Gene-edited T-cell therapy shows ‘promising efficacy’ for rare sarcomas
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Nearly 40% of patients with advanced or metastatic synovial sarcoma or myxoid/round cell liposarcoma responded to therapy with afamitresgene autoleucel, according to results of a phase 2 study.
Data from the SPEARHEAD-1 trial, presented during the virtual ASCO Annual Meeting, also showed an 84.8% disease control rate among patients who received the novel gene-edited T-cell therapy.
Afamitresgene autoleucel (ADP-A2M4; Adaptimmune) — also known as afami-cel — is an autologous, specific peptide-enhanced affinity receptor (SPEAR) T-cell therapy. The agent’s selectively engineered T-cell receptor is designed to target tumors that express the MAGE-A4 protein.
The standard of care for patients with relapsed or refractory sarcoma is cytotoxic chemotherapy, according to Sandra P. D’Angelo, MD, a medical oncologist and associate attending at Memorial Sloan Kettering Cancer Center.
“These drugs offer some benefit and often stabilize disease for some period of time, but ultimately these patients will pass away from metastatic disease because the responses are often not durable and do not provide an opportunity to go off therapy,” she told Healio.
Afami-cel undoubtedly would be a more durable treatment than the current standard-of-care options and thus far has exhibited “evidence of promising efficacy,” D’Angelo said. The responses seen in the trial are clinically meaningful in the context of standard therapies, she added.
“The data seem promising, and the responses appear to be durable, but there is a need for ongoing follow-up to evaluate these patients further,” D’Angelo said.
D’Angelo and colleagues evaluated the efficacy and safety of afami-cel among patients with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS).
The SPEARHEAD-1 trial included 37 patients (median age 42 years; range 24-73; 57% men; 87% white) with synovial sarcoma (n = 32) or MRCLS (n = 5) who received an infusion of afami-cel by the data cutoff date of March 29 and were eligible for analysis.
All patients were HLA-A*02-positive, had MAGE-A4 expression on at least 30% of tumor cells, and had previously been treated with either an anthracycline- or ifosfamide-containing regimen. Patients received a median three lines (range, 1-12) of previous systemic therapy.
Patients underwent lymphodepleting chemotherapy followed by an IV infusion of afami-cel at a dose of between 1 × 109 cells and 10 × 109 cells.
Overall response rate as determined by RECIST version 1.1 served as the study’s primary efficacy endpoint. Secondary endpoints included duration of response, PFS and OS. Researchers also evaluated treatment-related adverse events and adverse events of special interest.
Ninety-five percent of patients had at least one treatment-related adverse event, the most common of which included cytopenias.
“Adverse events do occur and almost all were tolerable and addressable,” D’Angelo said, adding that nearly all patients had complete resolution of adverse event-related symptoms.
This included patients who experienced cytokine release syndrome, which she said resolved and improved over time with the use of tocilizumab (Actemra, Genentech).
Twenty-two patients (59%) experienced CRS, but only one patient had grade 3 or greater CRS. Median time to onset of CRS was 3 days (range, 1-9), with a median time to CRS resolution of 3 days (range, 1-34).
Efficacy results showed an ORR of 41.4% for patients with synovial sarcoma and 25% for those with MRCLS, for a 39.4% ORR for the entire study population. Two patients with synovial sarcoma had a complete response to therapy as of the data cutoff date.
The disease control rate was 84.8% across the study.
Median OS, duration of response and PFS had yet to be reached.
“We hope the durability remains in further study of afami-cel to achieve that goal of FDA approval,” she told Healio. “Having an FDA-approved agent would add to our treatment options.”
FDA approval of afami-cel would allow patients to be treated with a cell infusion that could help them remain off therapy and would have a remarkable impact on quality of life, D’Angelo said.
“These are important data that will hopefully continue to evolve and offer a new standard of care for our patients in the near future,” she said.
Perspective
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Lisa Butterfield, PhD, PhD
The responses across MAGE-A4 tumor antigen expression levels in tumor tissue seen in this study are important because they indicate that low antigen levels and reduced antigen expression in tumor areas or during treatment won’t eliminate the potential for a positive clinical response. The clinical responses seen across cell dose levels also is important to allow flexibility in manufacturing outcomes because this is an autologous product and there is unavoidable variability in cell proliferation, ex vivo and in vivo. The translational science examining the biology of the T cells infused and whether there is epitope and antigen spreading in responders will be important mechanistic data for the future of this and related therapies. Any gene expression profile or phenotypic correlations with patient outcome will be important to investigate further. Also, because of the focus on a single epitope in a single HLA molecule, spreading of the response to include endogenous T cells of additional tumor specificities also could be important to investigate.
Perspective
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Robin L. Jones, BSc, MB, MRCP, MD
There are few prospective trials in advanced or metastatic synovial sarcoma or myxoid/round cell liposarcoma, and there remains a huge need for more effective systemic therapies in both diseases. This is highlighted by an EORTC analysis of 15 first-line clinical trials, which showed an ORR of approximately 29% and median PFS of 6.3 months for synovial sarcoma.
Beyond first-line therapy, the durability of the response and benefits seen in the study by D'Angelo and colleagues are important to note.
The investigators are to be congratulated for conducting this precision medicine trial — in a way, this is really a trial of subgroups of subtypes. There is a compelling and attractive scientific rationale for this precision medicine approach in these diseases. T-cell therapy trials require sufficient infrastructure and, for rare diseases, this could only be conducted at specialist centers.
Durable responses were observed in this study, and the major question now is, how can we identify patients most likely to benefit from this treatment?
Another question concerns the lymphodepletion schedule, which contains an alkylating agent, and whether it contributes to the efficacy of the overall treatment regimen.
This study shows that late-phase trials in rare sarcoma subtypes are possible. However, we need a comprehensive understanding of individual rare subtypes in terms of clinical behavior, quality-of-life measures and translational studies. It is challenging to perform randomized studies in rare subtypes, but information from prospective trials like this one can provide robust clinical and biological evidence for potential alternative designs and endpoints, leading to dialogue with regulatory agencies and approval of more therapies for our patients.
Reference:
Vlenterie M. Eur J Cancer. 2016;doi:10.1016/j.ejca.2016.02.002.
Institute for Cancer Research (London)
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D'Angelo SP, et al. Abstract 11504. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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