4):663–71.
    1. D’Angelo SP, Shoushtari AN, Agaram NP, Kuk D, Qin LX, Carvajal RD, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46(3):357–65.
    1. Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM, et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013;8(12):e82870.
    1. Kim C, Kim EK, Jung H, Chon HJ, Han JW, Shin KH, et al. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer. 2016;16:434.
    1. Bertucci F, Finetti P, Perrot D, Leroux A, Collin F, Le Cesne A, et al. PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas. Oncoimmunology. 2017;6(3):e1278100.
    1. Ben-Ami E, Barysauskas CM, Solomon S, Tahlil K, Malley R, Hohos M, et al. Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study. Cancer. 2017.
    1. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, et al. Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma. Immunity. 2017;46(2):197–204.
    1. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–24.
    1. Maki RG, Jungbluth AA, Gnjatic S, Schwartz GK, D’Adamo DR, Keohan ML, et al. A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma. Sarcoma. 2013;2013:168145.
    1. Shen JK, Cote GM, Choy E, Yang P, Harmon D, Schwab J, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2(7):690–8.
    1. Tsukahara T, Kawaguchi S, Torigoe T, Asanuma H, Nakazawa E, Shimozawa K, et al. Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8–5. Cancer Sci. 2006;97(12):1374–80.
    1. Mechtersheimer G, Staudter M, Majdic O, Dorken B, Moldenhauer G, Moller P. Expression of HLA-A,B,C, beta 2-microglobulin (beta 2m), HLA-DR, -DP, -DQ and of HLA-D-associated invariant chain (Ii) in soft-tissue tumors. Int J Cancer. 1990;46(5):813–23.
    1. Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol. 1992;10(8):1310–6.
    1. Brinkrolf P, Landmeier S, Altvater B, Chen C, Pscherer S, Rosemann A, et al. A high proportion of bone marrow T cells with regulatory phenotype (CD4+CD25hiFoxP3+) in Ewing sarcoma patients is associated with metastatic disease. Int J Cancer. 2009;125(4):879–86.
    1. Berghuis D, Santos SJ, Baelde HJ, Taminiau AH, Egeler RM, Schilham MW, et al. Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression. J Pathol. 2011;223(3):347–57.
    1. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, et al. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 2016;6:24.
    1. Italiano A, Le Cesne A, Bellera C, Piperno-Neumann S, Duffaud F, Penel N, et al. GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study. Ann Oncol. 2013;24(11):2922–6.
    1. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovee JV. Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol. 2016;29(9):1028–37.
    1. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–31.

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