In August 2024, Adaptimmune’s Tecelra (afami-cel) became the first engineered cell therapy to be approved (under FDA accelerated approval) for solid tumors. Tecelra is an autologous T-cell receptor (TCR) engineered therapy targeting the MAGE-A4 antigen. The approval was granted for the treatment of patients with advanced synovial sarcoma who are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen previously treated with chemotherapy (2L+).
Synovial sarcoma is an aggressive subtype of soft tissue sarcomas (STS), accounting for 5-10% of cases. Currently, most unresectable or metastatic sarcomas are treated either with single-agent chemotherapy or with anthracycline-based combinations in the 1L. Upon progression, patients typically switch to a different chemotherapy regimen such as Johnson & Johnson’s/PharmaMar’s Yondelis (trabectedin) or tyrosine kinase inhibitors (TKI), including Novartis’ Votrient (pazopanib) and Bayer’s Stivarga (regorafenib).
The approval was based on the Phase II SPEARHEAD-1 (Cohort 1) trial, with 44 patients, where Tecelra showed a 43% overall response rate (ORR) and a median duration of response of 6 months. The median overall survival (OS) in the synovial sarcoma population was not reached. Unfortunately, a control group was not included in this trial, therefore Tecelra’s efficacy cannot be properly assessed in context. In the REGOSARC Phase II trial, patients treated with Stivarga demonstrated a median progression-free survival (PFS) of 5.6 months vs 1 month for placebo. The mOS for Stivarga was 13.4 months vs 6.7 for placebo, however the ORR was only 8%. In the Phase III PALETTE trial, Votrient demonstrated a 4.6 month-mPFS vs 1.6 months for placebo across all STS patients. While the number was not provided for synovial sarcoma patients, a post-hoc analysis showed that the benefit was sustained in this subtype. ORR for Votrient was also only 8%. These results highlight the fact that physicians treating patients with synovial sarcoma will only have cross-trial comparisons available in order to decide whether Tecelra, one of the TKIs, or Yondelis, is the best option for a patient following progression on chemotherapy.
While Tecelra’s approval is a great step forward for the field, only a small subset of patients with synovial sarcoma will benefit from treatment. Firstly, only the fittest patients will be able to receive Tecelra given its side effect profile and the adverse effects of the myelosuppressive conditioning regimen. Secondly, it requires administration and short-term follow up in a designated center. Adaptimmune is currently on track to open 6-10 treatment centers and up to 30 in the first two years. Thirdly, the list price for the therapy is $727,000, which will make it prohibitively expensive for some US patients and will be much more expensive that either Stivarga or Votrient in the same line. Lastly, the number of US patients with the right HLA types and expressing MAGE-4 is only around 400. According to Adaptimmune’s latest presentation, the key to expanding the patient pool will be the introduction of the novel anti-NY-ESO-1 TCR agent lete-cel in both synovial and myxoid/round cell liposarcoma which would allow them to establish a sarcoma franchise worth up to $400M in peak sales. With the current data, this number seems optimistic given that many Tecelra-eligible patients will be treated with one of the competing established agents instead.
By Sakis Paliouras, PhD
References
[2] The Lancet Study
