Lurbinectedin-Based Triplet Shows Clinical Benefit in Advanced Soft Tissue Sarcoma

Lurbinectedin (Zepzelca) in combination with ipilimumab (Yervoy) and nivolumab (Opdivo) exhibited high clinical benefit (CBR) and disease control (DCR) rates in patients with advanced soft tissue sarcoma according to data from the phase 1/2 LINNOVATE study (NCT05876715) which were presented at the 2025 ESMO Congress.¹

Results from the phase 2 portion of the trial showed that efficacy-evaluable patients with previously untreated advanced soft tissue sarcoma who were treated with lurbinectedin plus ipilimumab and nivolumab (n = 6) achieved a CBR of 100%, DCR of 100%, and best overall response rate (BORR) of 33.33%. Best overall responses (BOR) included 1 complete response (CR), 1 partial response, and 4 instances of stable disease (SD) at 12 weeks.

In the phase 1 portion of the study, efficacy-evaluable patients with previously treated advanced soft tissue sarcoma (n = 5) achieved a CBR, DCR, and BORR of 80%, 80%, and 0%, respectively. In this group of patients, all achieved a BOR of SD.

All patients across both phases of the trial (n = 11) achieved CBR, DCR, and BORR rates of 90.91%, 90.91%, and 18.1%, respectively. Additionally, 9 patients achieved SD and a CR or PR was achieved by 1 patient each.

“Taken together, the interim results [with] lurbinectedin in combination with ipilimumab and nivolumab for advanced soft tissue sarcoma, demonstrated a 100% CBR…[in] phase 2, with manageable toxicity, warranting continuation of phase 2 of the study,” investigators wrote in a poster presentation of the data.

What was the rationale and design of LINNOVATE?

LINNOVATE was designed to evaluate the synergy and efficacy of immune checkpoint inhibitors like ipilimumab and nivolumab when combined with lurbinectedin as a first-line therapy for advanced soft tissue sarcoma. ²

The single-site, dose-seeking study enrolled patients who were at least 18 years of age and had a confirmed pathologic diagnosis of advanced soft tissue sarcoma. ^1,2 Patients also needed to have at least 1 measurable target lesion of 1 cm per RECIST 1.1 criteria, an ECOG performance status of 0 or 1 and a life expectancy of at least 3 months.² Additionally, patients in phase 1 of the trial must have been previously treated; patients in phase 2 were previously untreated.¹

Patients with untreated central nervous system disorders, prior immunotherapy with a PD1/PD-L1 and CTLA4 inhibitor, uncontrolled systemic disease, or history of autoimmune disease were not included in the trial.

In phase 1, eligible patients received the lurbinectedin at the first dose level of 2.6 mg/m² once every 3 weeks in combination with 1 mg/kg of ipilimumab once every 12 weeks, and 3 mg/kg of nivolumab once every 2 weeks. If patients had no dose-limiting toxicities at dose level 1 they progressed to dose level 2, where they received lurbinectedin at 3.2 mg/m² every 3 weeks plus ipilimumab and nivolumab at the same doses.

In phase 2 of the study, all patients received lurbinectedin at the maximum tolerated dose. Notably, lurbinectedin, ipilimumab, and nivolumab were all administered intravenously across both phases.

Interim end points for the study were CBR, DCR, and BORR per RECIST 1.1 criteria; all end points were measured via CT scans or MRI.

What were the safety data for lurbinectedin plus ipilimumab and nivolumab in advanced soft tissue sarcoma?

In the safety-evaluable population (n = 19), no grade 3 or higher adverse effects were reported during the dose-limiting toxicity period. Additionally, no grade 5 treatment-related adverse effects (TRAEs) or unexpected TRAEs were observed. Among patients who experienced at least one TRAE, 37% (n = 7) were grade 3, 42% (n = 8) were grade 3 or higher, and 11% (n = 2) were grade 4. The most common grade 3 or higher TRAEs were decreased lymphocyte count (26%), decreased white blood cell count (WBC; 11%), and decreased absolute neutrophil count (ANC; 11%), decreased platelet counts, anemia, flu-like symptoms, and fatigue (5% each).

References

1. Jeffery S, Agarwal AD, Syed S, et al. Clinical benefit analysis of a phase I/II study using lurbinectedin combined with ipilimumab and nivolumab as first-line therapy for advanced soft tissue sarcoma.Ann Oncol. 2025;36(2):S1346-S1347.doi:10.1016/j.annonc.2025.08.3316
2. LINNOVATE: Lurbinectedin, ipilimumab and nivolumab for soft tissue sarcoma (LINNOVATE). ClinicalTrials.gov. Updated July 5, 2024. Accessed January 27, 2026. https://clinicaltrials.gov/study/NCT05876715?term=LURBINECTEDIN&rank=1