Nivolumab with or without relatlimab exceeded historical benchmarks in TLS-positive soft tissue sarcoma, validating TLS as a predictive biomarker.
Nivolumab (Opdivo) with or without relatlimab (Opdualag) exceeded historical benchmarks in the treatment of patients with tertiary lymphoid structures (TLS)–positive soft tissue sarcoma, according to data from the phase 2 CONGRATS trial (NCT04095208).1
Data presented at the 2025 ESMO Congress demonstrated that the addition of relatlimab did not improve efficacy vs nivolumab alone. In patients treated with the combination (n = 30), best overall responses comprised partial response (PR) at 10.0%, stable disease (SD) at 46.7%, and progressive disease (PD) at 43.3%, translating to a disease control rate (DCR) of 56.7%. The 6-month progression-free survival (PFS) rate was 26.7% (95% CI, 12.3%-45.9%), and the median PFS was 3.7 months (95% CI, 1.8-5.8). The median overall survival (OS) was 12.6 months (95% CI, 9.3-19.8).
Among patients treated with nivolumab alone (n = 33), best overall responses included PR at 18.2%, SD at 36.4%, and PD at 45.5%, leading to a DCR of 54.5%. Patients achieved a median PFS of 5.2 months (95% CI, 1.8-9.0) and a 6-month PFS rate of 39.4% (95% CI, 23.1%-57.8%). The median OS was 29.0 months (95% CI, 12.7-not reached).
“This is the first study prospectively validating TLS as a predictive biomarker in sarcoma immunotherapy,” lead study author Florent Peyraud, MD, PhD, of the Early Phase Trials and Sarcomas Units at Institut Bergonié in Bordeaux, France, said in a presentation of the data.
Peyraud explained that for patients with metastatic soft tissue sarcoma, palliative chemotherapy remains the standard of care, with a historical median OS of approximately 18 months. Although immune checkpoint inhibition has demonstrated limited activity in this overall patient population, TLS-positive soft tissue sarcoma has shown higher sensitivity to this immunotherapy approach.2
The proof-of-concept phase 2 trial enrolled patients at least 18 years of age with advanced or metastatic soft tissue sarcoma who had confirmed mature TLS per central review.1 Patients needed to have documented PD, an ECOG performance status of 0 or 1, and adequate organ function. Up to 2 prior lines of therapy were allowed, but chronic use of glucocorticoids was not allowed.
Among 365 patients screened for TLS, 63 were randomly assigned to received nivolumab at 240 mg plus relatlimab at 80 mg once every 2 weeks; or nivolumab at 240 mg once every 2 weeks. Treatment in both arms continued until disease progression or unacceptable toxicity.
The study’s primary end point was 6-month PFS rate. Secondary end points included best overall response, PFS, OS, growth modulation index, and safety.
Treatment-related adverse effects (TRAEs) of any grade occurred in 91.2% of patients treated with nivolumab plus relatlimab (n = 34) vs 79.4% of patients treated with nivolumab alone (n = 34). The rate of grade 3 or higher TRAEs was 14.7% in both arms. In the combination arm, any-grade TRAEs led to treatment interruption in 14.7% of patients and treatment discontinuation in 5.9% of patients. These respective rates were 20.6% and 8.8% with nivolumab alone.
The most common TRAEs between the 2 arms included arthralgia, diarrhea, rash, pruritus, myalgia, hypothyroidism, nausea, increased troponin levels, vomiting, pyrexia, immune-related enterocolitis, increased GGT levels, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, immune-related encephalitis, and hypophysitis.
Investigators also conducted a translational analysis used tumor samples from 6 responders and 6 nonresponders treated with either the combination or nivolumab alone.
This analysis revealed upregulation of FZD4 and IGF2-IGF2R in patients who did not respond, compared with upregulation of CXCL12-CXCR4 axis driving interactions in patients who did respond.
Disclosures: Peyraud reported receiving travel, accommodations, or expenses support from Mundipharma.
