First-Line Combo Yields Strong Results in Advanced Sarcoma

As a first-line regimen, the investigative intravenous combination of trabectedin plus ipilimumab and nivolumab is likely safe and effective for untreated advanced soft tissue sarcoma, according to 7-year data (2017-2024) from the ongoing phase 2 portion of the SAINT study presented at the European Society for Medical Oncology (ESMO) Congress 2024.¹

The study investigators from City of Hope and Mayo Clinic noted that patients with advanced forms of the soft tissue sarcoma included in their analysis typically die because of their disease. Their primary end point was best response by RECIST 1.1 and secondary end points were 6-month progression-free survival and overall survival (OS). All patients (N = 97) received at least 2 cycles of treatment and had at least 1 CT scan.

Included adult patients had to have untreated locally advanced unresectable or metastatic soft tissue sarcoma with measurable disease according to RECIST 1.1. This means meeting the criteria for a complete response (CR); for a partial response (PR), no new lesions, no growth of nontarget lesions, and at least a 30% decrease in the sum of longest diameters of the target lesions (SLD); for stable disease (SD), no PR or progressive disease (PD); and for PD, a 20% or greater increase in SLD vs the smallest SLD, new lesions, or progression in nontarget lesions.²

Ipilimumab binds to the CD8+ killer T-cell CTLA-4 receptor, nivolumab binds to the CD8+ killer T-cell PD-1 receptor, and trabectedin inhibits the growth of tumor-associated macrophages while facilitating expression of PD-1, perforin, and granzyme B on CD8+ killer T cells and helping to increase CD8+ killer T cells themselves.¹ Ipilimumab (Yervoy; Bristol Myers Squibb) is currently approved to treat unresectable or metastatic melanoma and as adjuvant treatment of patients with cutaneous melanoma³; nivolumab (Opdivo; Bristol Myers Squibb) is currently approved to treat gastroesophageal, cancer, advanced melanoma, non–small cell lung cancer, and metastatic or unresectable urothelial carcinoma⁴; and trabectedin (Yondelis; Janssen/Pharma Maar), metastatic or unresectable liposarcoma or leiomyosarcoma.⁵

There were 17 partial responses and 6 complete responses in this analysis, with 16 patients still being alive at the April 30, 2024 data dut-off. | Image Credit: © Dzmitry-stock.adobe.com

The overall response rate was 24.7% and the disease control rate was 82.5%. The most common response to the treatment was SD in 57 patients (59%), and 17 patients (17.5%) showed evidence of PD.¹

There also were 17 PRs (17.5%) and 6 CRs (6%), and these patients had diagnoses of leiomyosarcoma, undifferentiated pleomorphic sarcoma, liposarcoma, synovial sarcoma, clear cell sarcoma, desmoplastic small round cell tumor, and chondrosarcoma.

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). The data cut-off for this analysis was April 30, 2024, and 16 patients were still alive at that date.

The treatment protocol encompassed ipilimumab 1 mg/kg every 2 weeks, nivolumab3 mg/kg every 12 weeks, and trabectedin 1.2 mg/m² every 3 weeks.

Phase 1 of the SAINT study is investigating this combination among previously treated patients.³

There were no hematologic toxicities from administration of nivolumab or ipilimumab, but grade 3/4 treatment-related adverse effects were increased or decreased thyroid stimulating hormone, increased thyroxine, transaminitis, hyponatremia, dehydration, pruritis, and psoriasis. Grade 3/4 treatment-related adverse effects associated with trabectedin were fatigue, nausea, vomiting, fever, exhaustion, dehydration, asthenia, cellulitis of port, anemia, neutropenia, thrombocytopenia, transaminitis, and elevated creatine kinase.

Although proven safe and effective for patients with untreated advanced soft tissue sarcoma, the study investigators emphasize that randomized studies are still needed “to confirm whether this regiment is superior to standard first-line therapy for advanced advanced soft tissue sarcoma.”

References

1. Agarwal AD, Jeffrey S, Cechini MR, et al. Seven year update on soc-1702: a phase 2 study using trabectedin (t) in combination with ipilimumab (i) and nivolumab (n) in previously untreated patients with advanced soft tissue sarcoma [NCT03138161]. Presented at: ESMO; September 13-17, 2024; Barcelona, Spain. Poster 1729P.

2. Smits F, Dirksen M, Schoots I. Recist 1.1 – the basics. Radiology Assistant. Accessed September 20, 2024. https://radiologyassistant.nl/more/recist-1-1/recist-1-1-1

3. SAINT: trabectedin, ipilimumab and nivolumab as first line treatment for advanced soft tissue sarcoma. ClinicalTrials.gov. Updated April 18, 2024. Accessed September 20, 2024. https://clinicaltrials.gov/study/NCT03138161

4. Opdivo. Prescribing information. Bristol Myers Squibb; 2024. Accessed September 20, 2024. https://www.opdivohcp.com

5. Yondeli. Prescribing information. Janssen; 2023. Accessed September 20, 2024. https://www.yondelis.com/