APROMISS, SPEARHEAD-1 Trials Flag Synovial Sarcoma Therapy Advances

medwireNews: The APROMISS trial indicates that patients with advanced synovial sarcoma may benefit from an oral multi-target tyrosine kinase inhibitor (TKI), while the SPEARHEAD-1 study suggests there could be a role for T-cell therapy in patients with MAGE-A4-positive synovial sarcoma and rare forms of liposarcoma. 

The studies, both presented at the 2021 ASCO Annual Meeting, prompted session discussant Robin Jones, from the Royal Marsden Hospital in London, UK, to remark “that late-phase trials in rare sarcoma subtypes are possible” and can be recruited for “in a feasible time frame.” 

Brian Van Tine, from Washington University in St Louis, Missouri, USA, reported the phase III APROMISS results for anlotinib (also known as AL3818 or catequentinib) targeting VEGFR1–3, FGFR1–3, PDGFRβ and c-Kit. 

The investigators recruited 79 patients who had progressive synovial sarcoma after receipt of an anthracycline-containing regimen, and prior use of other agents was also allowed including the TKI pazopanib. 

The primary endpoint of progression-free survival (PFS) was a median of 2.89 months for the 52 patients randomly assigned to receive anlotinib 12 mg/day on a 2-week on, 1-week off cycle versus 1.64 months for the 27 patients given dacarbazine instead, giving a significant hazard ratio for progression or death of 0.449 in favour of anlotinib use. 

The presenter noted that there was a statistically significant difference in PFS from 2 months of treatment, with 4, 6 and 12-month PFS rates in the anlotinib and dacarbazine arms of 48.1% versus 14.9%, 42.3% versus 11.1%, and 26.9% versus 3.7%, respectively. 

Six patients continued with anlotinib treatment at 1 year versus just one patient in the dacarbazine arm; there were three partial responses to anlotinib versus none with dacarbazine. 

Subgroup analysis indicated that prior use of pazopanib did not impact anlotinib efficacy, and the benefit of the TKI versus dacarbazine reached significance among patients older than 40 years, women, White individuals, US patients, and those with an ECOG performance status of 0–1. 

The investigator said that anlotinib was “well tolerated”, with grade 3 or more severe adverse events reported for 23% of anlotinib-treated patients and 26% of those given dacarbazine. 

He added that “as expected with tyrosine kinase inhibitors there were issues with diarrhoea [and] hypertension”, while one patient who crossed over to anlotinib from dacarbazine on disease progression developed pneumothorax that may have been treatment-related. 

Brian Van Tine concluded that anlotinib is “effective for the treatment of patients with synovial sarcoma.” 

The SPEARHEAD-1 results were presented by Sandra D’Angelo, from Memorial Sloan Kettering Cancer Center in New York, USA, who explained that the genetically modified SPEAR T-cell therapy afamitresgene autoleucel (afami-cel) targets tumours expressing autologous melanoma-associated antigen (MAGE)-A4. 

The phase II open-label trial enrolled 59 patients with heavily pretreated advanced or metastatic synovial sarcoma and myxoid/round cell liposarcoma, including receipt of an anthracycline- or ifosfamide-based regimen. Patients were eligible if they had strong MAGE-A4 expression in at least 30% of tumour cells and were positive for the HLA-A*02 antigen, the presenter said. 

Analysis of the 37 patients who had undergone leukapheresis and T-cell therapy at time of reporting showed that “most treatment-emergent adverse events were consistent with those typically [found] in patients undergoing cytotoxic therapy”, and likely related to the lymphodepletion regimen used, the investigator reported. 

There were 22 reports of cytokine release syndrome occurring after a median of 3 days but just one incidence at grade 3 or more severe; the median time to resolution was 3 days. Prolonged grade 3 or more severe neutropenia, thrombocytopenia and anaemia 4 weeks after infusion occurred in two, one and three patients, respectively. 

The overall response rate in the trial was 39.4% of 33 assessed patients and the disease control rate was 84.8%. This included responses in 41.4% of the 29 assessed synovial sarcoma patients, including two complete responses, and 25.0% of the four assessed myxoid/round cell liposarcoma patients.  

Sandra D’Angelo continued that the median duration of response has not yet been reached and that “responses appear to be protracted, deep and durable.” 

She concluded that “afami-cel is safe and well tolerated with mainly low-grade cytokine release syndrome and tolerable and reversible haematological toxicities”, as well as eliciting “encouraging” durability of responses. Ongoing follow-up of the trial will be used to support a US FDA Biologics Licence Application in the coming year, the presenter added. 

References  

Van Tine BA, Chawla SP, Trent JC, et al. A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma. J Clin Oncol 2021;39(suppl 15; abstr 11505). DOI: 10.1200/JCO.2021.39.15_suppl.11505

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; abstr 11504). DOI: 10.1200/JCO.2021.39.15_suppl.11504