Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial

  • Lancet. 2024 Apr 13;403(10435):1460-1471. doi: 10.1016/S0140-6736(24)00319-2.
Sandra P D'Angelo  1 ,  Dejka M Araujo  2 ,  Albiruni R Abdul Razak  3 ,  Mark Agulnik  4 ,  Steven Attia  5 ,  Jean-Yves Blay  6 ,  Irene Carrasco Garcia  7 ,  John A Charlson  8 ,  Edwin Choy  9 ,  George D Demetri  10 ,  Mihaela Druta  11 ,  Edouard Forcade  12 ,  Kristen N Ganjoo  13 ,  John Glod  14 ,  Vicki L Keedy  15 ,  Axel Le Cesne  16 ,  David A Liebner  17 ,  Victor Moreno  18 ,  Seth M Pollack  19 ,  Scott M Schuetze  20 ,  Gary K Schwartz  21 ,  Sandra J Strauss  22 ,  William D Tap  23 ,  Fiona Thistlethwaite  24 ,  Claudia Maria Valverde Morales  25 ,  Michael J Wagner  26 ,  Breelyn A Wilky  27 ,  Cheryl McAlpine  28 ,  Laura Hudson  28 ,  Jean-Marc Navenot  29 ,  Tianjiao Wang  29 ,  Jane Bai  29 ,  Stavros Rafail  29 ,  Ruoxi Wang  28 ,  Amy Sun  29 ,  Lilliam Fernandes  29 ,  Erin Van Winkle  29 ,  Erica Elefant  29 ,  Colin Lunt  28 ,  Elliot Norry  29 ,  Dennis Williams  29 ,  Swethajit Biswas  28 ,  Brian A Van Tine  30
Affiliations
  • 1. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: [email protected].
  • 2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. University Health Network, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • 4. City of Hope, Duarte, CA, USA.
  • 5. Mayo Clinic, Jacksonville, FL, USA.
  • 6. Centre Léon Bérard, Lyon, France.
  • 7. Hospital Virgen del Rocío, Seville, Spain.
  • 8. Medical College of Wisconsin, Milwaukee, WI, USA.
  • 9. Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • 10. Dana Farber Cancer Institute, Boston, MA, USA; Ludwig Center at Harvard Medical School, Boston, MA, USA.
  • 11. Moffitt Cancer Center, Tampa, FL, USA.
  • 12. Centre Hospitalier Universitaire de Bordeaux-Hôpital Haut-Lévêque, Bordeaux, France.
  • 13. Stanford Cancer Institute, Stanford Medicine at Stanford University, Palo Alto, CA, USA.
  • 14. Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.
  • 15. Vanderbilt University Medical Center, Nashville, TN, USA.
  • 16. Institut Gustave Roussy Cancer Center-DITEP, Villejuif, France.
  • 17. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 18. START Madrid-FJD, Hospital Universitario Fundación Jiménez Diaz, Madrid, Spain.
  • 19. Northwestern University, Chicago, IL, USA.
  • 20. University of Michigan Health System, Ann Arbor, MI, USA.
  • 21. Columbia University Vagelos School of Medicine, New York, NY, USA.
  • 22. UCL Cancer Institute, University College London NHS Foundation Trust, London, UK.
  • 23. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
  • 24. The Christie NHS Foundation Trust, Manchester, UK; University of Manchester, Manchester, UK.
  • 25. Hospital Universitari Vall d'Hebron, Barcelona, Spain.
  • 26. Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
  • 27. University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 28. Adaptimmune, Abingdon, UK.
  • 29. Adaptimmune, Philadelphia, PA, USA.
  • 30. Washington University School of Medicine, St Louis, MO, USA.
PMID: 38554725 DOI: 10.1016/S0140-6736(24)00319-2
Abstract

Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3.

Findings: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred.

Interpretation: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.

Funding: Adaptimmune.