A recent case study published in Frontiers in Oncology details the successful long-term management of a patient with advanced, unresectable dedifferentiated liposarcoma (DDLPS) through sequential treatment with trabectedin and nivolumab. This approach led to a sustained remission and offers a potential therapeutic strategy for this aggressive soft-tissue sarcoma. The case highlights the importance of exploring combination therapies and understanding the tumor microenvironment to improve outcomes in DDLPS.
Case Presentation
The patient, a 63-year-old male, was diagnosed with DDLPS of the retroperitoneum. Initial treatment included surgery followed by adjuvant chemotherapy with ifosfamide and doxorubicin, along with radiation therapy. However, the chemotherapy was discontinued due to severe hematotoxicity. The patient experienced multiple relapses, requiring several debulking surgeries and hyperthermic intraperitoneal chemotherapy (HIPEC).
Due to recurring disease, the patient was enrolled in the NitraSarc trial (NCT03590210), receiving trabectedin (1.5 mg/m² every three weeks) for the first three cycles, followed by the addition of nivolumab (240 mg every three weeks) from cycle four. Initial treatment with trabectedin alone resulted in disease stabilization with a 26% tumor regression. The combination therapy further deepened the response, achieving a partial response with an 86% reduction in tumor size per RECIST 1.1 criteria.
Treatment and Outcome
Trabectedin was discontinued after eleven cycles due to infectious complications, and the patient continued on single-agent nivolumab as maintenance therapy. After three cycles, a new tumorous nodule was detected, leading to the re-introduction of trabectedin and surgical resection, achieving an R0 resection (no residual tumor). The patient has remained with no evidence of disease (NED) for 4.3 years without any treatment, after living with DDLPS for 9.3 years.
Comparison with Existing Literature
Previous studies, such as the SARC028 trial, have shown limited efficacy of anti-PD-1 antibodies like pembrolizumab in liposarcoma patients, with only a minority achieving partial responses. Similarly, another phase-2 study evaluating nivolumab monotherapy in liposarcoma showed poor progression-free survival. These findings underscore the need to identify factors that can enhance the response to checkpoint inhibitors in DDLPS.
The NitraSarc trial's interim analysis showed a median PFS of 5.5 months in L-sarcomas (including LPS) treated with trabectedin/nivolumab, compared to 2.3 months in non-L-sarcomas. This case demonstrates an exceptional response duration, even within the L-sarcoma subgroup.
Potential Mechanisms and Clinical Implications
The study authors suggest that trabectedin may prime the sarcoma microenvironment, enhancing responsiveness to subsequent PD-1 inhibition. Trabectedin has been shown to induce re-exposure to neoantigens and eradicate M2 macrophages within the tumor microenvironment, potentially contributing to the observed therapeutic effect. The authors also performed IHC analysis which showed retained expression for the mismatch repair proteins MLH1, PMS1, MSH2 and MSH6. The rather mild inflammatory infiltrate, showed increased T-lymphocytes (CD5/CD3 positive) near the invasion front of the tumor, whereas centrally in the tumor only few T-lymphocytes could be found. These T-lymphocytes were mostly characterized by high CD8 but low CD4 expression. PD-1 staining revealed a minor fraction of intratumoral PD1 positive lymphocytes. 2% of tumor cells were positive for PD-L1 before versus <1% after treatment.
Conclusion
This case report suggests that sequential treatment with trabectedin followed by PD-1 inhibition may offer a viable strategy for achieving long-term disease control in advanced DDLPS. Further research is needed to identify predictive biomarkers and optimize treatment strategies for this challenging malignancy. The findings support the continued investigation of trabectedin and checkpoint inhibitor combinations in sarcoma subtypes that may benefit from this approach.
