Afami-cel T-Cell Therapy Shows Early Efficacy in Synovial Sarcoma

Afamitresgene autoleucel (afami-cel), a T-cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), showed efficacy and an acceptable benefit-risk profile in a phase 1 clinical trial of patients with metastatic solid tumors.¹

The multicenter phase 1 dose escalation trial (NCT03132922) of 38 patients with 9 different types of pretreated metastatic solid tumors reported an objective response rate (ORR) of 24% (95% CI, 11.4-40.2) for all patients but a 44% ORR (95% CI, 19.8-70.1) among 16 patients with synovial sarcoma.² However, all patients experienced grade 3 or higher hematologic toxicities.

“These high response rates are significant because patients with synovial sarcoma really have very few options after high-dose chemotherapy with ifosfamide,” David S. Hong, MD, principal investigator and professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said in a statement.¹

MAGE-A4 is a cancer/testis antigen expressed in multiple solid cancer types. Afami-cel is an autologous T-cell therapy designed to target a MAGE-A4 peptide on the cell surface.²

Investigators in the phase 1 trial screened patients for MAGE-A4 positivity and enrolled 63 eligible patients, but only 60 underwent leukapheresis and 38 received therapy with afami-cel. The disease types included in the trial were synovial sarcoma, myxoid/round cell liposarcoma ovarian cancer, head and neck cancer, urothelial cancer, gastric cancer, esophageal cancer, melanoma, and non–small cell lung cancer. They had received a median of 3 prior lines of therapy (range, 1-8). The majority were under 65 years old (73.7%; n = 28) and were male (57.9%, n = 22).

The primary end points included the number of adverse events (AEs) and serious AEs, dose-limiting toxicities, and persistence of genetically modified T cells. Secondary end points included ORR, duration of response (DOR), and time to progression.

Patients received lymphodepletion therapy with cyclophosphamide and fludarabine prior to dosing of afami-cel. The trial used a 3+3 design for dose escalation of afami-cel across 3 groups and an expansion group. Group 1 received between 0.08 × 10⁹ and 0.12 × 10⁹ cells, Group 2 received 0.5 × 10⁹ to 1.2 × 10⁹ cells,and Group 3 received 1.2 × 10⁹ to 6.0 × 10⁹ cells. The expansion group received between 1.2 × 10⁹ and 10 × 10⁹ cells. Eligible patients who had a confirmed response could receive a second cell infusion after disease progression.

The disease control rate (DCR) was 74% including 9 partial responses (PR) and 19 patients with stable disease (SD). The DCR for patients with synovial sarcoma was 94% including 7 PRs and 8 with SD. The median DOR was 25.6 weeks (95% CI, 12.286-not reached [NR]) for all patients and 28.1 weeks (95% CI, 12.286-NR) for 16 patients with synovial sarcoma. Three patients with synovial sarcoma were progression-free after 12 months, and 44% were alive at 12 months. Two of these patients received a second infusion after progression but had no response.

In terms of safety, the most common grade 3 or higher treatment-emergent AEs were decreased lymphocyte count in 37 patients (97.4%), decreased white blood cell count in 34 patients (89.5%), and decreased neutrophil count in 33 (86.8%). Non-hematologic AEs were rarely grade 3 or higher.

Twenty-one patients (55.3%) had cytokine release syndrome, 2 of which were grade 3 or 4, and all were resolved. Two patients (5%) had grade 1 or 2 immune effector cell-associated neurotoxicity syndrome/encephalopathy and 6 more had possibly treatment-related neurological AEs. Nine patients reported skin rash potentially related to afami-cel in the expansion cohort, including 3 with grade 3 toxicity.

There were 3 deaths attributed to AEs, 2 of which were potentially related to treatment: a 77-year-old patient with synovial sarcoma died of aplastic anemia following grade 3 cytopenia, and a 71-year-old patient with ovarian cancer died of ischemic cerebrovascular accident following grade 3 neurotoxicity.

The recommended phase 2 dose was determined to be 1.0 × 10⁹ to 10 × 10⁹ transduced cells. Based on these results, investigators initiated the phase 2 SPEARHEAD-1 trial (NCT04044768) of afami-cell for patients with synovial sarcoma or myxoid/round cell liposarcoma.

“The overall toxicity from afami-cel was manageable, and we saw evidence of early activity in other cancer types,” said Hong in a statement.¹ “These results suggest this is an approach with the potential to work in solid tumors where there are currently no approved cellular therapies.”

_References:

_{1. Novel T cell receptor therapy shows early anti-tumor activity. The University of Texas MD Anderson Cancer Center. January 9, 2023. Accessed January 11, 2023. https://bit.ly/3ityMUT}

_{2. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. Published online January 9, 2023. doi:10.1038/s41591-022-02128-z}