FDA Approval Summary: Afamitresgene Autoleucel for Adults With HLA-Restricted MAGE-A4 Positive Unresectable or Metastatic Synovial Sarcoma After Prior Chemotherapy

Abstract

On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel, a melanoma-associated antigen-A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with unresectable or metastatic synovial sarcoma (SS) who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4 as determined by FDA-approved or cleared companion diagnostic devices. Approval was based on results from the phase 2, single-arm, open-label, multicenter Study ADP-0044–002. Patients received a single dose of afamitresgene autoleucel following lymphodepleting chemotherapy. Of the 44 efficacy evaluable patients, the overall response rate was 43.2% (95% CI: 28.4, 59.0), with complete response in two patients (4.5%). The median duration of response was 6.0 months (95% CI: 4.6, not reached [NR]) with a median follow-up of 21.9 months. Among the 44 patients, cytokine release syndrome occurred in 75% (Grade ≥3, 2%) warranting a Boxed Warning. Grade ≥3 infections occurred in 14% of patients and prolonged severe cytopenias also occurred. One patient developed Grade 1 immune effector cell-associated neurotoxicity and one patient developed Epstein-Barr virus-positive lymphoproliferative disease. Notably, during review of this application, FDA identified issues with data quality and study conduct that prompted an independent re-review of imaging assessments. The results of the re-review were the basis for FDA’s determination of substantial evidence of effectiveness. This represents the first FDA approval of a T-cell receptor gene therapy. It is also the first FDA approval specifically for SS, representing a new treatment modality for this rare population who lack effective therapies.

Introduction

On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel (Tecelra) for the treatment of adults with unresectable or metastatic synovial sarcoma (SS) who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express the melanoma-associated antigen A4 (MAGE-A4) antigen as determined by FDA-approved or cleared companion diagnostic devices. Companion diagnostics were contemporaneously cleared for human leukocyte antigen (HLA) and approved for MAGE-A4 (1,2).

Synovial sarcoma is a rare soft-tissue sarcoma (STS) affecting 800 to 1,000 people in the U.S. annually. It primarily occurs in adolescents and young adults. Approximately 50% of patients with SS develop recurrent or metastatic disease following standard-of-care treatment (3). Advanced unresectable and metastatic SS has a poor prognosis, with a reported median overall survival (OS) of approximately 16 to 24 months (3,4). While standard first-line treatment of advanced unresectable or metastatic SS includes combination anthracycline-based chemotherapy regimens, there is no consensus on optimal second-line therapy. The kinase inhibitor pazopanib is approved in the U.S. for patients with STS who received prior chemotherapy (5). Before this approval, there were no U.S. Food and Drug Administration (FDA)-approved therapies specifically for SS in any treatment setting.

Afamitresgene autoleucel is a genetically modified autologous T-cell immunotherapy consisting of cluster of differentiation (CD)4- and CD8-positive T cells transduced with a self-inactivating lentiviral vector. The transduced, autologous T cells express an enhanced-affinity T-cell receptor (TCR) specific for HLA-A*02-restricted MAGE-A4 peptides. MAGE-A4 is a cancer-testis antigen with restricted expression in normal tissues that is overexpressed in the majority of SS (6).

This report summarizes the FDA’s clinical review and regulatory decision making.

Trial Design

The safety and efficacy of afamitresgene autoleucel was evaluated in Study ADP-0044–002 (Spearhead 1; NCT04044768), a phase 2, single-arm, open-label, multicenter, multicohort clinical trial of afamitresgene autoleucel. Eligible patients were required to be 16 years of age or older with MAGE-A4 expressing advanced SS or myxoid/round cell liposarcoma who had received at least one prior line of chemotherapy. Patients were required to have an ECOG performance status of ≤1, have been treated with prior anthracycline- or ifosfamide-containing regimen, be positive for HLA-A*02:01, HLA-A*02:03, or HLA-A*02:06 allele based on high-resolution HLA typing at a centralized testing site , and have had measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). MAGE-A4 expression was defined as a 2+ staining in ≥30% of the cells by an immunohistochemistry (IHC) clinical trial assay at a centralized testing site. The study excluded patients who were positive for HLA-A*02:05 allele, had symptomatic central nervous system (CNS) metastases, or had received or planned to receive allogeneic hematopoietic stem cell transplant or gene therapy using an integrating vector prior to leukapheresis or lymphodepleting chemotherapy.

Following lymphodepleting chemotherapy with fludarabine 30 mg/m²/day for 4 days (Days −7 to −4) and cyclophosphamide 600 mg/m²/day for 3 days (Days −7 to −5), patients received a single infusion of afamitresgene autoleucel at the recommended dose range of 2.68 × 10⁹ to 10 × 10⁹ MAGE-A4 TCR-positive T cells on Day 1. Bridging therapy selected at the investigator’s discretion was allowed for disease control between apheresis and the start of lymphodepleting chemotherapy. Patients remained hospitalized for observation for at least 24 hours post-T-cell infusion.

The primary efficacy endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) according to RECIST v.1.1. Duration of response (DOR) was a key secondary endpoint.

The primary evidence to support the safety and effectiveness derives from Cohort 1 of Study ADP-0044–002; Cohort 2 provided supportive safety data.

Trial Results

Study Population

Of the 52 patients with SS enrolled in Cohort 1, 45 patients (87%) received lymphodepletion and 44 (85%) received afamitresgene autoleucel. The primary efficacy analysis population consists of patients with SS treated with afamitresgene autoleucel in Cohort 1 (i.e., the modified intent-to-treat [mITT] population; n=44). The median time from leukapheresis to start of lymphodepletion for the primary efficacy analysis population was 1.7 months.

The demographic and baseline characteristics of the mITT population are shown in Table 1. Sixty-four percent (28 of 44) of patients lived in the United States and 82% of patients were between the ages of 18 and 49. The study enrolled no pediatric patients.

Table 1.

Baseline Demographics and Disease Characteristics for SPEARHEAD-1, Cohort 1, mITT Population

Demographics/Characteristics	Synovial Sarcoma (N=44)
Age at time of consent (years)
Median (range)	40.5 (19, 73)
Sex, n (%)
Female	22 (50.0)
Male	22 (50.0)
Ethnicity, n (%)
Hispanic or Latino	2 (4.5)
Not Hispanic or Latino	38 (86.4)
Not reported	4 (9.1)
Race, n (%)
Asian	3 (6.8)
Black or African American	2 (4.5)
White	39 (88.6)
Geographical region, n (%)
Europe	13 (29.5)
North America	31 (70.5)
Stage of cancer, n (%)
Stage IV	44 (100)
Time from initial diagnosis to T-cell infusion (months)
Median (range)	41.2 (7, 257)
Prior lines of systemic therapy
Median (range)	3.0 (1, 12)
Prior lines of systemic therapy (categorical), n (%)
1	7 (15.9)
2	14 (31.8)
3	9 (20.5)
4+	14 (31.8)

Sources: FDA analysis of data from Study ADP-0044–002

Abbreviations: mITT = modified intent-to-treat, n = number of patients in a specified category, N = number of patients

Sixteen patients (36.4%) received bridging therapy, with pazopanib (25%), ifosfamide (7%), trabectedin (2%), or doxorubicin (2%). The median dose of afamitresgene autoleucel administered was 8 × 10⁹ MAGE-A4 TCR-positive T cells (range: 2.68 × 10⁹ to 9.99 × 10⁹).

Efficacy

The efficacy results are shown in Table 2. The ORR was 43.2% (95% CI: 28.4, 59.0). The median duration of follow-up for all patients was 21.9 months by reverse Kaplan Meier (KM) estimate. Among the 19 patients who achieved a response, durable response at 6, 12, and 24 months was 45.6%, 39.0%, and 39.0%, respectively, based on KM estimate. DOR was censored for 8 of the 19 responders (42%) as of the data cut-off. Reasons for censoring included being alive and progressive disease free (n=5), end of intervention phase before progressive disease (n=2), and missing imaging assessments (n=1).

Table 2.

Efficacy Outcomes per IRC for SPEARHEAD-1, Cohort 1, mITT Population

Parameter	Efficacy population N=44
Overall response rate
CR+PR, n (%)	19 (43.2)
(95% CI)a	(28.4, 59.0)
Best overall response, n (%)
CR	2 (4.5)
PR	17 (38.6)
SD	20 (45.5)
PD	5 (11.4)
Duration of responseb#
Median	6.0 months
95% CI	(4.6, NR)
Range	1.9, 36.1+
Time to responseb
Median	4.9 weeks
95% CI	(4.4, 8)

Source: FDA analysis of independent re-review data from Study ADP-0044–002

^a.Two-sided 95% CI based on exact Clopper-Pearson (exact binomial) method.

^b.Estimated using the Kaplan-Meier method.

^#Duration of response only applies to patients with a complete or partial response.

Abbreviations: CI = confidence interval, CR = complete response, IRC = independent review committee, mITT = modified intent-to-treat, n = number of patients in a specified category, N = number of patients, NR = not reached, ORR = overall response rate, PD = progressive disease, PR = partial response, SD = stable disease

Safety

The primary safety analysis population consists of the 44 patients with SS enrolled in Cohort 1 who received afamitresgene autoleucel within the intended dose range.

The most common adverse reactions are shown in Table 3. Grade 3 or 4 laboratory abnormalities that worsened from baseline and occurred in ≥20% of patients were lymphopenia, neutropenia, leukopenia, anemia, and thrombocytopenia. A total of 37 patients died during the study, 24 patients in Cohort 1. All deaths were due to disease under study and occurred >30 days after afamitresgene autoleucel administration except for one patient in Cohort 2 who died due to septic shock 9 days after afamitresgene autoleucel administration and after the data cut-off date.

Table 3.

Adverse Reactions Occurring in ≥10% of Patients in SPEARHEAD-1, Cohort 1

SOC Grouped Term	(N=44)
	All Grades n (%)	Grade 3–4 n (%)
Investigations
Weight decreased	5 (11)	1 (2)
Gastrointestinal disorders
Nausea	29 (66)	1 (2)
Vomiting	16 (36)	0 (0)
Constipation	14 (32)	0 (0)
Abdominal pain	11 (25)	2 (5)
Diarrhea	9 (21)	0 (0)
General disorders and administration site conditions
Fatigue	15 (34)	0 (0)
Pyrexia	14 (32)	2 (5)
Non-cardiac chest pain	10 (23)	1 (2)
Chills	7 (16)	0 (0)
Edema	9 (21)	0 (0)
Asthenia	7 (16)	1 (2)
Chest pain	6 (14)	0 (0)
Immune system disorders
Cytokine release syndromea	33 (75)	1 (2)
Infections and infestations
Any infectionb	14 (32)	6 (14)
Nervous system disorders
Headache	8 (18)	1 (2)
Dizziness	5 (11)	0 (0)
Metabolism and nutrition disorders
Decreased appetite	10 (23)	1 (2)
Musculoskeletal and connective tissue disorders
Back pain	9 (21)	2 (5)
Pain in extremity	6 (14)	0 (0)
Respiratory, thoracic, and mediastinal disorders
Dyspnea	11 (25)	2 (5)
Cough	8 (18)	0 (0)
Vascular disorders
Hypotension	9 (21)	0 (0)
Hypertension	7 (16)	1 (2)
Cardiac disorders
Sinus tachycardia/tachycardia	9 (21)	0 (0)
Skin and subcutaneous tissue disorders
Alopecia	6 (14)	0 (0)

Source: FDA analysis of data from Study ADP-0044–002 and U.S. Prescribing Information

^aAs per American Society for Transplantation and Cellular Therapy (ASTCT) criteria (7)

^bAny infection includes all infection terms under the “Infections and infestations” System Organ Class

Abbreviations: n = number of patients in a specified category, N = number of patients

All but one case of CRS were Grade 1 or 2 in severity and the median time to first CRS event was 2 days with a time to resolution of 3 days, with tocilizumab used most commonly for supportive management. Only one case of immune effector cell-associated neurotoxicity syndrome (ICANS) (Grade 1) occurred, with a time to onset of 2 days and time to resolution of 1 day. Grade ≥3 cytopenia not resolved by Week 4 was considered prolonged. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia not resolved by Week 4 occurred in 9%, 11%, and 5% of patients, respectively. The median time to resolution was 7.3 weeks for anemia, 9.3 weeks for neutropenia, and 6.3 weeks for thrombocytopenia. Infection occurred following lymphodepleting chemotherapy and afamitresgene autoleucel in 32% of patients and Grade ≥3 infections occurred in 14% of patients. Febrile neutropenia was observed in 11% of patients. Secondary malignancies were observed in two patients. One patient enrolled in ADP-004–002 developed Epstein-Barr virus-positive lymphoproliferative disease and another in ADP-004–001 (supportive safety) developed myelodysplastic syndrome.

Regulatory Insights

Afamitresgene autoleucel is the first FDA-approved T-cell receptor immunotherapy that targets specific major histocompatibility complex-bound cancer antigens (Table 4). Genetically modified T-cell receptor T-cell therapy, or TCR-Ts, such as afamitresgene autoleucel enable targeting of intracellular cancer antigens representing an advancement from chimeric antigen receptor (CAR) T-cell therapies approved for hematologic malignancies that target cell surface antigens.

Table 4.

FDA Benefit-Risk Analysis

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	SS is a rare disease, with an estimated U.S. annual incidence of 800 to 1,000 cases a year. Advanced unresectable and metastatic synovial sarcoma has a poor prognosis, with a reported median OS of approximately 16 to 24 months.	SS is a serious and fatal disease.
Current Treatment Options	There are currently no FDA-approved therapies specifically for SS in any treatment setting, including after receiving standard systemic chemotherapy such as doxorubicin with or without ifosfamide. Published clinical trial and real-world data indicate that ORR for mSS in the second-line setting and later ranges from 10% to 22%.	The available systemic treatment options for patients with SS remain extremely limited and typically involve continuous treatment until disease progression. There is need for more innovative therapies with high and durable response rates.
Benefit	In this single-arm, multi-regional study, 44 adult patients with HLA-A*02 positive, MAGE-A4 expressing, advanced SS who previously received either an anthracycline- or ifosfamide-containing regimen were treated with afamitresgene autoleucel in ADP-0044–002 Cohort 1. The ORR was 43.2 (95% CI: 28.4, 59.0) with CR in 2 (4.5%) patients and PR in 17 (38.6%) patients by IRC re-review. The KM median DOR was 6.0 months (95% CI: 4.6, NR), with a median follow-up of 21.9 months by reverse KM estimate. Among the 19 responders, durable response at 6, 12, and 24 months was 45.6 %, 39%, and 39%, respectively by KM estimate.	ORR supported by DOR represents an improvement over available therapy in the intended patient population. Afamitresgene autoleucel is a short, single treatment course option that can provide a meaningful benefit of time off cancer directed therapy while maintaining disease control.
Risk and Risk Management	Substantial risks of afamitresgene autoleucel include CRS, ICANS, prolonged severe cytopenia, infections, secondary malignancies, and hypersensitivity reactions. CRS is included in the USPI Boxed Warning. Health care providers administering afamitresgene autoleucel should have immediate access to medications and resuscitative equipment to manage CRS and ICANS. There is a theoretical risk of secondary malignancy due to RCL or insertional mutagenesis. However, no such cases occurred by the data cut-off date in this study.	The evidence suggests that the risks of afamitresgene autoleucel do not outweigh the benefits in adult patients.

Source: FDA analysis

Abbreviations: CI = confidence interval, CR = complete response, CRS = cytokine release syndrome, DOR = duration of response, ICANS = immune effector cell-associated neurotoxicity syndrome, IRC = independent review committee, KM=Kaplan-Meier, mSS = mediastinal synovial, NR = not reached, ORR = overall response rate, OS = overall survival, PR = partial response, RCL = replication-competent lentivirus, SS = synovial sarcoma, USPI = United States Prescribing Information

Approval is based on the results of Study ADP-0044–002, a single-arm study initially intended as a multi-cohort dose expansion study not specifically planned to generate the primary data to support licensure of this product. However, given the unprecedented effects on ORR and durability of responses observed, the accelerated approval pathway was leveraged to facilitate expedited access to this therapy for patients with this rare and life- threatening cancer. Approval of afamitresgene autoleucel represents the first anti-cancer therapy approved specifically for the treatment of SS, thus addressing an unmet medical need.

Acceptance of the results of Study ADP-0044–002 to support regulatory approval reflects FDA’s regulatory flexibility in the rare disease settings with significant unmet need. However, in doing so in this case, the clinical review team encountered a major review issue in the assessment of data quality and study conduct. Specifically, during the review, the clinical review team identified irregularities in the accuracy of target lesion measurements, inconsistencies in adherence to RECIST v1.1, irregularities in the implementation of response adjudication, and the use of several cut-off dates for efficacy analyses. Another limitation of the study was that on-study tumor biopsies of target and non-target lesions were permitted, potentially confounding the response assessment. When taken together in the context of a single-arm study with a small sample size, these issues raised concerns regarding the reliability of the ORR and DOR results to establish effectiveness. On the basis of these findings, FDA requested that the Applicant conduct an independent, third party-facilitated blinded re-review of the imaging assessments conducted for the efficacy evaluable population.

The results of this independent re-review were generally in alignment with the initial results submitted in the biologics license application (i.e., in magnitude of response and durability), and ultimately formed the basis for FDA’s determination that Study ADP-0044–002 demonstrated the effectiveness of afamitresgene autoleucel.

The ORR of 43% and median DOR of 6.0 months were considered clinically meaningful in this pre-treated population with limited treatment options. Concordance in best overall response between the original IRC review and the IRC re-review was 80%. The median DOR by re-review was shorter than the median DOR by original review by 5.6 months, a difference primarily due to three new responders identified through the independent re-review who were not responders in original review and whose responses were not durable (<14 weeks). Additionally, one responder by re-review had a significantly shorter DOR as compared to the original review (20 weeks versus 50 weeks).

By FDA analysis, the on-study biopsies did not impact response assessment, primarily because either the biopsied lesion was very large in size, or the patient continued to meet criteria for a confirmed response if the biopsied lesion was changed to a non-target lesion. However, sponsors of clinical trials to support approval may note that where ORR is the primary endpoint, FDA strongly prefers that target lesions used to assess tumor response evaluation are not biopsied given the potential to confound response assessment.

Although SS affects both adolescents and adults, the approved indication is restricted to the adult population. While Study ADP-0044–002 allowed enrollment of adolescents 16 and older, no adolescent patients were ultimately enrolled in Cohort 1. Additionally, the molecular target MAGE-A4 is relevant to the growth or progression of pediatric cancers other than SS, including malignant peripheral nerve sheath tumor, neuroblastoma, and osteosarcoma. Thus, under the Pediatric Research Equity Act, or PREA (21 U.S.C. 355c), as amended by the FDA Reauthorization Act of 2017, FDA required that the Applicant conduct a molecularly targeted pediatric cancer investigation in patients with solid tumors expressing MAGE-A4 who have received prior systemic therapy for advanced disease to evaluate dosing, pharmacokinetics, safety, and antitumor activity of afamitresgene autoleucel following lymphodepletion with fludarabine and cyclophosphamide (8).

As a member of the established pharmacologic class for MAGE-A4-directed genetically modified autologous T-cell immunotherapy, afamitresgene autoleucel shares the same immune effector cell-associated toxicities and other risks of approved CAR T-cell products including CRS, ICANS, prolonged severe cytopenia, infections, secondary malignancies, and hypersensitivity reactions. There were no reports of T-cell related secondary malignancies, including in the ongoing long-term follow-up phase.

During the trial, CRS occurred in most patients (75%), and was treated soon after cell infusion starting on Days 0 to 3; with the exception of one case, the CRS events were Grade 1 and Grade 2 in severity. Patients were proactively treated with tocilizumab, corticosteroids, and antibiotics to avoid the toxicity worsening to a higher grade. It is unknown whether pre-emptive and early use of tocilizumab or corticosteroids impacts the product’s treatment effect or if this treatment strategy can effectively decrease symptom severity. However, patients treated with afamitresgene autoleucel should be closely monitored for CRS symptoms within the first hours after infusion and up to 7 days after cell infusion. Overall, the risks of afamitresgene autoleucel can be adequately mitigated through product labeling, which includes a Boxed Warning and medication guide for CRS and a warnings and precautions list that includes ICANS, prolonged severe cytopenia, infections, secondary malignancies, and hypersensitivity reactions, similar to other products in the class. Since CRS management has become standardized, Risk Evaluation and Mitigation Strategies were not considered necessary, which reflects the FDA’s evolving approach on this issue.

As with most accelerated approvals, FDA required and the Applicant agreed to submitting additional data to verify and confirm the benefit of afamitresgene autoleucel for the indicated population (9,10). A confirmatory study of additional cohorts in the single-arm trial ADP-0044–002 is underway to provide verification of ORR supported by DOR. FDA agreement to the Applicant’s confirmatory study plan was based on the consideration of several factors, most notably the rarity of the biomarker-positive subpopulation of patients with SS, which significantly impacts the practicality of timely completion of a randomized controlled trial in the post-approval setting.

Conclusion

Afamitresgene autoleucel represents a new treatment modality for patients with unresectable or metastatic SS. Prior to this approval, available systemic therapies involved repeated, and in the case of kinase inhibitors, daily treatment administration, until disease progression. Afamitresgene autoleucel is a short, single-treatment course that may provide patients the important benefit of time off cancer-directed therapy while maintaining disease control. The magnitude of ORR supported by DOR demonstrated in Cohort 1 of Study ADP-0044–002 is considered clinically meaningful and reasonably likely to predict clinical benefit in this rare patient population with a poor prognosis and lack of effective therapies. These results in the context of a manageable safety profile formed the basis of accelerated approval for adults with unresectable or metastatic SS who have received prior chemotherapy, are HLA- A*02:01P, - A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. Continued approval is contingent upon verification of clinical benefit in an ongoing confirmatory study.