Results of the phase 2 SPEARHEAD-1 trial were presented at the 2021 ASCO Annual Meeting, with a high overall response rate reported with afamitresgene autoleucel in advanced synovial sarcoma or myxoid/round cell liposarcoma.
The experimental therapy afamitresgene autoleucel (afami-cel) induced a promising response rate in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS) in the phase 2 SPEARHEAD-1 trial (NCT04044768), results of which were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1
As of the March 29, 2021, the evaluable population included 33 patients with synovial sarcoma and 4 with MRCLS. The overall response rate (ORR) for the intention-to-treat population was 39.4% with a disease control rate of 84.8%. Broken down by histology the ORR for patients with synovial sarcoma was 41.4% (n = 12) and 25.0% (n = 1) for patients with MRCLS. Of note, 2 complete responses were observed in patients with synovial sarcoma. Additionally, 1 partial response and stable disease in 2 other patients were reported for patients with MRCLS.
The median duration of response has not yet been reached (range, 4.3+–38.0+).
“The responses [with afami-cel] appear to be protracted, deep, and durable,” Sandra P. D’Angelo, MD, explained in a presentation of the data adding that the data is “encouraging.” D’Angelo is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.
Afami-cel is a specific peptide enhanced affinity receptor (SPEAR) T-cell therapy that is engineered to target MAGE-A4 peptide expressed on tumor cells. In the context of HLA-A*02, MAGE-A4 is highly expressed in synovial sarcoma and MRCLS.2 The T-cell therapy previously demonstrated clinical activity in in various tumors in a phase 1 study (NCT03132922). At the time of data cutoff all partial responses reported for the trial were in patients with synovial carcinoma.3
SPEARHEAD-1 is designed to further evaluate the safety and efficacy of afami-cel in HLA-A*02 eligible and MAGE-A4-positive patients with metastatic or advanced synovial sarcoma or MRCLS. Patients must have previously received either an anthracycline- or ifosfamide-containing regimen. The primary end point is ORR. Disease is assessed using CT/MRI every 4 weeks for 6 months and then every 2 months after that via independent review per RECIST v1.1.2 Secondary outcomes include duration of response, time to response, progression-free and overall survival.
Prior to afami-cel infusion, patients received lymphodepleting chemotherapy consisting of fludarabine (30 mg/m2 daily for 4 days) and cyclophosphamide (600 mg/m2 daily for 3 days). Patients then received a single infusion of autologous genetically modified afami-cel at a dose of 1 to 10 × 109 transduced T cells.2
At the time of presentation, 330 patients were screened for HLA-A*02 and of those 176 were determined to have positive disease.1 From these patients, 106 were determined to have MAGE-A4 expression in at least 30% of tumor cells that were at least 2+ as determined by immunohistochemistry.4 In total, 59 patients were enrolled and underwent leukapheresis across the 2 cohorts of the study and 37 were treated with afami-cel. Sixteen patients are awaiting treatment and 5 discontinued prior to T-cell therapy.1
At the time of data cutoff, 4 patients who received afami-cel were still awaiting their first efficacy assessment and were not included in the initial analysis.
Of the 37 evaluable patients, the median age was 42 years (range, 24-73) and has a median of 3 prior lines of systemic therapy (range, 1-12). The median cell dose was 8.8 × 109 (range, 2.7-9.9).
In terms of safety, treatment-emergent adverse effects (TEAEs) were consistent with those observed for patients who undergo cytotoxic chemotherapy, D’Angelo noted. “The most common TEAEs were likely related to the lymphodepleting regimens [with the] incidence of cytopenia in a majority of patients, with a majority being grade 3 or greater in severity,” she said.
Specifically, the most common TEAEs of any grade were lymphopenia (84%), neutropenia (73%), nausea (65%), and pyrexia (51%). Two AEs were of special interest: cytokine release syndrome and grade 3 or higher prolonged cytopenia at 4 weeks post infusion.
Cytokine release syndrome of any grade was observed in 22 patients (59%) and was grade 3 or higher in 1 patient (3%). The median time to onset was 3 days (range, 1-9) and the median time to resolution was 3 days (range, 1-34). D’Angelo highlighted that more than half (55%) of patients with cytokine release syndrome required treatment with tocilizumab (Actemra).
“Patients often experience cytopenia on these clinical trial for several weeks following lymphodepletion and T-cell infusion. We have seen neutropenia, thrombocytopenia, and anemia of grade 3 or greater in less than 10% of patients,” D’Angelo said. Of the 37 patients treated, 2 experienced grade 3 or higher neutropenia, 1 had thrombocytopenia, and 3 had anemia at the 4-week post infusion analysis.
Additionally, D’Angelo highlighted early analysis of responses that demonstrated clinical activity across a wide range of MAGE-A4 H-scores and cell doses. “Translational data from this trial are continuing to be evaluated and early results from 13 patients with clinical responses [are available] to date,” D’Angelo said.
The median H-score via immunohistochemistry was 225 (range, 134-300) and the median cell dose in the responders was 6.45 × 109 (range, 2.7-9.9).
Primary efficacy analysis will be for cohort 1 of the trial and enrollment is complete, according to the agent’s developer Adaptimmune Therapeutics.4
“SPEARHEAD-1 is ongoing and data from this trial will be used to support Adaptimmune’s BLA [biologic license application] submission next year ,” D’Angelo said.
1. D'Angelo SP, Van Tine BA, 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. J Clin Oncol. 2021;39(suppl 15):11504. doi:10.1200/JCO.2021.39.15_suppl.11504
2. Araujo DM, Druta M, Agulnik M, et al. SPEARHEAD-1: a phase II trial of ADP-A2M4 SPEAR T cells in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. J Clin Oncol. 2021;38(suppl 15):TPS11569. doi:10.1200/JCO.2020.38.15_suppl.TPS11569
3. Hong DS, Van Tine BA, Olszanski AJ, et al. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. J Clin Oncol. 2021;38(suppl 15):102. doi:10.1200/JCO.2020.38.15_suppl.102
4. Two complete responses and response rate of 41% for people with synovial sarcoma reported at ASCO in Adaptimmune’s phase 2 SPEARHEAD-1 trial. News release. Adpatimmune Therapeutics. May 19, 2021. Accessed June 4, 2021. https://www.adaptimmune.com/investors-and-media/news-events/press-releases/detail/193/two-complete-responses-and-response-rate-of-41-for-people