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Engineered TCR Therapy Demonstrates Durable Responses in Rare Sarcomas

NEW YORK – Based on data from biomarker-selected advanced sarcoma patients treated in the Phase II SPEARHEAD-1 trial, Adaptimmune expects to file a biologics license application with regulators next year for its engineered autologous T-cell product, afamitresgene autoleucel (afami-cel).

The data, presented during the American Society of Clinical Oncology's virtual annual meeting on Friday, showed that patients with synovial sarcoma whose tumors were HLA-A*02 serotype and expressed the MAGEA4 peptide had durable responses to afami-cel. Specifically, among 33 biomarker-selected patients with advanced, heavily pretreated sarcoma — 29 with synovial sarcoma and four with myxoid round-cell liposarcoma, or MRCLS — the response rate was 39 percent, and the disease control rate was 85 percent. Two of the responding synovial sarcoma patients experienced a complete response to afami-cel, and at the data cutoff, the median duration of response had not been reached. Only one patient experienced grade three or higher cytokine release syndrome.

"Responses appear to be protracted, deep, and durable," Sandra D'Angelo, a medical oncologist specializing in sarcoma treatment at Memorial Sloan Kettering, said during her presentation of the SPEARHEAD-1 data. "Afami-cel is safe and well tolerated [and] responses were observed across a broad range of MAGEA4 expression and cell doses."

While the trial is still ongoing in a second 45-patient cohort that D'Angelo hopes will aid in further descriptive subgroup analyses, the primary efficacy analysis from the first cohort was encouraging to investigators and will support Adaptimmune's afami-cel BLA filing next year.

"This was really a trial of subgroups of subtypes," Robin Jones, a sarcoma specialist with the Royal Marsden National Health Service Foundation Trust, said in a discussion following the presentation. "There's a compelling and attractive rationale for this precision medicine approach in [rare sarcomas]."

Jones praised the highly specific biomarker approach in the SPEARHEAD-1 trial, in which researchers screened 330 patients for the HLA-A*02 serotype and then tested 176 HLA-A*02-positive patients' tumors for MAGEA4 expression. The 106 patients deemed positive for the latter biomarker had to have MAGEA4 expression in at least 30 percent of tumor cells with immunohistochemistry scores of two or more.

Of the biomarker-positive patients, 59 enrolled on the trial, and as of the most recent data cutoff, 37 had undergone the full treatment regimen of leukapheresis, lymphodepletion, then reinfusion of the engineered T cells. At the meeting, D'Angelo presented data on 33 of these patients who had at least one completed post-infusion scan at the time of the data cutoff.

The manufacturing process for the final afami-cel product, which collectively comprises Adaptimmune's Specific Peptide Enhanced Affinity Receptor, or SPEAR, T-cell platform, involves cryopreserving patients' CD4 and CD8 T cells, delivering the genes encoding the affinity-enhanced T-cell receptors, or TCRs, to the T cells through lentiviral transduction, harvesting the cells, cryopreserving them once more, and shipping them back to the patient for infusion after lymphodepleting chemotherapy. In total, the manufacturing cycle from leukapheresis to infusion takes roughly a month.

When considering response rates from the SPEARHEAD-1 trial in historical context, Jones acknowledged that prospective clinical trial data on systemic therapy is lacking for these rare cancers. He pointed out that there have been a number of negative randomized Phase III trials in advanced sarcomas over the past few years, but within these trials, "the efficacy signal in a very rare subtype could easily be lost [among] all comers."

Given the absence of prospective trial data, Jones loosely compared the findings from SPEARHEAD-1 to an analysis of 15 pooled first-line clinical trials in synovial sarcoma that collectively showed chemotherapy response rates of about 29 percent and median progression-free survival times of 6.3 months. Among the heavily pretreated synovial sarcoma patients treated in the SPEARHEAD-1 trial, the response rate was 41 percent. Jones expressed hope that SPEARHEAD-1 could add to the dearth of treatment data in synovial sarcoma.

As for MRCLS, D'Angelo acknowledged that afami-cel response data were only available for four patients, so more data are needed. For now, referencing the one patient who responded, she said, "a 25 percent response rate in refractory MRCLS certainly has value, particularly if it is durable and allows patients to remain off regular and ongoing chemotherapy."

Looking ahead, D'Angelo was optimistic about the durability of responses in the SPEARHEAD-1 trial so far but acknowledged that possible mechanisms of resistance remain "a big unknown." She and her co-investigators plan to look at the persistence of the engineered cells and their expansion and whether these variables affect the durability of response. Additionally, they plan to look for biomarkers of progression, such as the presence of T-cell exhaustion markers, which could shed light on opportunities for combination or sequential treatment strategies.

"Obviously, these are compelling data," she said. "But there is more work to be done to really understand mechanisms of both response and resistance other than the obvious markers that we're already aware of."