Rationale for Requested Change: On Aug 1, 2024 the FDA approved afamitresgene autoleucel (afami-cel), an autologous T-cell therapy engineered to target MAGE-A4 peptides, for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared Companion Diagnostic device. The approval was based on the efficacy and safety data reported in Lancet Oncology for the pivotal phase 2 SPEARHEAD-1 trial. [1-3]
Synovial Sarcoma and T Cell Receptor (TCR) T Cell Therapy
Synovial sarcoma is a rare cancer that most commonly arises from the deep soft tissues of the extremities though it may also arise from the soft tissues of the trunk, thorax, and neck. Rarely, synovial sarcoma may develop in the retroperitoneal/intra-abdominal region. Diagnosis of synovial sarcoma is typically based on histology and the presence of t(X;18) chromosomal translocation. Treatment is multimodal, including surgery, chemotherapy, and radiotherapy. Although there is initial sensitivity to chemotherapy, these tumors have very poor outcomes after metastasis [4], highlighting the need for new and innovative treatment options.
Afami-cel is a TCR T cell therapy transduced to express an affinity-enhanced melanoma-associated antigen 4 (MAGE-A4) presented in an HLA-restricted manner. As a novel adoptive immunotherapy, early integration of biomarker testing is key in determining patient eligibility. A recent publication reported the validation of the HLA and MAGE-A4 assays, including the data from the SPEARHEAD-1 trial and a multinational screening study that prospectively evaluated HLA subtypes and MAGE-A4 profiles to determine eligibility for metastatic solid cancers. [5] These results, in combination with the FDA-approved screening assays, provide the necessary basis for identifying the target patient population for afami-cel.
SPEARHEAD-1 Clinical Trial Efficacy Data
SPEARHEAD-1 is a phase 2, single-arm, multicenter study that evaluated the efficacy and safety of afami-cel in HLA-A*02 eligible and MAGE-A4 positive patients with metastatic or inoperable synovial sarcoma or myxoid round cell liposarcoma (MRCLS), tumors that highly express MAGE-A4. Patients with metastatic or unresectable synovial sarcoma or MRCLS (comprising 5–10% of all soft-tissue sarcomas) typically have very poor long-term survival, especially after disease recurrence on first-line therapy. [4] The SPEARHEAD-1 trial enrolled 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and MRCLS (n=8). Patients received at least 1 prior line of systemic therapy (median, 3 [IQR 2–4]). [2,3]
At a median follow-up of 32.6 months, the overall response rate (ORR) was 37% (19 of 52; 95% CI 24–51) with all patients achieving a partial response. The trial met the primary endpoint of improved ORR as the lower limit of the 95% CI exceeded the prespecified null hypothesis rate of 18%, as defined in the protocol criterion. The ORR was 39% (17 of 44; 95% CI 24–55) for patients with synovial sarcoma and 25% (two of eight; 95% CI 3–65) for patients with MRCLS. There was a high-level of concordance between the independently assessed and investigator-assessed response rates. Median time to initial confirmed response was 4.9 weeks (95% CI 4.3–8.1) in patients with a response. Median duration of response was 11.6 months (95% CI 4.4–18.0) in patients with synovial sarcoma and 4.2 months (2.9–5.5) in patients with MRCLS. [2,3]
Median overall progression-free survival (PFS) was 3.7 months (95% CI 2.8–5.6). Median PFS was 3.8 months (2.8–6.4) and 2.4 months (0.9–7.4) in patients with synovial sarcoma and MRCLS, respectively. Median overall survival (OS) was 15.4 months (95% CI 10.9–28.7) in the overall population, with an OS probability of 60% (95% CI 46-73) at 12 months. Median OS was not reached (95% CI 15.4–not estimable) in patients with synovial sarcoma with a RECIST response. The estimated OS probability for patients with synovial sarcoma and a RECIST response was 90% (95% CI 65-99) at 12 months and 70% (95% CI 43-87) at 24 months. [2,3]
Median time from leukapheresis until manufacturing and completed release testing of afami-cel was 40 days (IQR 35–50); 38% of patients received bridging therapy. Median time from leukapheresis to the start of lymphodepletion in the modified intention-to-treat population was 53 days (IQR 43–73) overall, 56 days (50–87) in those receiving bridging therapy, and 50 days (40–68) in those who did not. The ORR was higher in patients who did not receive bridging therapy compared to patients who did (46% [95% CI 28–66] vs. 25% [95% CI 7–52]). [2,3]
Phase 1 Clinical Trial Efficacy Data
The multicenter, dose-escalation, phase 1 trial of afami-cel in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4 included patients with synovial sarcoma, ovarian cancer, and head and neck cancer. In the 16 patients with synovial sarcoma, ORR was 44% (95% CI 19.8–70.1) with a disease control rate of 94% including 7 partial responses and 8 stable disease. The median duration of response was 28.1?weeks (95% CI 12.3–not reached). Median PFS was 20.4?weeks (95% CI 10.0–52.1), and the median OS was 58.1?weeks (95% CI 36.3–not reached). The survival rates at 6 months, 12 months, and 18 months were 81%, 44% and 13%, respectively. Three patients were progression free for greater than 12?months. [6]
Safety data
In the SPEARHEAD-1 clinical trial, the most common grade 3 or higher adverse events included lymphopenia (96%), neutropenia (85%), and leukopenia (81%). Cytokine release syndrome events were mostly grade 1–2 with one patient reporting a grade 3 event. Cytokine release syndrome was managed with supportive care, and all cases were resolved. No treatment-related deaths occurred. [2,3] The safety profile was consistent with the phase 1 clinical trial. [6]
On [approval date], the FDA approved afamitresgene autoleucel (afami-cel), an autologous T-cell therapy engineered to target MAGE-A4 peptides, for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared Companion Diagnostic device. The approval was based on the efficacy and safety data reported in Lancet Oncology for the pivotal phase 2 SPEARHEAD-1 trial. [1-3]
Synovial Sarcoma and T Cell Receptor (TCR) T Cell Therapy
Synovial sarcoma is a rare cancer that most commonly arises from the deep soft tissues of the extremities though it may also arise from the soft tissues of the trunk, thorax, and neck. Rarely, synovial sarcoma may develop in the retroperitoneal/intra-abdominal region. Diagnosis of synovial sarcoma is typically based on histology and the presence of t(X;18) chromosomal translocation. Treatment is multimodal, including surgery, chemotherapy, and radiotherapy. Although there is initial sensitivity to chemotherapy, these tumors have very poor outcomes after metastasis [4], highlighting the need for new and innovative treatment options.
Afami-cel is a TCR T cell therapy transduced to express an affinity-enhanced melanoma-associated antigen 4 (MAGE-A4) presented in an HLA-restricted manner. As a novel adoptive immunotherapy, early integration of biomarker testing is key in determining patient eligibility. A recent publication reported the validation of the HLA and MAGE-A4 assays, including the data from the SPEARHEAD-1 trial and a multinational screening study that prospectively evaluated HLA subtypes and MAGE-A4 profiles to determine eligibility for metastatic solid cancers. [5] These results, in combination with the FDA-approved screening assays, provide the necessary basis for identifying the target patient population for afami-cel.
SPEARHEAD-1 Clinical Trial Efficacy Data
SPEARHEAD-1 is a phase 2, single-arm, multicenter study that evaluated the efficacy and safety of afami-cel in HLA-A*02 eligible and MAGE-A4 positive patients with metastatic or inoperable synovial sarcoma or myxoid round cell liposarcoma (MRCLS), tumors that highly express MAGE-A4. Patients with metastatic or unresectable synovial sarcoma or MRCLS (comprising 5–10% of all soft-tissue sarcomas) typically have very poor long-term survival, especially after disease recurrence on first-line therapy. [4] The SPEARHEAD-1 trial enrolled 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and MRCLS (n=8). Patients received at least 1 prior line of systemic therapy (median, 3 [IQR 2–4]). [2,3]
At a median follow-up of 32.6 months, the overall response rate (ORR) was 37% (19 of 52; 95% CI 24–51) with all patients achieving a partial response. The trial met the primary endpoint of improved ORR as the lower limit of the 95% CI exceeded the prespecified null hypothesis rate of 18%, as defined in the protocol criterion. The ORR was 39% (17 of 44; 95% CI 24–55) for patients with synovial sarcoma and 25% (two of eight; 95% CI 3–65) for patients with MRCLS. There was a high-level of concordance between the independently assessed and investigator-assessed response rates. Median time to initial confirmed response was 4.9 weeks (95% CI 4.3–8.1) in patients with a response. Median duration of response was 11.6 months (95% CI 4.4–18.0) in patients with synovial sarcoma and 4.2 months (2.9–5.5) in patients with MRCLS. [2,3]
Median overall progression-free survival (PFS) was 3.7 months (95% CI 2.8–5.6). Median PFS was 3.8 months (2.8–6.4) and 2.4 months (0.9–7.4) in patients with synovial sarcoma and MRCLS, respectively. Median overall survival (OS) was 15.4 months (95% CI 10.9–28.7) in the overall population, with an OS probability of 60% (95% CI 46-73) at 12 months. Median OS was not reached (95% CI 15.4–not estimable) in patients with synovial sarcoma with a RECIST response. The estimated OS probability for patients with synovial sarcoma and a RECIST response was 90% (95% CI 65-99) at 12 months and 70% (95% CI 43-87) at 24 months. [2,3]
Median time from leukapheresis until manufacturing and completed release testing of afami-cel was 40 days (IQR 35–50); 38% of patients received bridging therapy. Median time from leukapheresis to the start of lymphodepletion in the modified intention-to-treat population was 53 days (IQR 43–73) overall, 56 days (50–87) in those receiving bridging therapy, and 50 days (40–68) in those who did not. The ORR was higher in patients who did not receive bridging therapy compared to patients who did (46% [95% CI 28–66] vs. 25% [95% CI 7–52]). [2,3]
Phase 1 Clinical Trial Efficacy Data
The multicenter, dose-escalation, phase 1 trial of afami-cel in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4 included patients with synovial sarcoma, ovarian cancer, and head and neck cancer. In the 16 patients with synovial sarcoma, ORR was 44% (95% CI 19.8–70.1) with a disease control rate of 94% including 7 partial responses and 8 stable disease. The median duration of response was 28.1?weeks (95% CI 12.3–not reached). Median PFS was 20.4?weeks (95% CI 10.0–52.1), and the median OS was 58.1?weeks (95% CI 36.3–not reached). The survival rates at 6 months, 12 months, and 18 months were 81%, 44% and 13%, respectively. Three patients were progression free for greater than 12?months. [6]
Safety data
In the SPEARHEAD-1 clinical trial, the most common grade 3 or higher adverse events included lymphopenia (96%), neutropenia (85%), and leukopenia (81%). Cytokine release syndrome events were mostly grade 1–2 with one patient reporting a grade 3 event. Cytokine release syndrome was managed with supportive care, and all cases were resolved. No treatment-related deaths occurred. [2,3] The safety profile was consistent with the phase 1 clinical trial. [6]
On [approval date], the FDA approved afamitresgene autoleucel (afami-cel), an autologous T-cell therapy engineered to target MAGE-A4 peptides, for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared Companion Diagnostic device. The approval was based on the efficacy and safety data reported in Lancet Oncology for the pivotal phase 2 SPEARHEAD-1 trial. [1-3]
Synovial Sarcoma and T Cell Receptor (TCR) T Cell Therapy
Synovial sarcoma is a rare cancer that most commonly arises from the deep soft tissues of the extremities though it may also arise from the soft tissues of the trunk, thorax, and neck. Rarely, synovial sarcoma may develop in the retroperitoneal/intra-abdominal region. Diagnosis of synovial sarcoma is typically based on histology and the presence of t(X;18) chromosomal translocation. Treatment is multimodal, including surgery, chemotherapy, and radiotherapy. Although there is initial sensitivity to chemotherapy, these tumors have very poor outcomes after metastasis [4], highlighting the need for new and innovative treatment options.
Afami-cel is a TCR T cell therapy transduced to express an affinity-enhanced melanoma-associated antigen 4 (MAGE-A4) presented in an HLA-restricted manner. As a novel adoptive immunotherapy, early integration of biomarker testing is key in determining patient eligibility. A recent publication reported the validation of the HLA and MAGE-A4 assays, including the data from the SPEARHEAD-1 trial and a multinational screening study that prospectively evaluated HLA subtypes and MAGE-A4 profiles to determine eligibility for metastatic solid cancers. [5] These results, in combination with the FDA-approved screening assays, provide the necessary basis for identifying the target patient population for afami-cel.
SPEARHEAD-1 Clinical Trial Efficacy Data
SPEARHEAD-1 is a phase 2, single-arm, multicenter study that evaluated the efficacy and safety of afami-cel in HLA-A*02 eligible and MAGE-A4 positive patients with metastatic or inoperable synovial sarcoma or myxoid round cell liposarcoma (MRCLS), tumors that highly express MAGE-A4. Patients with metastatic or unresectable synovial sarcoma or MRCLS (comprising 5–10% of all soft-tissue sarcomas) typically have very poor long-term survival, especially after disease recurrence on first-line therapy. [4] The SPEARHEAD-1 trial enrolled 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and MRCLS (n=8). Patients received at least 1 prior line of systemic therapy (median, 3 [IQR 2–4]). [2,3]
At a median follow-up of 32.6 months, the overall response rate (ORR) was 37% (19 of 52; 95% CI 24–51) with all patients achieving a partial response. The trial met the primary endpoint of improved ORR as the lower limit of the 95% CI exceeded the prespecified null hypothesis rate of 18%, as defined in the protocol criterion. The ORR was 39% (17 of 44; 95% CI 24–55) for patients with synovial sarcoma and 25% (two of eight; 95% CI 3–65) for patients with MRCLS. There was a high-level of concordance between the independently assessed and investigator-assessed response rates. Median time to initial confirmed response was 4.9 weeks (95% CI 4.3–8.1) in patients with a response. Median duration of response was 11.6 months (95% CI 4.4–18.0) in patients with synovial sarcoma and 4.2 months (2.9–5.5) in patients with MRCLS. [2,3]
Median overall progression-free survival (PFS) was 3.7 months (95% CI 2.8–5.6). Median PFS was 3.8 months (2.8–6.4) and 2.4 months (0.9–7.4) in patients with synovial sarcoma and MRCLS, respectively. Median overall survival (OS) was 15.4 months (95% CI 10.9–28.7) in the overall population, with an OS probability of 60% (95% CI 46-73) at 12 months. Median OS was not reached (95% CI 15.4–not estimable) in patients with synovial sarcoma with a RECIST response. The estimated OS probability for patients with synovial sarcoma and a RECIST response was 90% (95% CI 65-99) at 12 months and 70% (95% CI 43-87) at 24 months. [2,3]
Median time from leukapheresis until manufacturing and completed release testing of afami-cel was 40 days (IQR 35–50); 38% of patients received bridging therapy. Median time from leukapheresis to the start of lymphodepletion in the modified intention-to-treat population was 53 days (IQR 43–73) overall, 56 days (50–87) in those receiving bridging therapy, and 50 days (40–68) in those who did not. The ORR was higher in patients who did not receive bridging therapy compared to patients who did (46% [95% CI 28–66] vs. 25% [95% CI 7–52]). [2,3]
Phase 1 Clinical Trial Efficacy Data
The multicenter, dose-escalation, phase 1 trial of afami-cel in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4 included patients with synovial sarcoma, ovarian cancer, and head and neck cancer. In the 16 patients with synovial sarcoma, ORR was 44% (95% CI 19.8–70.1) with a disease control rate of 94% including 7 partial responses and 8 stable disease. The median duration of response was 28.1?weeks (95% CI 12.3–not reached). Median PFS was 20.4?weeks (95% CI 10.0–52.1), and the median OS was 58.1?weeks (95% CI 36.3–not reached). The survival rates at 6 months, 12 months, and 18 months were 81%, 44% and 13%, respectively. Three patients were progression free for greater than 12?months. [6]
Safety data
In the SPEARHEAD-1 clinical trial, the most common grade 3 or higher adverse events included lymphopenia (96%), neutropenia (85%), and leukopenia (81%). Cytokine release syndrome events were mostly grade 1–2 with one patient reporting a grade 3 event. Cytokine release syndrome was managed with supportive care, and all cases were resolved. No treatment-related deaths occurred. [2,3] The safety profile was consistent with the phase 1 clinical trial. [6]
