Predictive Value of Quantitative Parameters of 18F-FDG PET/CT in Patients with Liposarcoma.

The purpose of this study was to evaluate the predictive features of baseline F-18-fluorodeoxy-D-glucose positron emission tomography (18F-FDG PET)/computed tomography (CT) parameters in patients with dedifferentiated liposarcomas (DDLPSs) and well-differentiated liposarcomas (WDLPSs) receiving systemic treatment. A total of 24 patients with liposarcoma who underwent longitudinal 18F-FDG PET/CT in systemic therapy were included. All volumetric segmentation of each tumor section and semiquantitative imaging parameters were extracted from the axial field of view from both PET and CT images. Maximum, mean, and minimum standardized uptake values (SUVmax, SUVmean, and SUVmin), Hounsfield units (HUs), and their respective changes from baseline and posttreatment were calculated. The voxel values from unenhanced CT images were correlated with PET-derived parameters. The 18F-FDG uptake decreased by more than 56% on average in responders for both SUVmax and SUVmean in DDLPS. There was a decrease in HUmax in DDLPS among responders. Using AUC > 0.8 as a reasonable predictor, we found that the ratios of SUVmaxD/HUmean, SUVmaxD/HUmedian, and SUVmeanD/HUmedian at baseline were significant indicators of the response to treatment in patients with liposarcoma. The changes in SUVmean and not just SUVmax parameters could be considered as accurate tumor response indicators. For the first time, we introduced baseline SUV/HU ratios as a valuable diagnostic tool in predicting liposarcoma treatment outcomes. This ability was not revealed by classic semiquantitative PET or CT parameters at baseline.

Does the Primary Tumor Site Drive Biology for Patients With Synovial Sarcoma?

OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

Patterns of Care and Outcomes of Patients with Small Gastrointestinal Stromal Tumors at a High-Volume Sarcoma Center.

BACKGROUND: The course of subclinical gastrointestinal stromal tumors (GISTs) is variable. The management of small GISTs is not well-defined. METHODS: Records of patients presenting with small GISTs with documented follow-up appointment at our institution between 2016 and 2022 were identified and reviewed. Comparative univariate analysis to compare patient and tumor characteristics and outcomes was performed. RESULTS: Eighty-six patients were followed for a median of 3.7 years (range 0.1-20 years). The median size at presentation was 1.7 (range 0.1-2.5) cm. A total of 51.2% (n = 44) underwent surgery before or immediately after initial presentation for pain (18.2%), bleeding (15.9%), or patient preference (6.8%). Another 17.4% (n = 15) had delayed surgery for tumor growth (40%), patient preference (2.7%), bleeding (6.7%), or pain (6.7%). The remaining 31.4% (n = 27) of patients never underwent surgery for reasons that included no growth/stability (44.4%), concomitant cancer diagnosis/treatment (29.6%), comorbidities (14.8%), and patient preference (3.7%). Patients who underwent surveillance without intervention compared with those who had delayed surgery were older (71.1 vs. 60.8 years, p < 0.001) with multiple comorbidities or a concurrent cancer diagnosis (70.3% vs. 20%, p = 0.005). There were no differences in survival or rate of distant metastases. Average time to surgery in the delayed group was 2 (range 0.1-10.3) years, and 86% of these patients underwent surgery by 5.5 years after diagnosis. CONCLUSIONS: In older patients with comorbidities or concurrent cancer diagnoses, opting out of surgery does not affect survival. Conversely, younger patients, free from significant comorbidities or other diagnoses, may consider surgery or active surveillance for up to 5 years, with comparable outcomes.

The INSIGHT study: a randomized, Phase III study of ripretinib versus sunitinib for advanced gastrointestinal stromal tumor with KIT exon 11 + 17/18 mutations.

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA.Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).

Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in KIT exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in KIT exon 11 and KIT exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes.

Clinical characteristics and outcomes of adult alveolar rhabdomyosarcoma patients on first-line systemic therapies: A single-institution cohort.

Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.

Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS): Updated local control, late toxicities, and patient-reported outcomes.

BACKGROUND: Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS; ClinicalTrials.gov identifier NCT03819985) investigated a radiobiologically equivalent, moderately hypofractionated course of preoperative radiotherapy (RT) 15 × 2.85 Gy in patients with soft tissue sarcoma (STS). Here, the authors report longer term follow-up to update local control and report late toxicities, as well as functional and patient-reported outcomes. METHODS: HYPORT-STS was a single-center, open-label, single-arm, prospective phase 2 clinical trial that enrolled 120 eligible adult patients with localized STS of the extremities or superficial trunk between 2018 and 2021. Patients received a 3-week course of preoperative RT followed by surgery 4-8 weeks later. End points and follow-up were analyzed from the date of surgery. RESULTS: The median follow-up was 43 months (interquartile range, 37-52 months), and the 4-year local recurrence-free survival rate was 93%. Overall RT-related late toxicities improved with time from local therapy (p < .001), and few patients had grade ≥2 toxicities (9%; n = 8 of 88) at 2 years. These included: 2% grade ≥2 skin toxicity, 2% fibrosis, 3% lymphedema, and 1% joint stiffness. Four patients (3%) had bone fractures. Both functional outcomes, as measured by the Musculoskeletal Tumor Society Rating Scale (p < .001), and quality of life, as measured by the Functional Assessment of Cancer Therapy-General (p < .001), improved with time from treatment, and both measures were better in follow-up at 2 years compared with baseline. CONCLUSIONS: Long-term follow up suggests that moderately hypofractionated preoperative RT for patients with STS is safe and effective. Higher grade late toxicities affect a minority of patients. Late toxicities decrease over time, whereas functional outcomes and health-related quality of life seem to improve with more time from combined modality treatment.

Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations.

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1-4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors.

Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous, Aggressive Cancer with Diverse Biomarkers and No Targeted Standard of Care: Review of the Literature and Ongoing Investigational Agents.

BACKGROUND: Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs. OBJECTIVE: The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments. RESULTS: MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials. CONCLUSIONS: Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.

Safety and Efficacy of Percutaneous Cryoablation for Recurrent or Metastatic Soft-Tissue Sarcoma in Adult Patients.

BACKGROUND. Treatment options are limited in patients with recurrent or metastatic disease after initial treatment of soft-tissue sarcoma (STS) by surgical resection, radiation, or systemic therapy. Percutaneous cryoablation may provide a complementary minimally invasive option in this setting. OBJECTIVE. The purpose of this article was to assess the safety and efficacy of percutaneous cryoablation performed for local control of treatment-refractory recurrent or metastatic STS. METHODS. This single-institution retrospective study included adult patients who underwent percutaneous cryoablation from January 2016 to April 2023 to achieve local control of recurrent or metastatic STS after earlier treatment (surgery, radiation, or chemotherapy). For each treated lesion, a single interventional radiologist rereviewed intraprocedural images to assess for adequate coverage by the ice ball of the entire lesion and a 5-mm or greater margin in all dimensions. Complications and outcomes were extracted from medical records. The primary end point for procedure efficacy was 1-year local progression-free survival. RESULTS. The study included 141 patients (median age, 66 years; 90 women, 51 men) who underwent 217 cryoablation procedures to treat 250 recurrent or metastatic STS lesions. The most common STS histologic types were leiomyosarcoma (56/141) and liposarcoma (39/141). Lesions had a mean long-axis diameter of 2.0 cm (range, 0.4-11.0 cm). Adequate ice-ball coverage was achieved for 82% (204/250) of lesions. The complication rate was 2% (4/217), including three major complications and one minor complication. Patients' median postablation follow-up was 25 months (range, 3-80 months). Local progression-free survival rate was 86% at 1 year and 79% at 2 years. The chemotherapy-free survival rate was 45% at 1 year and 31% at 2 years. The overall survival (OS) rate was 89% at 1 year and 80% at 2 years. In Kaplan-Meier analysis, leiomyosarcoma, in comparison with liposarcoma, had significantly higher local progression-free survival but no significant difference in OS. In multivariable analysis, factors independently associated with an increased risk for local progression included inadequate ice-ball coverage (HR = 7.34) and a lesion location of peritoneum (HR = 3.63) or retroperitoneum (HR = 3.71) relative to lung. CONCLUSION. Percutaneous cryoablation has a favorable safety and efficacy profile in patients with recurrent or metastatic STS after earlier treatments. CLINICAL IMPACT. Percutaneous cryoablation should be considered for local control of treatment-refractory STS.

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.

Mapping the Single-Cell Differentiation Landscape of Osteosarcoma.

PURPOSE: The genetic intratumoral heterogeneity observed in human osteosarcomas poses challenges for drug development and the study of cell fate, plasticity, and differentiation, which are processes linked to tumor grade, cell metastasis, and survival. EXPERIMENTAL DESIGN: To pinpoint errors in osteosarcoma differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs mesenchymal stem cells toward adipogenic and osteoblastic fates. Incorporating preexisting chondrocyte data, we applied trajectory analysis and non-negative matrix factorization to generate the first human mesenchymal differentiation atlas. RESULTS: This "roadmap" served as a reference to delineate the cellular composition of morphologically complex osteosarcoma tumors and quantify each cell's lineage commitment. Projecting a bulk RNA-sequencing osteosarcoma dataset onto this roadmap unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. CONCLUSIONS: Our study quantifies osteosarcoma differentiation and lineage, a prerequisite to better understanding lineage-specific differentiation bottlenecks that might someday be targeted therapeutically.

Safety and efficacy of percutaneous image-guided ablation for soft tissue sarcoma metastases to the liver.

PURPOSE: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver. MATERIALS AND METHODS: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival. RESULTS: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes were leiomyosarcoma (23/55), followed by gastrointestinal stromal tumor (22/55). The median treated liver lesions was 2 (range, 1-8), whereas the median size of metastases were 1.8 cm (0.3-8.7 cm). Complete response at 2 months was achieved in 90.5% of the treated lesions. LPFS was 83% at 1 year and 80% at 2 years. Liver-specific progression-free survival was 66% at 1 year and 40% at 2 years. The overall survival at 1 and 2 years was 98% and 94%. The chemotherapy-free holiday from the start of ablation was 71.2% at 12 months. The complication rate was 3.6% (2/55); one of the complications was Common Terminology Criteria for Adverse Events grade 3 or higher. LPFS subgroup analysis for leiomyosarcoma versus gastrointestinal stromal tumor suggests histology-agnostic outcomes (2 years, 89% vs 82%, p = .35). CONCLUSION: Percutaneous image-guided liver ablation of soft tissue sarcoma metastases is safe and efficacious.

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.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

SABR for Sarcoma Lung Metastases: Indications for Treatment and Guidance for Patient Selection.

PURPOSE: The lungs are the most common site of metastasis for patients with soft tissue sarcoma. SABR is commonly employed to treat lung metastases among select patients with sarcoma with limited disease burden. We sought to evaluate outcomes and patterns of failure among patients with sarcoma treated with SABR for their lung metastases. METHODS AND MATERIALS: We performed a retrospective review of patients treated at a tertiary cancer center between 2006 and 2020. Patient disease status at the time of SABR was categorized as either oligorecurrent or oligoprogressive. The Kaplan-Meier method was used to estimate disease outcomes. Uni- and multivariable analyses were conducted using the Cox proportional hazards model. RESULTS: We identified 70 patients with soft tissue sarcoma treated with SABR to 98 metastatic lung lesions. Local recurrence-free survival after SABR treatment was 83% at 2 years. On univariable analysis, receipt of comprehensive SABR to all sites of pulmonary metastatic disease at the time of treatment was associated with improved progression-free survival (PFS; hazard ratio [HR], 0.51 [0.29-0.88]; P = .02). On multivariable analysis, only having systemic disease controlled at the time of SABR predicted improved PFS (median PFS, 14 vs 4 months; HR, 0.37 [0.20-0.69]; P = .002) and overall survival (median overall survival, 51 vs 14 months; HR, 0.17 [0.08-0.35]; P < .0001). CONCLUSIONS: SABR provides durable long-term local control for sarcoma lung metastases. The most important predictor for improved outcomes was systemic disease control. Careful consideration of these factors should help guide decisions in a multidisciplinary setting to appropriately select the optimal candidates for SABR.

MDM2-p53 in liposarcoma: The need for targeted therapies with novel mechanisms of action.

Well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are rare tumors that arise from lipocytes in soft tissue. There is a high unmet need in patients with these liposarcomas given poor outcomes, particularly for DDLPS. WDLPS and DDLPS share important genetic and histological characteristics - most notably, the amplification of the 2 genes MDM2 and CDK4. Both genes are considered oncogenes because of their ability to shut down tumor suppressor pathways. There are multiple therapeutic approaches that aim to target MDM2 and CDK4 activity for the purpose of restoring intrinsic tumor suppressor cellular response and terminating oncogenesis. However, current understanding of the molecular mechanisms involved in WDLPS and DDLPS pathology is limited. In recent years, significant efforts have been made to refine and implement targeted therapy for this patient population. The use of patient-derived cell and tumor xenograft models has been an important tool for recapitulating WDLPS and DDLPS biology. These models also offer valuable insights for drug development and drug combination studies. Here we offer a review of the current understanding of WDLPS and DDLPS biology and its therapeutic implications.