Detailed information about Afamitresgene autoleucel Intravenous (IV)

Oncology-Cellular

Afamitresgene autoleucel Intravenous (IV)

Adaptimmune

Proposed indications

Advanced synovial sarcoma

U.S. Food and Drug Administration (FDA) approval timeline

August 4, 2024

• Orphan drug
• Priority review
• Regenerative Medicine Advanced Therapy (RMAT)

Place in therapy

Afamitresgene autoleucel (afami-cel) is an autologous T-cell therapy transduced via a lentiviral vector (LVV) to express a high-affinity and specific T-cell receptor that targets melanoma-associated antigen A4 (MAGE-A4) peptides expressed along with human leukocyte antigen-A2 (HLA-A2) on the tumor cell surface.

• Afami-cel will be a first-in-class T-cell receptor T-cell therapy directed at MAGE-A4 demonstrating benefit in treating advanced cases of synovial sarcoma
• If approved, it may prove to be an important treatment option for patients with advanced synovial sarcoma, a population with poor prognosis and limited options
• Compared to the historical overall survival (OS) in patients with synovial sarcoma, patients who received ≥ 2 prior lines of therapy had better outcomes with afami-cel
• Afami-cel is also being evaluated in SPEARHEAD-3 which includes pediatric patients ≥ 2 years of age with malignant peripheral nerve sheath tumors, neuroblastoma, osteosarcoma, or synovial sarcoma
• If approved, afami-cel may compete with pipeline agent letetresgene autoleucel (lete-cel) IV, an autologous T-cell agent targeting cancer cells that express the cancer testis antigen New York esophageal squamous cell carcinoma (NY-ESO-1), which is also in development for soft tissue sarcoma

Understanding your data

Afamitresgene autoleucel (afami-cel) is a CD4+ and CD8+ T-cell product taken from a person’s own tissues. It is converted with a self-inactivating LVV to express a T-cell receptor that has an enhanced affinity to MAGE-A4. Afami-cel has demonstrated durable responses in heavily pre-treated patients with synovial sarcoma who are positive for MAGE-A4 and HLA-A*02. There are several ongoing clinical trials that include:

• NCT04044768 SPEARHEAD-1: A phase 2 single arm open-label clinical trial of ADP-A2M4 SPEAR™ T cells in subjects with advanced synovial sarcoma or myxoid/round cell liposarcoma
• NCT05642455: A phase 1/2 open label, basket study to assess the safety, tolerability, and anti-tumor activity of afami-cel in pediatric subjects with MAGE-A4 positive tumors
• NCT03132922: Phase 1 dose escalation, multi-tumor study to assess the safety, tolerability, and antitumor activity of genetically engineered MAGE-A4ᶜ¹º³²T in HLA-A2+ subjects with MAGE-A4 positive tumors
• NCT05642455 SPEARHEAD-3: A phase 1/2 open label, basket study to assess the safety, tolerability, and anti-tumor activity of afami-cel in pediatric subjects with MAGE-A4 positive tumors

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

• Age between 10 and 75 years old
• Diagnosis of synovial sarcoma or myxoid/round cell liposarcoma
• Previously received anthracycline or ifosfamide containing regime

Common measurable exclusion criteria:

• Symptomatic CNS metastases
• Active infection with HIV, HBV, HCV, or human T cell leukemia virus
• Pregnant or breastfeeding

Appendix

Clinical deep dive

Disease state overview

Sarcoma is a rare type of cancer and is the general term used for a group of cancers that begin in the bones and in the soft tissues (muscle, fat, blood vessels, nerves, tendons, lining of joints). Synovial sarcoma is a soft tissue sarcoma that is usually slow growing and it typically occurs near large joints such as the knee manifesting as swelling or a lump under the skin. It can occur anywhere in the body and most common places are the extremities (arms and legs) (43%), followed by the visceral areas (19%), retroperitoneum (15%), trunk (10%) or head and neck (9%).

Synovial sarcoma is a mesenchymal tumor caused by translocation between chromosomes X and 18 that results in the expression of several SS18:SSX fusion proteins. Synovial sarcoma is primarily diagnosed in adolescents and adults under 30 years of age. It is an aggressive tumor with a high likelihood for metastasis. The overall five-year survival rate is estimated between 36% to 76%, and depends on tumor size, location, and tumor spread. MAGE-A4 is present in up to 82% of synovial sarcoma tumors and is not expressed in normal tissue, making it a potential target for treatment. The HLA-A2 tissue marker is present in about 40% of synovial sarcomas.

Epidemiology

According to American Cancer Society, soft tissue sarcomas will be diagnosed in about 13,590 persons in the US in 2024. Synovial sarcoma accounts for 5% to 10% of soft tissue sarcomas, with about 800 to 1,000 new cases occurring each year in the U.S.

Treatment

Surgical resection with radiation therapy is the standard of care for localized synovial sarcoma. Neoadjuvant or adjuvant chemotherapy (anthracycline-based regimen ± ifosfamide) is also used and is associated with an estimated response rate of 25% to 60%. Certain tyrosine kinase inhibitors are recommended in the presence of neurotrophic tyrosine receptor kinase (NTRK) gene mutation (Vitrakvi^® [larotrectinib], Rozlytrek^® [entrectinib]) or in the advanced or metastatic setting (Votrient^® [pazopanib]).

Drug and clinical trial overview

Afami-cel is being evaluated in SPEARHEAD-1, the ongoing, open-label, single-arm, phase 2 trial in patients (n=52) with metastatic or inoperable advanced synovial sarcoma or myxoid round cell liposarcoma. Enrolled patients are 16 to 75 years of age (10 years of age at select sites) and have tumors that are HLA-A*02 and MAGE-A4 positive. Patients received previous treatment with an anthracycline agent or ifosfamide, with a median of three prior lines of systemic therapy (range, 1 to 12). The median follow-up time was 32.6 months with an overall response rate (primary endpoint) of 39% in the synovial sarcoma group and 25% in the myxoid round cell liposarcoma group. In patients with synovial sarcoma, median time to initial response was 4.9 weeks, median duration of response was 11.6 months, and median progression-free survival was 3.8 months. There were insufficient number of patients in the myxoid round cell liposarcoma group to draw a conclusive analysis.The median overall survival (OS) with afami-cel in synovial sarcoma patients was higher compared to the historical OS in patients who received ≥ 2 prior lines of therapy (approximately 17 months versus < 12 months, respectively), and 70% of patients were alive 2 years after receiving afami-cel. Treatment emergent adverse events with afami-cel included cytokine release syndrome (71%, one grade 3 event) and hematologic toxicities (lymphopenia, neutropenia, leukopenia). There were no treatment-related deaths.

Afami-cel is administered via IV infusion as a single dose of 1 x 10⁹ to 10 x 10⁹ transduced specific peptide-enhanced affinity receptor (SPEAR) T cells. Patients received SPEAR T cells after leukapheresis and receiving lymphodepleting chemotherapy (cyclophosphamide and fludarabine). The median time from leukapheresis to manufacturing of afami-cel and completing release testing was 40 days. Thirty-eight percent of patients received bridging therapy during this period.

Pipeline (late-stage development)