Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience.

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. RESULTS: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. CONCLUSIONS: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

The Future of Targeted Therapy for Leiomyosarcoma.

Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma that arises from smooth muscle cells, most commonly in the uterus and retroperitoneum. LMS is a heterogeneous disease with diverse clinical and molecular characteristics that have yet to be fully understood. Molecular profiling has uncovered possible targets amenable to treatment, though this has yet to translate into approved targeted therapies in LMS. This review will explore historic and recent findings from molecular profiling, highlight promising avenues of current investigation, and suggest possible future strategies to move toward the goal of molecularly matched treatment of LMS. We focus on targeting the DNA damage response, the macrophage-rich micro-environment, the PI3K/mTOR pathway, epigenetic regulators, and telomere biology.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.