Innovative Therapy for MAGE-A4+ Synovial Sarcoma: Afami-Cel’s Results in the SPEARHEAD-1 Trial

Afamitresgene autoleucel (afami-cel, Tecelra; Adaptimmune Therapetics plc) may be an effective treatment for adult patients with advanced melanoma-associated antigen A4 (MAGE-A4)+ synovial sarcoma who received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen. Positive results from the SPEARHEAD-1 trial (NCT04044768) demonstrated the success of afami-cel, the first approved engineered cell therapy for treating synovial sarcoma, and highlighted its capabilities in improving overall response rate (ORR) and duration of response (DoR) in patients.¹

The promising findings have substantial implications for patients with advanced MAGE-A4+synovial sarcoma who are in need of alternative therapeutic options. Image Credit: © kamonrat - stock.adobe.com

Synovial sarcoma, also called soft tissue sarcoma, is a rare, soft tissue malignancy that occurs in the body’s connective tissues near large joints in the arms or legs and typically affects young adults. There are over 50 types that are categorized by tumors present in the fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. The main treatment for synovial sarcoma is typically surgery to remove the malignant tissues, in addition to radiation therapy or chemotherapy. The 5-year survival rate for diagnosed patients with metastatic disease is about 20%; most patients relapse, often requiring them to undergo multiple lines of therapy.²

Afami-cel is the first engineered cell therapy, marking a significant advancement in treatment options for patients with synovial sarcoma. It is a MAGE-A4-directed genetically modified autologous T-cell immunotherapy.³

“[Afami-cel], which uses each patient’s own immune cells to recognize and attack their cancer cells in a one-time infusion treatment, is significantly different than the current standards of care for advanced synovial sarcoma,” said Sandra D’Angelo, MD, sarcoma medical oncologist and cell therapist at Memorial Sloan Kettering Cancer Center and principal trial investigator, in a press release. “This approval represents a much-needed new option for people diagnosed with this sarcoma, and an important milestone for the use of cell therapies in solid tumor cancers.”³

The SPEARHEAD-1 trial is an open-label, non-randomized, phase 2 study conducted at 23 sites across Canada, the US, and Europe. Investigators enrolled 44 participants divided into 3 cohorts, with a primary focus on cohort 1 consisting of HLA-A*02-positive patients aged 16 to 75 years with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma expressing MAGE-A4, and who had previously undergone at least 1 line of anthracycline- or ifosfamide-containing chemotherapy. They received intravenous afami-cel (transduced dose range 1·0 × 109–10·0 × 109 T cells) after lymphodepletion. The primary end point was ORR, which was assessed by a masked independent review using Response Evaluation Criteria in Solid Tumours.⁴

The results showed that patients receiving afami-cel had a 43% ORR with a complete response rate of 4.5%. Additionally, median DoR was 6 months (95% CI: 4.6, not reached), of which responsive patients had a 39% DoR of 12 months or longer. There were some adverse events (AEs) associated with the treatment, including cytokine release syndrome in 71% of 52 patients. The most common grade 3 or worse AEs were lymphopenia (96%), neutropenia (85%), and leukopenia (81%); no treatment-related deaths occurred.⁴

The promising findings have substantial implications for patients with advanced MAGE-A4+ synovial sarcoma who are in need of alternative therapeutic options. On August 2, 2024, afami-cel received accelerated approval, advancing access to the treatment for patients in need.

“For decades, therapeutic options for people diagnosed with synovial sarcoma have been limited. With a current [5]-year survival rate as low as 36%, and for those with metastatic disease at diagnosis as low as 20%, it is long past time that [patients with] synovial sarcoma have expanded treatment options,” said Brandi Felser, chief executive officer of the Sarcoma Foundation of America, in a press release. “Since one third of patients are diagnosed under age 30, improved outcomes can have a tremendous impact. Today, there is a renewed sense of hope for this patient community.”³

REFERENCES

1. NCT04044768. A study of selinexor in patients with advanced solid tumors. ClinicalTrials.gov. Updated August 22, 2023. Accessed August 2, 2024. https://clinicaltrials.gov/ct2/show/NCT04044768
2. Soft tissue sarcoma. Mayo Clinic. April 27, 2023. Accessed August 2, 2024. https://www.mayoclinic.org/diseases-conditions/synovial-sarcoma/cdc-20387747#:~:text=Synovial%20sarcoma%20is%20a%20rare,a%20lump%20under%20the%20skin
3. Adaptimmune Receives U.S. FDA Accelerated Approval of TECELRA® (afamitresgene autoleucel), the First Approved Engineered Cell Therapy for a Solid Tumor. Business Wire. August 1, 2024. Accessed August 2, 2024. https://www.businesswire.com/news/home/20240801538240/en
4. D’Angelo S, Araujo D, Razak A, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. The Lancet. March 27, 2024. doi:10.1016/S0140-6736(24)00319-2