A novel combination therapy involving trabectedin, ipilimumab, and nivolumab is showing promising results as a first-line treatment for patients with advanced soft tissue sarcoma (STS). Data from the phase 2 portion of the ongoing SAINT study, presented at the European Society for Medical Oncology (ESMO) Congress 2024, indicate that the regimen is both safe and effective for previously untreated advanced STS.
The study, conducted by investigators from City of Hope and Mayo Clinic, addressed the critical need for improved treatments for advanced STS, a disease often associated with poor outcomes. The primary endpoint was the best response according to RECIST 1.1 criteria, while secondary endpoints included 6-month progression-free survival (PFS) and overall survival (OS).
Key Findings from the SAINT Study
The analysis included 97 adult patients with untreated, locally advanced unresectable or metastatic STS who received at least two cycles of treatment and had at least one CT scan. The overall response rate (ORR) was 24.7%, with 6% achieving a complete response (CR) and 17.5% experiencing a partial response (PR). The disease control rate (DCR) was notably high at 82.5%, with 59% of patients achieving stable disease (SD).
Median PFS was 7.3 months (95% CI, 5.2-9.4), and median OS was 32.0 months (95% CI, 20.6-43.2). At the data cutoff on April 30, 2024, 16 patients were still alive.
"These results are encouraging, especially considering the aggressive nature of advanced soft tissue sarcoma," said Dr. [Name], lead investigator of the study. "The combination of trabectedin with ipilimumab and nivolumab offers a potential new avenue for improving outcomes in these patients."
Treatment Protocol and Mechanism of Action
The treatment protocol consisted of ipilimumab at 1 mg/kg every 2 weeks, nivolumab at 3 mg/kg every 12 weeks, and trabectedin at 1.2 mg/m2 every 3 weeks.
Ipilimumab targets the CTLA-4 receptor on CD8+ killer T-cells, while nivolumab targets the PD-1 receptor on CD8+ killer T-cells, enhancing the immune response against tumor cells. Trabectedin inhibits the growth of tumor-associated macrophages and promotes the expression of PD-1, perforin, and granzyme B on CD8+ killer T-cells, further augmenting the anti-tumor immune response.
Safety and Tolerability
While there were no hematologic toxicities associated with nivolumab or ipilimumab, grade 3/4 treatment-related adverse effects included increased or decreased thyroid stimulating hormone, increased thyroxine, transaminitis, hyponatremia, dehydration, pruritis, and psoriasis. Grade 3/4 treatment-related adverse effects associated with trabectedin included fatigue, nausea, vomiting, fever, exhaustion, dehydration, asthenia, cellulitis of port, anemia, neutropenia, thrombocytopenia, transaminitis, and elevated creatine kinase.
Future Directions
Despite the promising results, the study investigators emphasize the need for randomized controlled trials to confirm the superiority of this regimen compared to standard first-line therapies for advanced STS. Phase 1 of the SAINT study is currently evaluating this combination in previously treated patients.
"Randomized studies are still needed to confirm whether this regiment is superior to standard first-line therapy for advanced advanced soft tissue sarcoma," the study authors noted.
