Purpose: Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma. Patients and Methods: This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety. Results: Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively. Conclusions: We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.

Background: In September of 2024, the 2nd annual meeting of the Strategic Advances in Sarcoma Science (SASS) convened at the National Institutes of Health. This gathering of national sarcoma experts focused on preclinical studies, clinical trials, opportunities, challenges, and future directions in sarcoma biology and clinical care with a focus on immunotherapy. The Immunology in Sarcoma breakout group conducted a dedicated discussion focused on the current and future implementation of adoptive cellular therapies (ACTs) in sarcomas. The current manuscript summarizes these discussions and provides a comprehensive resource for researchers and clinicians. Results: Adoptive cell therapy (ACT) has shown encouraging results in sarcomas with afami-cel achieving durable responses in synovial sarcoma and early TCR-T trials against NY-ESO-1 and MAGE-A4 demonstrating meaningful response rates. Building on these outcomes will require discovering new targets, selecting optimal cell types, refining conditioning regimens, combining with alternative treatment strategies such as TKIs, and leveraging predictive biomarkers informed by a deeper understanding of the tumor microenvironment. Conclusions: Sarcomas are promising targets for adoptive cell therapy (ACT), as shown by afami-cel’s success in synovial sarcoma, but broader impact requires new target discovery, optimal cell selection, improved conditioning, combination treatments, deeper tumor microenvironment understanding, and predictive biomarkers to achieve more durable responses for more patients.

Purpose: This study investigated factors that affected ctDNA detection and ctDNA as a molecular biomarker in a phase II trial of imatinib and binimetinib in newly diagnosed advanced gastrointestinal stromal tumor, including patients exposed to imatinib within 4 weeks of trial enrollment. Experimental Design: Plasma and tumor tissue samples were collected at baseline, during treatment, and upon progression. DNAs extracted from plasma and tumor tissue were analyzed using genomic assays, Memorial Sloan Kettering Analysis of Circulating cfDNA to Evaluate Somatic Status and Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, respectively. Sequenced ctDNA detection of the primary oncogenic driver was determined and correlated with clinical characteristics. Results: Patients (n = 31) included in this analysis had KIT mutations (n = 29, 94%) and metastatic disease (n = 24, 77%) and achieved the best response of partial response (n = 22, 71%), stable disease (n = 8, 26%), or progressive disease (n = 1, 3%). Sixteen patients (52%) were exposed to imatinib at baseline. The ctDNA detection rate of the primary oncogenic driver at baseline was 39% (n = 12/31) and was significantly more likely in patients who were treatment-naïve (n = 15) or had ≤4.2 weeks of treatment (n = 8) than in those otherwise (48% vs. 13%; P value = 0.004). Baseline ctDNA detection did not correlate with tumor burden or stage. The ctDNA serial analysis of the primary oncogenic driver paralleled and sometimes preceded radiographic response. ctDNA detected resistance mutations in KIT (n = 4). Active treatment influenced the detection of secondary KIT alterations in one patient. Conclusions: Active therapy at the time of ctDNA collection negatively affected the ability to detect primary and secondary KIT alterations in sequenced ctDNA from patients with advanced gastrointestinal stromal tumor. ctDNA responses may precede radiographic responses and merit further investigation.

» Synovial sarcoma is a soft tissue sarcoma that most commonly presents in the extremity in a periarticular location. » As the history and physical examination of patients with synovial sarcoma can overlap considerably with those of patients with non-oncologic orthopedic conditions, it is important that orthopedic surgeons maintain a high level of suspicion when caring for patients with extremity masses. » Soft tissue sarcomas are best treated using a team approach. Early recognition and referral to a multidisciplinary sarcoma team are crucial to ensure the best clinical outcome for the patient.

Purpose: The CDK4/6 inhibitor palbociclib delays progression in patients with advanced dedifferentiated liposarcoma (DDLPS). In carcinoma models, CDK4/6 and PD-1 inhibition induce intratumoral inflammation and synergistic activity. Comprehensive assessment of tumor and host dynamics is needed to understand response and resistance to this combination. Patients and Methods: We performed a phase 2 study of palbociclib and the PD-1 inhibitor retifanlimab in advanced DDLPS. Palbociclib was administered 2 weeks prior to retifanlimab. Tumor biopsies were analyzed by single-cell RNA sequencing (scRNA-seq), and peripheral blood by high-parameter flow cytometry. Analyses focused on cell cycle, senescence, and immune-related changes. Results: Twelve patients were treated before the study was halted because of a 42% immune-related toxicity rate. The overall response rate was 8.3%, and the disease control rate was 75%. Median progression-free and overall survival rates were 7.1 and 26.8 months, respectively. Nine patients had at least one tumor biopsy analyzed; three had paired. Ten patients had paired blood samples analyzed. Following treatment, tumor cells demonstrated decreased cycling and increased cell-cycle checkpoint activity. Transcriptional scores for senescence increased in cancer cells, as did the proportion of intratumoral T and B cells. A cluster of cells emerged with upregulated cell-cycle genes and downregulated HLA class I, suggesting innate or acquired resistance to treatment. In blood, a subset of CD4+ T cells decreased, whereas expression of LAG-3, ICOS, and CD38 increased in select subsets. Conclusions: A palbociclib lead-in prior to retifanlimab had a high rate of immune-related toxicities. Correlative analyses identified changes in tumor and immune cells attributable to treatment. A study of concurrent dosing of the combination is ongoing. Significance: In this phase 2 study of palbociclib and retifanlimab, treatment led to immune-related adverse events, halting enrollment. scRNA-seq and flow cytometry revealed cell-cycle suppression, senescence, and T-cell changes. These findings highlight the rationale for this combination and the need for safer dosing strategies in larger cohorts.