Afami-cel Achieves Durable Responses and Acceptable Safety Profile in Synovial Sarcoma
The overall response rate was 44% among 16 patients with synovial sarcoma.
Adaptimmune Therapeutics’ afamitresgene autoleucel (afami-cel), an investigational autologous engineered T-cell receptor (TCR) T-cell therapy intended to target MAGE-A4-expressing solid tumors, has demonstrated early and durable responses in patients with synovial sarcoma (SS), along with an acceptable safety profile, according to data from a phase 1 clinical trial (NCT03132922) recently published in Nature Medicine.1,2
The trial treated 38 patients with 9 different tumor types. Among the 16 treated patients with SS the overall response rate (ORR) was 44% (n = 7) and the median duration of response (DOR) was 28.1 weeks (95% CI[12.286-not reached {NR}]). However, for the 22 treated patients with other tumor types, the ORR was much lower at 9% (n = 2). It was noted that all responses seen in the trial across all tumor types were partial responses, and the median DOR for all treated patients was 25.6 weeks (95% CI[12.286-NR]).
In terms of safety, grade 3 or greater hematologic toxicities were observed in all patients and therapy-related cytokine release syndrome (CRS) was observed in 55% of patients (90% grade 2 or lower). All CRS cases were able to be reversed via treatment with anti-IL-6(R) monoclonal antibody when indicated. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in patients with SS, and cases in patients with other indications were noted to be of low severity overall. Other neurological adverse events occurred among the treated patients, but a definite causal relationship with afami-cel was not determined. Cases of prolonged cytopenia were observed in 45% of the treated patients, and 1 death of a patient with SS occurred in relation to prolonged cytopenia. The investigators noted that the death may have been related to the higher dose of cyclophosphamide this patient received during lymphodepletion but could also have been contributed to by 2 high-grade CRS events experienced by the patient. Another potentially treatment-related fatality occurred in a patient with ovarian cancer who died from an ischemic cerebrovascular accident after experiencing a grade 3 neurotoxicity. In general, the safety profile was deemed consistent with expectations for patients receiving lymphodepleting chemotherapy and cell therapy for cancer.
"The potential of afami-cel to transform the treatment landscape for people with SS was evident in this phase 1 trial and we are eager to provide this new therapeutic option," Dennis Williams, PharmD, senior vice president, Late-Stage Development, Adaptimmune Therapeutics, said in a statement regarding the data's publication.2
The multicenter, dose-escalation trial treated 22 male and 16 female patients whose ages ranged from 31 to 78 years (median, 58).1 In addition to the 16 patients with SS, the trial treated 2 patients with esophageal cancer, 1 patient with gastric cancer, 3 patients with head and neck cancer, 1 patient with melanoma, 2 patients with non-small cell lung cancer, 9 patients with ovarian cancer, 2 patients with urothelial cancer, and 2 patients with myxoid/round cell liposarcoma. The patients had received between 1 and 8 prior lines of systemic therapy (median, 3). The ages of the patients with SS ranged from 31 to 76 years (median, 49) and these patients had received between 1 and 6 prior lines of therapy (median, 3). It was noted that all patients with SS had previously been treated with ifosfamide. All patients underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine before receiving afami-cel, and 21 of the patients were additionally administered cytotoxic bridging chemotherapy.
The investigators noted a potential confounding effect in the efficacy data, pointing out that the higher rate of responses seen in patients with SS could have been related to the cyclophosphamide-containing lymphodepletion chemotherapy or the bridging therapy. However, they also noted that therapeutic activity of afami-cell was indicated in cell pharmacokinetic and serum pharmacodynamic data, and that the durable reductions in the sum of longest diameter of the target lesions seen would not be expected after 1 cycle of the lymphodepleting chemotherapy. In addition to the potentially confounding factors, the small sample size for patients with SS was noted as another limitation of the study.
“Responses were limited in non-sarcoma cancers, perhaps due to small numbers of patients with specific cancer types or lower MAGE-A4 expression relative to SS,” first author David S. Hong, MD, professor and deputy chair, department of investigational cancer therapeutics, MD Anderson Cancer Center, The University of Texas, and colleagues wrote.1 “Although the number of patients with SS was small, the emergent ORR of 44%, median progression-free survival of 20.4 weeks and median overall-survival of 58.1 weeks are better than the historical low ORRs reported for current standard-of-care therapies, including pazopanib and trabectedin, used in the post-first-line metastatic setting. SS is sensitive to alkylators, and the use of cyclophosphamide in the lymphodepletion regimen is a confounder in the interpretation of the response rate in SS.”
The investigators concluded that afami-cel could be a potentially promising treatment for patients with SS who have previously received ifosfamide, and that further study is warranted. Afami-cel is currently also being investigated in the phase 2 SPEARHEAD-1 clinical trial (NCT04044768), which will provide additional data for the therapy in patients with metastatic SS.
