SPEAR T-Cell Therapy Induces Durable Responses in Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Brian A. Van Tine, MD, PhD

Afamitresgene autoleucel (Afami-cel) formerly ADP-A2M4) has demonstrated efficacy and an encouraging durability of responses in patients with advanced synovial sarcoma or myxoid/ round cell liposarcoma (MRCLS), according to results from the SPEARHEAD 1 trial (NCT04044768).¹

“The data demonstrate that afami-cel is efficacious in a heavily pretreated patient population,” Brian A. Van Tine, MD, PhD, said in a presentation during the Connective Tissue Oncology Society (CTOS) 2021 Virtual Annual Meeting. Van Tine is a professor of medicine in the Division of Oncology at Washington University School of Medicine in St Louis, Missouri.

Afami-cel is an autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy that is engineered to target MAGE-A4 in tumor cells in the context of HLA-A*02 expression.^1,2

The ongoing, single-arm, open-label phase 2 SPEARHEAD 1 trial is examining the potential of afami-cel in patients with advanced synovial sarcoma or MRCLS, both of which express MAGE-A4. The study is enrolling patients aged 16 to 75 years with HLA-A*02–positive disease, as identified by immunohistochemistry. Patients must have an ECOG performance status of 0 or 1, MAGE-A4 expression in tumor cells, and previous treatment with an anthracycline- or an ifosfamide-containing regimen.

The primary end point is overall response rate (ORR) per RECIST criteria by independent review, and secondary end points are duration of response (DOR), time to response (TTR), progression-free survival, overall survival, and safety and tolerability.

Following screening for HLA-A*02 and MAGE-A4, eligible patients undergo leukapheresis and manufacturing of afami-cel. Lymphodepletion occurs at days –7 to –4 prior to infusion. Patients will then be followed for up to 15 years.

Clinical Results

The trial is ongoing with 90 patients expected to be treated between the 2 cohorts. Enrollment is complete in cohort 1. Cohort 2 is expected to help strengthen the efficacy and safety data of cohort 1 and aid in subgroup analyses. Thus far, as of the CTOS presentation data cutoff date of September 1, 2021, 59 patients have undergone leukapheresis, 84.7% of whom have received T-cell infusion; 8 patients discontinued prior to infusion, and 1 patient is pending infusion.¹

Of the patients who have undergone afamicel infusion, the median age was 41 years (range, 19-73), 54% are male, 86% are White, 74% are from North America, and 56% had an ECOG performance status of 0. Eighty-four percent of the participants had synovial sarcoma, and 16% had MRCLS. Median MAGE-A4 expression score was 230.6 and was higher in those with synovial sarcoma. The median number of prior lines of systemic therapy was 3 (range, 1-12).

By independent review, 47 patients were evaluable for response and showed an ORR of 34.0% (95% CI, 20.86%-49.31%), all partial responses. Stable disease was achieved by 51.1%, resulting in a disease control rate of 85.1%. Among patients with synovial sarcoma, the ORR was 35.9%, and it was 25.0% in those with MRCLS.

By investigator review of all 50 infused patients, the ORR was 34.0% (95% CI, 21.21%- 48.77%), consisting of 2 complete responses and 15 partial responses. Half of the patients had stable disease, leading to a disease control rate of 84.0%.

The median TTR was 4.9 weeks (range, 4.1- 12.0), and the median DOR was not reached (range, 4.3+ to 65.3+).

Treatment-emergent adverse events (TEAEs) were observed in all patients and were grade 3 or higher in all patients. The most common TEAEs were lymphocyte count decrease (94%), neutrophil count decrease (86%), white blood cell count decrease (84%), cytokine release syndrome (66%), and nausea (62%). Grade 3 or higher TEAEs of lymphocyte count decrease (94%), neutrophil count decrease (80%), and white blood cell count decrease (80%) were most common.

Serious TEAEs related to T-cell infusion were reported in 24% of patients, including cytokine release syndrome in 6%, pyrexia in 4%, and pleural effusion, deep vein thrombosis, empyema, and pulmonary embolism in 2% each. Cytokine release syndrome occurred in 66% of patients at any grade but was only grade 3 or higher in 2%. The time to onset was a median of 3 days (range, 1-23), and the time to resolution was a median of 3 days (range, 1-14). Thirty percent required use of tocilizumab (Actemra) for resolution. Immune effector cell–associated neurotoxicity syndrome was reported in 2% of patients.

“The benefit-to-risk profile of afami-cel has been favorable with low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities,” Van Tine said, adding that the data from the first cohort are expected to support a biologics license application to be submitted to the FDA in 2022.

Translational Results

In a poster presentation during the CTOS meeting, investigators examined translational findings from the SPEARHEAD 1 trial.²

Investigators reviewed peripheral blood-derived samples and tumor biopsy samples from before and after infusion of afami-cel. They found that cytotoxic activity of afami-cel was driven more by CD8-positive SPEAR T cells than CD4 (P <.0001), but the tumor-killing capacity was similar in both synovial sarcoma and MRCLS patient populations.

Afami-cel persistence was noted at all sampling time points in most patients. At 24 weeks or beyond, 70% of 20 evaluable patients had persistence above 20,000 vector copies per μg of peripheral blood mononuclear cell DNA.

Infusion of afami-cel was associated with upregulation of certain peripheral markers related to interferon-γ markers. The investigators found that tumor response could be sustained because of the peripheral persistence of the drug and serum immune response.

The SPEAR T cells colocalized with both tumor and immune cells, showing evidence of an activated state and proliferation as well as an adaptive immune response.

Responses to treatment with afami-cel were found regardless of MAGE-A4 expression levels (H-score; range, 134-300). These results were found to be consistent with analyses of afamicel from prior phase 1 and 2 clinical studies.

_REFERENCES

_{1. Van Tine BA, D’Angelo SP, Attia S, et al. SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. Paper presented at: Connective Tissue Oncology Society 2021 Virtual Annual Meeting; November 10-13, 2021; virtual. Paper 30.}

_{2. D’Angelo SP, Attia S, Blay JY, et al. SPEARHEAD-1: preliminary translational insights from a phase 2 trial of Afamitresgene Autoleucel (formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. Poster presented at: Connective Tissue Oncology Society 2021 Virtual Annual Meeting; November 10-13, 2021. Poster P146.}