Afamitresgene Autoleucel Demonstrates Efficacy in Advanced Synovial Sarcoma and Myxoid Round Cell Liposarcoma

Treatment with the autologous CD4- and CD8-positive T-cell product afamitresgene autoleucel (afami-cel) led to durable responses in heavily pretreated patients with advanced synovial sarcoma or myxoid round cell liposarcoma, according to findings from cohort 1 of the phase 2 SPEARHEAD-1 trial (NCT04044768) published in The Lancet.¹

At a median follow-up of 32.6 months (IQR 29.4-36.1), patients with synovial sarcoma (n = 44) and myxoid round cell liposarcoma (n = 8) who received afami-cel achieved an overall response rate (ORR) of 39% (95% CI, 24%-55%) and 25% (95% CI, 3%-65%), respectively. In the overall population (n = 52), the ORR was 37% (95% CI, 24%-51%).

“It is exciting to see The Lancet share the afami-cel SPEARHEAD-1 trial results in advanced sarcomas with the broader clinical and research communities,” Dennis Williams, PharmD, senior vice president, Late-Stage Development, Adaptimmune, said in a press release.² “The study further demonstrates the ability of engineered T-cell therapies to effectively target solid tumors and we are eager to introduce the first engineered T-cell therapy, afami-cel, to more patients later this year.”

In January 2024, the FDA accepted the biologics license application for afami-cel for the treatment of patients with advanced synovial sarcoma for priority review. The regulatory decision was supported by findings from cohort 1 of SPEARHEAD-1, which met the study’s primary end point for efficacy, presented during the Connective Tissue Oncology Society 2023 Annual Meeting.³

SPEARHEAD-1 is an open-label, non-randomized study that enrolled patients with advanced synovial sarcoma or myxoid round cell liposarcoma confirmed by cytogenetics. Patients were aged 16 to 75 years and positive for HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:06, or other HLA-A*02 alleles with the same protein sequence as those in the peptide-binding domain. Additionally, eligible patients had MAGE-A4-expressing disease and received a prior anthracycline- or ifosfamide-containing regimen; an ECOG performance status of 1 or less as well as adequate organ function was also required. Data from cohort 1, the main investigational cohort was reported in The Lancet; cohorts 2 and 3 were meant to provide continued access to afami-cel and to generate supplemental data in patients with advanced synovial sarcoma and will be reported separately.¹

After leukapheresis, and lymphodepleting therapy with intravenous fludarabine 30 mg/m² on 4 consecutive days and intravenous cyclophosphamide 600 mg/m² on 3 consecutive days, patients received a single afami-cel infusion. Afami-cel was given intravenously at a transduced dose range of 1.0 × 10⁹ to 10.0 × 10⁹ T cells. Treatment with tocilizumab (Actemra) was allowed if a patient experienced grade 1 cytokine release syndrome (CRS) and symptoms persisted for at least 24 hours or if the patient had comorbidities.

The primary end point was ORR per RECIST 1.1 in cohort 1 per masked independent review committee. Secondary end points included safety, duration of response, best overall response, time to initial confirmed response, progression-free survival, and overall survival (OS), among others.

At baseline, the median age in the overall population was 41.0 years (range, 31.0-46.5). Most patients were male (54%), White (87%), from Canada and the US (71%), had stage IV disease (79%), did not receive bridging therapy (62%), had an ECOG performance status of 0 (52%), and had a baseline sum of longest diameters in target lesions of at least 100 mm (52%). In terms of histological grade, patients had well differentiated (4%), moderately well differentiated (17%), poorly differentiated (50%) undifferentiated (10%), or unknown (19%) histology. Patients received 1 (19%), 2, (29%), 3 (17%), or 4 or more (35%) prior lines of therapy.

Further, the MAGE-A4 expression H score at pre-screening was 232 (174–294) and the P score at pre-screening was 84 (62–99).

Additional findings from SPEARHEAD-1 showed that the median OS in the overall population was 15.4 months (95% CI, 10.9-28.7), with a 12-month OS probability rate of 60% (95% CI, 46%-73%). The median OS in the synovial sarcoma patient population was not yet reached (95% CI, 15.4-not estimable). The median PFS for patients with synovial sarcoma and myxoid round cell liposarcoma was 3.8 months (95% CI, 2.8-6.4) and 2.4 months (95% CI, 0.9-7.4), respectively; the median PFS in the overall population was 3.7 months (95% CI, 2.8-5.6). Notably, responses were observed across key subgroup covariates.

In terms of safety, every patient treated with afami-cel experienced an any-grade treatment-emergent adverse effect (TEAE). The most common any-grade TEAEs included CRS (71%), decreased white blood cell count or leukopenia (27%), pyrexia (23%), and decreased neutrophil count or neutropenia (23%). Grade 4 effects included decreased neutrophil count or neutropenia (12%), decreased lymphocyte count or lymphopenia (12%), decreased white blood cell count or leukopenia (10%), decreased platelet count or thrombocytopenia (4%), pancytopenia (2%), and pyrexia (2%).

No deaths occurred in the first 30 days following afami-cel infusion and no treatment-related deaths were reported; all 28 deaths were determined to be due to disease progression by the investigators.

“The reported findings are clinically impactful, considering the current standard of care and limited therapies available in advanced sarcomas,” Sandra P. D’Angelo, MD, sarcoma oncologist and cellular therapist at Memorial Sloan Kettering Cancer Center in New York, New York, and the lead author of SPEARHEAD-1, said in the press release.² “Treatment with afami-cel resulted in [a] 39% overall response rate in synovial sarcoma with durable responses. These results suggest that a one-time treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy. The publication of this data further validates the potential of afami-cel to offer a new tool to address the unmet needs of people diagnosed with these often-devastating diseases.”

References

1. D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. Published online March 27, 2024. doi:10.1016/S0140-6736(24)00319-2
2. Results of Adaptimmune’s SPEARHEAD-1 trial with afami-cel in advanced sarcomas published in the Lancet. News release. Adaptimmune Therapeutics plc. March 27, 2024. Accessed April 2, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/264/results-of-adaptimmunes-spearhead-1-trial-with-afami-cel
3. Adaptimmune announces U.S. FDA acceptance of biologics license application for afami-cel for the treatment of advanced synovial sarcoma with priority review. News release. Adaptimmune Therapeutics plc. January 31, 2024. Accessed April 2, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/260/adaptimmune-announces-u-s-fda-acceptance-of-biologics