Afami-cel Shows Clinical Benefit in Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Brian A. Van Tine, MD, PhD

The SPEAR T-cell therapy afamitresgene autoleucel (afami-cel; formerly ADP-A2M4) was found to elicit encouraging responses and a favorable risk/benefit profile in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS), according to data from the phase 2 SPEARHEAD-1 trial (NCT04044768).1

At a data cutoff of September 1, 2021, the therapy induced an overall response rate of 34% per independent review among 47 evaluable patients; 16 of these patients experienced partial responses. The disease control rate achieved with this approach was 85% per independent review. These rates were comparable to those observed via investigator assessment, which were 34% and 84%, respectively.

Notably, the median duration of response (DOR) had not yet been reached and 75% of patients were still responding at the time of data cutoff. DOR was noted to have ranged from 4.3+ to 65.3+ weeks.

Regarding safety, 66% of patients experienced cytokine release syndrome (CRS), although most of these events were grade 1 or 2 (n = 32); only 1 patient experienced grade 3 CRS. The most common serious adverse effect (AE) of any grade was CRS, and this was observed in 6% of patients. Sixteen percent of patients experienced grade 3 or higher cytopenia at week 4.

“It is important to remember that at the end of the day, [that] for the young adolescent population with synovial sarcoma, and the older population with [this disease], this is a breakthrough that I have not [yet] seen in my career,” said Brian A. Van Tine, MD, PhD. “I am excited to have been along for the journey.”

In an interview with OncLive^®, Van Tine, professor of medicine in the Division of Oncology, Section of Medical Oncology at the Washington University School of Medicine, Siteman Cancer Center, shed light on the promise of SPEAR T-cell therapy in patients with synovial sarcoma and MRCLS, the safety and efficacy observed with afami-cel in the SPEARHEAD-1 trial, and next steps for research.

OncLive®: Could you provide some background on the SPEARHEAD-1 trial? What is the mechanism of action of afami-cel?

Van Tine: This is a phase 2 registration trial that 2 phases. In the first phase, patients are screened for their HLA, which is a limiting factor in [terms of] enrollment [with] synovial sarcoma. If [patients had] the right HLA, which is HLA-A*02, [they were] then screened for MAGE-A4 surface expression by immunohistochemistry.

If [patients] were positive for both, they [were] then enrolled into the second half of the study. In the second half of the study, [patients] undergo leukapheresis, from which the T cells are removed from the body and modified in a laboratory. Then, after a 3-day conditioning regimen with fludarabine and cyclophosphamide, these cells are put back into the patient's body. At this point, the patient begins to treat themselves with the targeted T cell from their own T-cell lineage that goes after their tumor cells, which are expressing MAGE-A4.

How does SPEAR T-cell therapy represent a new way to target synovial sarcoma? What makes this approach unique from other options under exploration, like CAR T-cell therapy?

SPEAR T cells differ from traditional CAR T cells because they look for human leukocyte antigen [HLA] peptides that are present on the cell surface of disease. Because of this, there is a natural HLA restriction, but this is something that is being worked on to expand beyond the traditional HLA-A*02. For now, we are looking for a link between a certain T-cell receptor that is expressed on the SPEAR T cell and the peptide that is expressed on the cancer cell.

What were the key findings from the study presented during the 2021 Connective Tissue Oncology Society meeting?

The highlights of this trial come from 2 observations. The first is looking at the independent review. [We saw] a 34% ORR, and this is a high number for late-line therapy within the treatment of [patients with] synovial sarcoma.

The other observation that is more important is the durability of response. We have patients [achieving a response] from a single therapy that [persists for longer] than 1 year. [When you combine that with] a positive response rate, [it underscores] the fact that we are now translating cellular therapies into [the treatment of patients with] solid tumors. The synovial sarcoma population is at the front of the line [with this research]. Hopefully, we will have an FDA-approved therapy, at least for the subset who have the right HLA and express this antigen.

What was observed in terms of toxicity?

Most of what we saw was expected with this kind of therapy. No new [signals were observed] in this confirmatory trial [vs what] we had seen in the original phase 1 trial [NCT03132922]. Patients experienced anemia, thrombocytopenia, and neutropenia, but we used a conditioning regimen with cyclophosphamide and fludarabine.

What is really a mixed blessing is that we are seeing CRS; that is a sign not only that [the product is] working, but that in experienced hands, especially within this trial, [it can be] well managed.

What are the next steps for this regimen?

Multiple trials are going on right now, 1 of which is the phase 1 SURPASS trial [NCT04044859]. This is where we are utilizing this in other solid tumors that are not synovial or MRCLS. This is a solid tumor–expanding trial, where I am hoping we can use this [product in] the right patients, if they can be identified.

What is your key take-home message from this research?

If you are seeing a [patient with] synovial sarcoma or MRCLS, you need to screen them for their HLA and their MAGE-A4 status, whether [you do it] at your site or a site that is enrolling in the expansion cohorts of the SPEARHEAD clinical trial across the [United States] and in Europe.

Reference

1. Adaptimmune reports positive results from its pivotal SPEARHEAD-1 trial in patients with synovial sarcoma and MRCLS at CTOS. News release, Adaptimmune Therapeutics plc; November 11, 2021. Accessed February 4, 2022. https://bit.ly/3G2mAR2