Afami-cel Elicits Durable Response Rates in Patients With Synovial Sarcoma or MRCLS

Encouraging initial durability has been observed with afamitresgene autoleucel (afami-cel) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS), according to data from the phase 2 SPEARHEAD-1 trial (NCT04044768) presented at 2021 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 [2022],” D’Angelo said.

References

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