Afami-Cel Outcomes Are Tied to MAGE-A4 Expression, Tumor Burden in Synovial Sarcoma

Higher MAGE-A4 expression was associated with improved response and progression-free survival (PFS), and lower baseline tumor burden with longer overall survival (OS), in patients with advanced synovial sarcoma treated with afamitresgene autoleucel (afami-cel; Tecelra), according to a post hoc analysis of the phase 2 SPEARHEAD-1 trial (NCT04044768) presented at the 2026 SITC Annual Meeting.¹

Data showed that across the modified intention-to-treat population (n = 137), the overall response rate (ORR) per independent review was 43.8% (95% CI, 35.3%-52.5%), including complete responses in 3.6% of patients and partial responses in 40.1%. In the multivariate analysis, patients with a MAGE-A4 H-score at or above the median (n = 69) achieved an ORR of 53.6% vs 33.8% for those with an H-score below the median (n = 68; adjusted OR, 3.03; 95% CI, 1.29-7.09; P = .011). A higher H-score was also independently associated with longer PFS (adjusted HR, 0.60; 95% CI, 0.38-0.93; P = .024).

Patients with a baseline sum of lesion diameters (SLD) of at least 10 cm (n = 54) had a significantly higher risk of death than those with a baseline SLD under 10 cm (n = 75; adjusted HR, 2.77; 95% CI, 1.53-4.99; P = .0007).

"In SPEARHEAD-1, a higher MAGE-A4 [H-]score was associated with an increased likelihood of response and longer progression-free survival," lead study author Sandra P. D'Angelo, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation of the data. "Baseline sum of largest diameter influenced survival. [Patients] that had [a] tumor burden of less than 10 [cm] had longer overall survival on the multivariate analysis."

Why were predictors of afami-cel benefit explored?

Afami-cel is an autologous T-cell therapy composed of CD4-positive and CD8-positive cells that carry an engineered T-cell receptor directed against MAGE-A4. In June 2026, the FDA granted full approval to afami-cel for adults and children 12 years of age and older who have advanced synovial sarcoma and previously received chemotherapy, drawing on independently reviewed efficacy from all SPEARHEAD-1 cohorts.²

D'Angelo noted, however, that benefit with afami-cel varies considerably between patients and that the factors driving that variability have not been established.¹ The current analysis set out to determine which baseline characteristics of the patient, the tumor, and the infused cells' kinetics tracked with efficacy.

How was the analysis designed?

Patients in the SPEARHEAD-1 trial underwent prescreening for HLA type and MAGE-A4 tumor antigen expression, followed by leukapheresis and afami-cel manufacturing. Patients then received lymphodepletion with fludarabine (Fludara) at 30 mg/m² for 4 days and cyclophosphamide (Cytoxan) at 600 mg/m² for 3 days, followed by a single infusion of 1 × 10⁹ to 10 × 10⁹ transduced cells. Bridging therapy was permitted. Overall, 171 patients underwent leukapheresis and 137 received afami-cel across cohorts 1, 2, and 3. As of the December 27, 2025, data cutoff, the median follow-up was 41.8 months.

Among treated patients, the median age was 40.0 years (range, 13-73), 53.3% were male, and 86.1% were White. The median number of prior systemic therapy lines was 2.0 (range, 1-12), the median MAGE-A4 H-score was 256.0 (range, 66.0-300.0), and the median transduced cell dose was 7.2 × 10⁹ cells (range, 1.0-10.0). Additionally, 40.1% of patients received bridging therapy.

The investigators examined 5 factors selected in advance: sex (male vs female), line of therapy (3 or more vs 2 or fewer prior lines), baseline SLD (10 cm or more vs less than 10 cm), MAGE-A4 H-score (at or above vs below the median), and T-cell persistence, measured as the area under the curve from 0 to 6 months (at or above vs below the median). Associations with ORR were tested using logistic regression in both univariate and multivariate models, whereas Cox proportional hazards models and Kaplan-Meier methods were applied to duration of response (DOR), PFS, and OS; the multivariate models included all 5 factors as covariates.

What did the additional efficacy analyses show?

The median DOR was 5.3 months (95% CI, 4.5-8.2), the median PFS was 3.8 months (95% CI, 2.9-5.5), and the median OS was 20.8 months (95% CI, 14.8-26.3).

For ORR, no other factor reached statistical significance on multivariate analysis. The ORR was 49.1% vs 40.0% for patients with 3 or more vs 2 or fewer prior lines (adjusted OR, 2.23; 95% CI, 0.91-5.45; P = .079), 56.6% vs 45.3% for those with T-cell persistence at or above vs below the median (adjusted OR, 1.52; 95% CI, 0.63-3.67; P = .354), 39.7% vs 48.4% for male vs female patients (adjusted OR, 0.98; 95% CI, 0.42-2.29; P = .968), and 38.9% vs 52.0% for a baseline SLD of 10 cm or more vs less than 10 cm (adjusted OR, 0.58; 95% CI, 0.23-1.43; P = .236).

None of the 5 factors was significantly associated with DOR among responders (n = 60), although a higher MAGE-A4 H-score (adjusted HR, 0.57; 95% CI, 0.28-1.15; P = .118) and higher T-cell persistence (adjusted HR, 0.69; 95% CI, 0.34-1.39; P = .296) trended toward longer DOR. For PFS, higher T-cell persistence showed a nonsignificant trend toward benefit (adjusted HR, 0.65; 95% CI, 0.41-1.05; P = .077). For OS, neither T-cell persistence (adjusted HR, 0.62; 95% CI, 0.34-1.12; P = .112) nor MAGE-A4 H-score (adjusted HR, 0.65; 95% CI, 0.37-1.14; P = .135) was independently associated with survival.

What are the limitations and next steps?

The investigators cautioned that the relatively small sample constrains these post hoc findings, which will need confirmation in additional studies before they can be used to identify which patients are most likely to benefit from cellular therapy. They added that because sex and treatment line did not track with efficacy, afami-cel remains a reasonable option regardless of either factor.

References

1. D'Angelo SP, Abdul Razak A, Le Cesne A, et al. The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel) in advanced synovial sarcoma: factors associated with clinical outcomes. Paper presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 504
2. US WorldMeds receives Full U.S. FDA approval of Tecelra (afamitresgene autoleucel) with an expanded indication, extending the first approved engineered T-cell therapy for a solid tumor to children as young as 12. News release. US WorldMeds. June 22, 2026. Accessed June 22, 2026. https://www.prnewswire.com/news-releases/us-worldmeds-receives-full-us-fda-approval-of-tecelra-afamitresgene-autoleucel-with-an-expanded-indication-extending-the-first-approved-engineered-t-cell-therapy-for-a-solid-tumor-to-children-as-young-as-12-302806599.html?tc=eml_cleartime