The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includeTERTamplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

Purpose: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes. Patients and Methods: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1. Results: Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline. Conclusions: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.

PURPOSE: Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS: In this trial ( NCT01991379 ), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS: Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION: The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

PURPOSE: To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS: Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS: Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION: Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.

Kirsten rat sarcoma viral oncogene homolog ( KRAS ) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRAS ^G12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRAS ^G12V , partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRAS ^G12V - transgenic mouse model. We explored the therapeutic potential of KRAS ^G12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRAS ^G12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRAS ^G12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8 ⁺ T cells. Our work provides insights into the effect of KRAS ^G12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS -mutant cancers.