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PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.

Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.

Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. Patients and Methods: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163

Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition.Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure.We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST.These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Purpose: Leiomyosarcoma (LMS) is a neoplasm characterized by smooth muscle differentiation, complex copy-number alterations, tumor suppressor loss, and the absence of recurrent driver mutations. Clinical management for advanced disease relies on the use of empiric cytotoxic chemotherapy with limited activity, and novel targeted therapies supported by preclinical research on LMS biology are urgently needed. A lack of fidelity of established LMS cell lines to their mesenchymal neoplasm of origin has limited translational understanding of this disease, and few other preclinical models have been established. Here, we characterize patient-derived xenograft (PDX) models of LMS, assessing fidelity to their tumors of origin and performing preclinical evaluation of candidate therapies. Experimental Design: We implanted 49 LMS surgical samples into immunocompromised mice. Engrafting tumors were characterized by histology, targeted next-generation sequencing, RNA sequencing, and ultra-low passage whole-genome sequencing. Candidate therapies were selected based on prior evidence of pathway activation or high-throughput dynamic BH3 profiling. Results: We show that LMS PDX maintain the histologic appearance, copy-number alterations, and transcriptional program of their parental tumors across multiple xenograft passages. Transcriptionally, LMS PDX cocluster with paired LMS patient-derived samples and differ primarily in host-related immunologic and microenvironment signatures. We identify susceptibility of LMS PDX to transcriptional cyclin-dependent kinase (CDK) inhibition, which disrupts an E2F-driven oncogenic transcriptional program and inhibits tumor growth. Conclusions: Our results establish LMS PDX as valuable preclinical models and identify strategies to discover novel vulnerabilities in this disease. These data support the clinical assessment of transcriptional CDK inhibitors as a therapeutic strategy for patients with LMS.

Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST). Patients and Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11–positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed. Results: Forty-five patients enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11–positive; primary endpoint) and 20% (KIT ex11–negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11–positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related. Conclusions: Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11–positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.

PURPOSE: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). While similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. EXPERIMENTAL DESIGN: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. RESULTS: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL-6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab (bevacizumab HR = 1.51, 95% CI 1.10–2.06; cetuximab HR = 0.94, 95% CI 0.71–1.25; P(interaction) = 0.0298) in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR = 1.70, 95% CI 1.19–2.42; FOLFOX/cetuximab HR = 0.92, 95% CI 0.68–1.24; P(interaction) = 0.0097). CONCLUSIONS: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for mCRC patients enrolled in CALGB80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.

Background Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P Conclusion PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. Trial registration ClinicalTrials.gov Identifier: NCT03353753; first posted: November 27, 2017.

PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501 ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/ platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.

Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Purpose: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor a kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a >fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. Methods: Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. Results: Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third-and >fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. Conclusion: Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

Globally, there has been little change in mortality rates from cardiovascular (CV) diseases or cancers over the past two decades (1997–2018). This is especially true for heart failure (HF) where 5-year mortality rates remain as high as 45–55%. In the same timeframe, the proportion of drug revenue, and regulatory drug approvals for cancer drugs, far out paces those for CV drugs. In 2018, while cancer drugs made 27% of Food and Drug Administration drug approvals, only 1% of drug approvals was for a CV drug, and over this entire 20 year span, only four drugs were approved for HF in the USA. Cardiovascular trialists need to reassess the design, execution, and purpose of CV clinical trials. In the area of oncology research, trials are much smaller, follow-up is shorter, and targeted therapies are common. Cardiovascular diseases and cancer are the two most common causes of death globally, and although they differ substantially, this review evaluates whether some elements of oncology research may be applicable in the CV arena. As one of the most underserved CV diseases, the review focuses on aspects of cancer research that may be applicable to HF research with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to patients who need them. The paper is based on discussions among clinical trialists, industry representatives, regulatory authorities, and patients, which took place at the Cardiovascular Clinical Trialists Workshop in Washington, DC, on 8 December 2019 (https://www.globalcvctforum.com/2019 (14 September 2020)).

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein–coupled receptor 20 (GPR20) as a novel non–tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody–drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression–dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. Significance: GPR20 is selectively expressed in GIST across all treatment lines, regardless of KIT/PDGFRA genotypes. We generated DS-6157a, a DXd-based antibody–drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles. This article is highlighted in the In This Issue feature, p. 1307

Purpose: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data. Experimental Design: Multistakeholder working groups were appointed by an ASCO-Friends leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status. Results: The four working groups, ASCO Board of Directors, and Friends leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations. Conclusions: Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual. See related commentary by Giantonio, p. 2369

Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant GIST. The two main clinical challenges for the forthcoming years entail tumor eradication in patients with early-stage GIST, and maximization of tumor response in late-stage disease. To succeed, we will need to better understand the mechanisms behind adaptation to KIT inhibition and apoptosis evasion, tumor evolution after successive lines of treatment, and to explore clinically novel creative therapeutic strategies, with the overarching goal to tackle the intrinsic oncogenic complexity while minimizing adverse events.

Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed across sarcoma subtypes. We hypothesised that generation of anti-ganglioside antibodies would control micrometastases and improve outcomes in sarcoma patients who were disease-free after metastasectomy.We conducted a randomised phase II trial of the immunological adjuvant OPT-821 with a KLH-conjugated ganglioside vaccine targeting GM2, GD2 and GD3, versus OPT-821 alone in patients with metastatic sarcoma following complete metastasectomy. Patients received 10 subcutaneous injections at Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84 and were followed for evidence of recurrent disease. The primary end-point was relapse-free survival. Secondary end-points included overall survival and serologic response.A total of 136 patients were randomised, 68 to each arm. The mean age was 51.2, 52.2% were male, 90.4% had relapsed disease, 86.8% had high-grade tumours and 14% had ≥4 metastases resected. Histologies included leiomyosarcoma (33%), spindle cell sarcoma (14%), undifferentiated pleomorphic sarcoma (13%), osteosarcoma (10%), synovial sarcoma (9%), liposarcoma (9%) and others (12%). Most adverse events were Grade ≤2 (83.8% and 70.6% in the vaccine and adjuvant arms, respectively). The most common (≥20% of patients) were injection site reaction (89.7%), fatigue (44.1%) and pyrexia (27.9%) on the vaccine arm, and injection site reaction (69.1%) on the adjuvant only arm. The 1-year relapse-free survival rate (34.5% and 34.8% in the vaccine and OPT-821 monotherapy arm, respectively) did not differ between arms (P = 0.725). One-year overall survival rates were 93.1% and 91.5% in the vaccine and OPT-821 monotherapy arm, respectively (P = 0.578). Serologic responses at week 9 were more frequent on the vaccine arm (96.5% of patients) than in the adjuvant arm (32.8%), and the difference between groups was durable.A sustained serologic response to vaccination was induced with the vaccine, but no difference in recurrence-free or overall survival was observed between treatment arms.gov identifier: NCT01141491.

Sarcomas are a rare group of tumors with many subtypes, conventionally classified into soft-tissue sarcomas and bone sarcomas. Chemotherapeutic regimens form the mainstay of systemic therapy but are not well defined beyond the first-line setting and clinical outcomes are variable. Tyrosine kinase inhibitors (TKIs), with a broad inhibition profile which have been shown to target tumor angiogenesis, have an established role in the treatment of sarcomas without characteristic driver alterations. One such TKI, regorafenib, has been evaluated in sarcomas and clinical data are discussed in this review. An overview of regorafenib data from five phase 2 and one phase 1b clinical trials in over 10 sarcoma subtypes (both soft-tissue and bone) in adult and pediatric patients is reviewed. Regorafenib demonstrated clinical benefit in patients with non-adipocytic soft-tissue sarcomas, osteosarcoma and Ewing sarcoma who had progressed on prior therapy. Patients with otherwise limited treatment options may therefore benefit from regorafenib therapy.

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

Introduction: Ripretinib (Rip) is a kinase inhibitor with broad preclinical activity against mutant KIT. Based on the INVICTUS trial, Rip was approved for patients with Gastrointestinal Stromal Tumors (GIST) after treatment with 3 or more kinase inhibitors. Most patients in this ≥4th-line setting progress on Rip within one year. Here, we characterized Rip-progressing GIST samples to identify resistance mechanisms. Methods: Progressing lesions in 25 patients were analyzed by NGS after Rip failure. KIT mutations (muts) were recapitulated by gene editing. Activities of Rip, sunitinib (SU), and novel TKIs were characterized by cell viability assays and immunoblot. Mutagenesis experiments were performed using ENU. SU- and Rip-resistant cell lines were pooled and treated with various regimens, with clonal composition deconvoluted by cDNA-based amplicon sequencing. Results: 19/25 Rip-progressing GISTs displayed muts in the ATP-binding pocket (ATP-BP; e13/14). Four of these had pre-existing muts in the activation loop (AL; e17/18), which were confirmed to be in-cis with the primary and ATP-BP muts (triple in cis; TIC). Mutagenesis screens using a double KIT-mutant GIST line (e11 + AL) as a starting point confirmed that TIC-muts are a predominant escape mechanism when treated with Rip. A GIST subline (T1-triple) with TIC-muts in e11, e18 (A829P), and e13 (V654A) was highly resistant to Rip (GR50 > 2µM). Structural analyses of ATP-BP muts suggest steric interference and loss of van der Waals interactions that impede Rip binding and thereby confer Rip resistance. Another 3/25 Rip-progressing GISTs harbored pathogenic KIT muts in e9 only. A novel GIST cell line with primary KIT e9 mut (T1-e9) was 14-fold less sensitive to Rip than isogenic e11-driven cells (GR50 = 115 vs 8nM). Notably, adding a typical AL mut to T1-e9 (T1-e9-N822K) sensitized the cells to Rip (GR50 = 20nM). Immunoblots showed >95% inhibition of phospho-KIT in AL-mutant cell lines at Rip 100nM, whereas inhibition was weaker in T1-e9 (77%) and T1-V654A (46%), and absent in T1-triple. A compound screen of FDA-approved kinase inhibitors identified Nintedanib (NIN) as the most active compound against T1-triple. Clonal outgrowth assays of mixed cultures revealed SU (93% inhibition), and a weekly switch between Rip and either SU (96%) or NIN (79%) as the most effective inhibitors of pooled cell growth. Conclusions: KIT e9 primary muts and e13/14 (ATP-BP) secondary muts are enriched in post-progression biopsies following Rip treatment. KIT TIC-muts are novel frequent events driving GIST clinical progression and confer a high degree of resistance. Strategies to overcome resistance may include combinations or sequences of approved drugs, and novel drugs that more efficiently inhibit TIC-mutant KIT. Citation Format: Thomas Mühlenberg, Johanna Falkenhorst, Tom Schulz, Benjamin S. Fletcher, Alina Teuber, Dawid Krzeciesa, Isabella Klooster, Jonas Lategahn, Wen-Bin Ou, Meijun Lundberg, Margaret von Mehren, Susanne Grunewald, Alicia I. Tüns, Mehdi Brahmi, Michael C. Heinrich, Cesar Serrano, Hans-Ulrich Schildhaus, Sonja Sievers, Jürgen Treckmann, Lydia Wilson, Chandrajit P. Raut, Adrian Marino-Enriquez, Suzanne George, Daniel Rauh, Jonathan A. Fletcher, Sebastian Bauer. ATP-binding pocket substitutions as secondary or tertiary in-cis mutations are major on-target ripretinib resistance mechanisms in gastrointestinal stromal tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3887.

Osteosarcoma (OS) and Leiomyosarcoma (LMS) are sarcomas with complex genomes for which there has been limited progress in identifying new treatments and improving outcomes. Slow progress in OS and LMS is partially due to insufficient characterization of the genomic landscape. Generating large genomic datasets in OS and LMS is challenging because of the rarity of these sarcomas and recruitment barriers such as care fragmentation between institutions and specialties. The OS and LMS Project research studies aim to: 1) establish a network of engaged pediatric and adult participants with OS and LMS who will co-create a shared database of clinical, genomic, molecular, and patient reported data to enable research; 2) define the clinicogenomic landscape of OS and LMS; and 3) optimize the approach to direct patient engagement in cancer research. Count Me In, a research initiative with prior success in angiosarcoma, working with patients and advocates created websites (OSProject.org and LMSProject.org) where patients register and consent to participation. Within two months of launching, 233 patients age 6-79 from 149 Institutions have consented. Blood and saliva are collected from consented participants, tumor samples are obtained from pathology departments and medical records are requested from treating hospitals. WES and WGS of tumor and normal, and RNASeq of tumor is performed. ctDNA is obtained and sequenced. Results are shared with patient, advocacy, physician and research communities in several ways. Individual participants receive a shared learning report describing the somatic variants identified in their tumor from paired tumor-normal WES and are offered genetic counseling and clinical germline testing. Registered participants receive updates via email and Project websites. There are regular pre-publication data releases to the genomic data commons and to cBioPortal. A physician engagement committee meets regularly to discuss clinical insights and conundrums from shared learning reports and germline testing. Patient accrual over the next 3 years is anticipated to result in sequencing of 750 tumor-normal pairs and 500 ctDNA samples. Citation Format: Katherine A. Janeway, Suzanne George, Corrie Painter, Carrie Cibulskis, Taylor Cusher, Jordan Doucette, Elana Anastasio, Benjamin Zola, Ashley Mathews, Evelina Ceca, Maeve Smart, Beena Thomas, Jason Hornick, Alanna Church, Lorena Lazo De La Vega, Jill Stopfer, Sidney Benich, Ellen Sukharevsky, Sarah Winnicki, Brendan Reardon, Brian Crompton, Priscilla Merriam, Adrian Marino-Enriquez, Diane Diehl, Eliezer VanAllen, Judy Garber, Gad Getz, Stacey Gabriel, Timothy Rebbeck, Jennifer Mack, Nikhil Wagle. The Osteosarcoma and Leiomyosarcoma Count Me In Projects of the Cancer Moonshot funded PE-CGS Network directly engage patient participants in genomics research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6084.

11541 Background: Ripretinib (R) is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of patients (pts) with advanced gastrointestinal stromal tumor (GIST) after prior treatment with ≥3 TKIs. In the INTRIGUE study (NCT03673501) there was no significant difference in median PFS (primary endpoint) between R and sunitinib (S). We present exploratory analyses of tolerability data and selected pt reported outcomes (PROs). Methods: Pts were randomized 1:1 to R 150 mg QD or S 50 mg QD 4 weeks on/2 weeks off.Dose modification was allowed for toxicity management. The event of interest was severe or life-threatening (grade ≥3) treatment-related adverse event prior to progression (sTRAE). Days with at least one sTRAE were summed for all treated pts and for pts with ≥1 sTRAE event. PROs were assessed using questions from EORTC QLQ-C30 and Dermatology Life Quality Index (DLQI) at cycle 1 (C1) day 1 (D1), D15, and D29; D1 and D29 of all other cycles; as well as at end of treatment. Differences in PRO scores between baseline and later assessments were calculated across visits. Long-term data will be presented. Results: Pts receiving R (n = 223) versus (vs) S (n = 221) experienced fewer sTRAEs (24% vs 51%, respectively). For all treated pts, the mean time with sTRAEs was 11 days for R and 42 days for S (ratio 0.27, P

101 Background: The genotype of primary mutations predicts imatinib response in untreated metastatic GIST. However, the sequence of salvage treatments in metastatic GIST is based solely on the chronological order of registration trials. ctDNA sequencing offers a powerful diagnostic tool to detect resistance mutations in GIST but has not been shown to correlate with outcomes in clinical trials of pretreated patients (pts). We analyzed ctDNA samples collected at baseline in the phase III VOYAGER trial (NCT03465722) to describe the landscape of KIT alterations and its association with outcomes of pts treated with avapritinib or regorafenib. Methods: In VOYAGER, 476 pts with advanced KIT-mutant GIST were randomly assigned to avapritinib (240 pts) or regorafenib (236 pts) in 3rd-4th line. Baseline plasma was collected and ctDNA analyzed with the Guardant 360 (G360), 74-gene panel. KIT molecular subgroups were determined and correlated with outcomes. PDGFRA-mutant GISTs were excluded from outcomes analysis. Results: Baseline ctDNA analysis was performed in 386/476 pts (81%). ctDNA was detected in 333 pts (86%), with 250 and 18 pts showing at least one KIT (75%) or PDGFRA (5%) variant, respectively. KIT primary mutations were detected in 71% pts (exon 11, 56%; exon 9, 14%; exon 13, 1%) and KIT secondary mutations in 55% of pts. Activation loop (AL, exons 17 and 18) was more commonly affected (44%) than the ATP-binding pocket (ABP, exons 13 and 14; 23%). Among KIT-mutant tumors, multiple KIT mutations were commonly detected within individual tumors (mean, 2.56; range, 1-14). Notably, 17% of pts had > 3 mutations (mean, 6.07; range, 4 to 14). Median PFS and OS were shorter for patients whose ctDNA was positive for V654A or T670I (ABP hot spots) when treated with avapritinib vs. regorafenib: mPFS, 1.9 mo vs. 7.4 mo; log-rank p

TPS483 Background: The majority of GISTs are driven by constitutively activated kinases, either KIT or platelet-derived growth factor-alpha ( PDGFRA), and respond to TKI treatment (eg, imatinib, sunitinib, regorafenib, ripretinib). Most GISTs develop heterogeneous resistance to TKI during treatment, usually driven by secondary mutations in the primary kinase oncogene ( KIT or PDGFRA). Novel therapies are needed to prevent emergence of resistant subclones or to treat TKI-resistant GISTs. IDRX-42 (formerly M4205) is a potent, highly selective, orally administered small-molecule TKI targeting disease-specific oncogenic drivers and a range of clinically relevant resistance mutations of KIT. Nonclinical studies of IDRX-42 have demonstrated robust antitumor activity in patient and cell line-derived GIST xenograft models, including models with relevant KIT mutations and TKI resistance mutations (De Sutter et al AACR 2022). Methods: IDRX-42-001 is a phase 1/1b, first-in-human, open-label, multicenter study to evaluate single-agent IDRX-42 in participants with metastatic and/or surgically unresectable GISTs. Phase 1 dose escalation utilizes a 3+3 design to evaluate safety, tolerability, PK, and preliminary antitumor activity of IDRX-42 to establish the MTD and RP2D. Phase 1b will consist of exploratory cohorts with selected lines of prior therapy to assess the antitumor activity of IDRX-42 and further characterize its safety profile at RP2D. Eligible participants are ≥18 yr old with ECOG PS 0–1, documented pathogenic mutation in KIT or any PDGFRA mutation other than exon 18 mutations, and ≥1 measurable lesion per mRECIST v1.1 by investigator assessment. Phase 1 dose-escalation participants must have documented progression on at least imatinib. For phase 1b exploratory cohorts, cohort 1 participants must have progressed on imatinib only (2nd line); cohort 2 participants must have progressed on imatinib and sunitinib (3rd line) or progressed on imatinib, sunitinib, and an additional agent (ie, regorafenib or ripretinib; 4th line); cohort 3 participants must have progressed on imatinib, sunitinib, regorafenib, and ripretinib (≥5th line). IDRX-42 will be initiated at 120 mg PO QD in 28-d cycles until disease progression, unacceptable toxicity, or other reason. Primary endpoints are to determine the nature, incidence, & severity of IDRX-42 TEAEs and DLTs (phase 1), and to evaluate safety and determine ORR per investigator assessed mRECIST v1.1 (phase 1b). Secondary efficacy endpoints include PK parameters, DoR, PFS, and time to response related to IDRX-42. Exploratory endpoints will evaluate potential predictive and pharmacodynamic markers using ctDNA, as well as changes in KIT, PDGFRA, and other relevant gene mutant allele fractions and their correlation with clinical outcomes. Enrollment is ongoing (NCT05489237). Clinical trial information: NCT05489237 .

Purpose: We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival. Experimental Design: Using ultra–low-passage whole-genome sequencing (ULP-WGS) of plasma cell-free DNA from patients treated on a prospective clinical trial, we tested whether detection of ctDNA evaluated prior to the start of therapy and after two cycles of chemotherapy was associated with treatment response and outcome. Associations between detection of ctDNA and pathologic measures of disease burden were evaluated. Results: We found that ctDNA was detectable by ULP-WGS in 49% patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pretreatment ctDNA was significantly associated with a lower overall survival [HR, 1.55; 95% confidence interval (CI), 1.03–2.31; P = 0.03] and a significantly lower likelihood of objective response [odds ratio (OR), 0.21; 95% CI, 0.06–0.59; P = 0.005]. After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR, 1.77; 95% CI, 1–3.14; P = 0.05) and were unlikely to experience an objective response (OR, 0.05; 95% CI, 0–0.39; P = 0.001). Conclusions: Our results demonstrate that detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy. See related commentary by Kasper and Wilky, p. 2480

Summary Background Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). Methods NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov , NCT02508532 . Findings Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Interpretation Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Funding Blueprint Medicines.

Purpose: Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution. Experimental Design: We interrogated whole-exome sequencing (WES) from “trios” of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios. Results: Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype. Conclusions: From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.

Due to the efficacy of immune checkpoint inhibitor therapy in tumors with deficient mismatch repair, there has been a surge in demand for mismatch repair deficiency testing in various tumor types. Mismatch repair deficiency is not known to play a significant role in the pathogenesis of sarcomas, and the utility of testing these tumor types is not established. This study aimed to determine the frequency, pattern, and clinicopathologic correlates of mismatch repair deficiency in sarcomas. Three hundred and four sarcomas were profiled using a genomic platform that employs massively parallel sequencing to interrogate 447 cancer-associated genes. Mismatch repair status was evaluated by determining the number of small insertion/deletion events occurring in homopolymer regions per megabase of exonic sequence data across all genes. Molecular characteristics of mismatch repair-deficient sarcomas were compared to mismatch repair-deficient carcinomas (n = 70) also identified using the sequencing panel. Seven sarcomas (2.3%) were classified as mismatch repair-deficient: four unclassified sarcomas, and one each of pleomorphic rhabdomyosarcoma, epithelioid leiomyosarcoma and malignant PEComa. One patient had an established diagnosis of Lynch syndrome. In the remaining patients, the mismatch repair gene mutation was confirmed or suspected to be somatic. Mismatch repair immunohistochemistry confirmed the mismatch repair-deficiency status of all cases with alterations in the tested proteins. As expected, mismatch repair-deficient sarcomas showed a significantly elevated tumor mutation burden relative to mismatch repair-proficient sarcomas (median 16 versus 4.6, p

Management of leiomyosarcoma is based on the specifics of each individual case. Specifically, the location of the disease and whether the disease is metastatic or localized and if localized disease, whether the tumor is resectable or unresectable. In patients with recurrent or metastatic disease, factors such as disease-free interval and pattern of spread should be considered within the context of treatment planning. In general, patients with metastatic disease are typically treated with systemic chemotherapy with either an anthracycline-based regimen or gemcitabine-based regimen as first-line therapy. Additional systemic options include trabectedin, pazopanib, eribulin, and DTIC. Uterine LMS has been the most studied site-specific LMS with respect to systemic therapy. The increasing use of tumor genomics may ultimately define subsets which may benefit from tailored systemic therapies.

Advanced GIST is characterized by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor (CDK4/6i) therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximizing response to therapeutic CDK4/6 inhibition. Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples (N=18), including 8 metastatic TKI-resistant GISTs. Multiple metastases were analyzed in 3 patients. The impact of CDK2i (CDK2 inhibitor-II), CDK4/6i (palbociclib or abemaciclib), and CDK2/4/6i (PF-06873600) was determined through cell proliferation and protein detection assays in vitro and in vivo. Mechanisms of acquired CDK2i and CDK4/6i resistance were characterized in GIST cell lines after long-term exposure. The results demonstrate recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways. Identical aberrations of p16, RB1, and TP53 were present in all metastases from 3 patients. We show that therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation (P Citation Format: Inga-Marie Schaefer, Matthew L. Hemming, Meijun Z. Lundberg, Matthew P. Serrata, Isabel Goldaracena, Ninning Liu, Peng Yin, Joao A. Paulo, Steven P. Gygi, Suzanne George, Jeffrey A. Morgan, Monica M. Bertagnolli, Ewa T. Sicinska, Adrian Mariño-Enríquez, Jason L. Hornick, Chandrajit P. Raut, George D. Demetri, Wen-Bin Ou, Sinem K. Saka, Jonathan A. Fletcher. CDK2 and CDK4/6 inhibition in GIST: Mechanisms of response and resistance [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A013.

Background Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. Methods The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. Results It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. Conclusions Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

BackgroundAvapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST).MethodsThis retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression.ResultsFifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002.ConclusionsIn this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.Trial registrationThe NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier:NCT02508532.

Avapritinib; Tumors de l'estroma gastrointestinal; PDGFRA Avapritinib; Tumores del estroma gastrointestinal; PDGFRA Avapritinib; Gastrointestinal stromal tumours; PDGFRA Background PDGFRA D842V mutations occur in 5–10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. Methods NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. Results Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6–not reached [NR]); median PFS was 34.0 months (95% CI: 22.9–NR). Median OS was not reached. Conclusion Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients. The NAVIGATOR study (NCT02508532) was supported by Blueprint Medicines Corporation, Cambridge, Massachusetts, USA.

Background Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single‐arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. Materials and Methods Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. Results As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10–25). Median duration of response was 10.2 months (95% CI, 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI, 2.8–4.6). Conclusion Avapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations. Implications for Practice In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist., This article presents safety and efficacy findings of the phase I NAVIGATOR trial of avapritinib in patients with metastatic or unresectable KIT‐ or PDGFRA‐ mutant gastrointestinal stromal tumors with the efficacy analysis focused on patients who had previously received a minimum of three prior lines of therapy.

PURPOSE Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha ( PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study ( NCT02508532 ), avapritinib showed clinical activity against PDGFRA D842V–mutant and later-line KIT-mutant GIST. VOYAGER ( NCT03465722 ), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.

© 2020 The Author(s)., Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions., GDD was supported in part by the Ludwig Center at Harvard; the Dr Miriam and Sheldon G. Adelson Medical Research Foundation; and the Pan Mass Challenge (no grant numbers). IMS is supported by the National Institutes of Health/National Cancer Institute (grant number K08 CA241085). JYB was supported by NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS), EURACAN (EC 739521), LYRICAN (INCA-DGOS-INSERM 12563), LabEx DEvweCAN (ANR-10-LABX-0061), Institut Convergence PLASCAN (17-CONV-0002), RHU4 DEPGYN (ANR-18-RHUS-0009).

PURPOSE In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

Highlights • A woman with a history of Stage IA low-risk uterine adenosarcoma presented with shortness of breath and rib pain. • She was found to have recurrent metastatic disease with resultant fatal SVC Syndrome. • Better methods to determine which patients with uterine adenosarcoma are at risk of recurrence and death are needed.

Predictive markers; Sarcoma; Gastrointestinal stromal tumours Marcadores predictivos; Sarcoma; Tumores del estroma gastrointestinal Marcadors predictius; Sarcoma; Tumors estromals gastrointestinals Background Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. Methods We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. Results Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. Conclusions Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST. This work was supported in part by an ASCO Young Investigator Award (CS), a Spanish Society of Medical Oncology Translational Award (CS), Río Hortega-ISCIII CM14/00241 (CS) FERO Foundation (CS), US National Institutes of Health grants 1P50CA127003 (GDD, ES, JAF), 1P50CA168512 (JAF, AME), GIST Cancer Research Fund (JAF, MCH), Life Raft Group (JAF, MCH, SB), V Foundation Translational Grant (MCH), VA Merit Review Award (2I01BX000338–05) (MCH) and the Deutsche Krebshilfe (SB). CS acknowledges to the Cellex Foundation for providing facilities and equipment.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma, with approximately 5,000 patients diagnosed per year in the US. Approximately 80% of patients with GIST present with mutations in the c-KIT oncogene at exon 9 or 11, which leads to constitutive, ligand-independent activation of the KIT receptor tyrosine kinase. For patients with metastatic GIST, frontline therapy with imatinib is effective, with a response rate of approximately 51-54% and median progression-free survival (PFS) of 19-23 months, in a molecularly unselected population. Other agents are approved for advanced GIST, without molecular selection, after progression on imatinib, including sunitinib, regorafenib, and ripretinib; however, response rates are less than 10% with PFS of approximately 5-6 months. Notably, patients who progress on imatinib and other tyrosine kinase inhibitors may develop a variety of on-target resistance mutations in the KIT oncogene, such as those in exon 17 (including at amino acids D816 and D820, activation loop mutation), exon 13 (V654A, ATP-binding region mutation), and less frequently in exon 14 (T670I, gatekeeper mutation). Several KIT inhibitors have been developed to potently target the exon 17 resistance mutations (avapritinib and ripretinib); however, there remains an important medical need in 2nd- and 3rd-line therapy in a molecularly unselected population of imatinib-resistant GIST. This suggests more broad-spectrum KIT inhibition is likely required, a hypothesis supported by the observation of large inter- and intra-patient heterogeneity of KIT secondary mutations across hundreds of samples obtained from patients with GIST treated with avapritinib. Sequencing data from the NAVIGATOR phase 1 trial (NCT02508532) revealed that patients with KIT mutant GIST and with the KIT V654A secondary resistance mutation had a poor response to treatment with avapritinib. To address this, we developed a highly potent and selective inhibitor of KIT V654A. This inhibitor showed dose-dependent modulation of downstream pharmacodynamic markers and induced tumor regression in a mastocytoma xenograft model driven by an exon 11 plus 13 V654A resistance mutation. Importantly, this inhibitor was generally well-tolerated and showed high selectivity over wild-type KIT. These findings suggest this novel KIT inhibitor has the potential to be used as a single agent or combination therapy for patients with imatinib-resistant GIST harboring the KIT V654A mutation. Citation Format: Alexandra R. Grassian, Joseph Kim, Omar Ahmad, Kevin Barvian, Alison Davis, Tom Dineen, Wei Hu, Ebby Job, Ludivine Moine, Kate Newberry, Maria Roche, Doug Shorten, Yeon Sook Choi, Francis Wolenski, Sebastian Bauer, Cesar Serrano, Jonathan Trent, Suzanne George. Efficacy of a highly potent and selective KIT V654A inhibitor for treatment of imatinib resistant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB565.

Background: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few effective treatment options. Cediranib (C) and sunitinib (S) are potent oral inhibitors of all 3 VEGF receptors. Cediranib showed substantial single-agent activity (objective response rate [ORR] = 35%) in our previous trial in patients (pts) with metastatic ASPS (NCT00942877). Here we report a phase 2 randomized multicenter trial of single agent C or S in pts with ASPS (NCT01391962). Methods: We conducted a multicenter phase 2 trial with an optimal 2-stage design targeting an ORR of 40%. Enrolled pts were >16 years with metastatic ASPS, previously not treated (N) and unresectable, or previously treated (T), who have progressed per RECIST 1 within the 6-month period preceding enrollment. Pts were randomized to receive C (30 mg) or S (37.5 mg) orally, once a day, in 28-day cycles and could crossover to the other treatment arm at disease progression. ORR (primary endpoint), median progression-free survival (mPFS), and PFS rate at 24 weeks for the 2 arms (C and S) were evaluated; T and N cohorts were assessed separately in each arm. Arm accrual closed if ≤ 1 of the first 10 enrolled pts responded to the first treatment. Results: Thirty-four pts (47% white, 29.4% black, 17.6% Asian, 5.8% Pacific Islander) were enrolled; 29 pts were evaluable for response. One pt on each of the initial treatment arms had a confirmed partial response (PR), rates of 6.7% (1/154) and 7.1% (1/14) for C and S tx or tx-naive, respectively. Among pts who crossed over, there was 1 PR in a pt receiving C after initially responding (PR) on S (1/9; ORR 11.1%). Twenty-four pts had a best response of stable disease (86.7% and 78.6%) for C and S, respectively. The mPFS was 7.6 months (mo) (95% CI: 3.7-9.9 mo) and 5.5 mo (95% CI: 1.8-14.5 mo) for C and S, respectively administered as first therapy (p=0.92). PFS rate at 24 weeks was 62.5% (95% CI: 29.5-76.2%) and 50% (95% CI: 25.9-70.1%) for pts receiving C and S respectively, as initial therapy. There was no difference in mPFS between T or N pts in the C (6.7 mo [95% CI: 1.4-9.9 mo] vs 8.3 mo [95% CI: 2.7 - 16.6 mo]; P=0.35) arm, but some evidence of a potential difference in the S (4.8 mo [95% CI: 0.9-7.9 mo] vs 14.7 mo 95% CI: 1.8 - 21.6 mo]; P=0.058) arm. Overall, 43.7% (C) and 77.8% (S) of pts experienced grade ≥3 adverse events (AEs) at least possibly related to the study drug. Common grade ≥3 AEs included: diarrhea (C), neutropenia (S), hypertension (C and S). AEs were in line with the known safety profiles of each agent. As of August 2021, 1 pt (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. There were no differences in mPFS for the 2 treatment arms. The selection of pts with more aggressive disease, who had progressed in the 6 months prior to enrollment, may account for the low patient response rates compared to our previous study of cediranib in ASPS. Funded by NCI Contract No. HHSN261200800001E. The study was a collaboration between NCI and Pfizer. Citation Format: Naoko Takebe, James Nguyen, Shivaani Kummar, Albiruni Abdul Razak, Sant P. Chawla, Suzanne George, Shreyaskumar R. Patel, Mary Louise Keohan, Sujana Movva, Geraldine O’Sullivan, Khanh Do, Larry Anderson, Lamin Juwara, Brooke Augustine, Seth Steinberg, Laura Kuhlmann, S. Percy Ivy, James H. Doroshow, Alice P. Chen. Randomized phase 2 trial of sunitinib or cediranib in alveolar soft part sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT168.

Previous studies have suggested liquid biopsy may be a useful prognostic biomarker for patients with leiomyosarcoma (LMS) but this has never been tested prospectively in a patient cohort receiving uniform therapy. We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival. Our cohort consisted of 98 patients treated on the SARC021 trial, an open-label, randomized, phase 3, multicenter trial testing the efficacy of adding evofosfamide to doxorubicin compared to treatment with doxorubicin alone for patients with advanced soft-tissue sarcomas. Using ultra-low passage whole genome sequencing of plasma cell-free DNA we tested whether detection of ctDNA evaluated prior to the start of therapy and after 2 cycles of chemotherapy were associated with treatment response and outcome. Associations between detection of ctDNA and pathological measures of disease burden were evaluated. Kaplan Meier curves were used to estimate survival in patients with or without detectable ctDNA and the log-rank test was used to estimate the significance of the difference between these two groups. We also tested for an association between disease response, stage and number of metastatic sites with the presence or absence of ctDNA with Fisher’s exact test and with ctDNA levels by Student t test. We found that ctDNA was detectable by ULP-WGS in 49% of patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pre-treatment ctDNA was associated with a lower overall survival (hazard ratio [HR] = 1.55; 95% CI: 1.03 - 2.31; p=0.03) and a lower likelihood of objective response (odds ratio [OR] = 0.21; 95% CI: 0.06 - 0.59; p=0.005). After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR=1.77; 95% CI: 1 - 3.14; p=0.05) and were unlikely to experience an objective response (OR=0.05; 95% CI: 0 - 0.39; p=0.001). We found that detectable levels of ctDNA prior to the start of treatment was significantly associated with patients who had primary tumors measuring greater than 10 cm (75% versus 28%, respectively; p < 0.001), and had more than 5 sites of metastatic disease (73.9% versus 26.1%, respectively; p < 0.001). Detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy.Ongoing work focuses on identification of ctDNA features, such as copy-number alterations or changes in ctDNA levels over time, that may also be associated with disease progression or response to therapy. Citation Format: Laura Madanat-Harjuoja, Kelly Klega, Yao Lu, David S. Shulman, Aaron R. Thorner, Anwesha Nag, William Tap, Denise K. Reinke, Lisa Diller, Karla V. Ballman, Suzanne George, Brian D. Crompton. Circulating tumor DNA is associated with response and survival in patients with advanced leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3407.

Introduction: The hallmark of sporadic desmoid tumors is increased nuclear β-catenin levels. Tegavivint (BC2059) selectively disrupts the interaction of β-catenin and TBL1/TBLR1 resulting in the specific degradation of nuclear β-catenin. The primary objective of this dose escalation study was to determine the maximum tolerated dose (MTD) and safety of tegavivint. Methods: This phase I study (NCT03459469) utilized an accelerated dose escalation phase for the initial two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D). The study included adult patients with desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery or desmoid symptoms), unresectable, and measurable via WHO criteria. Patients were excluded if they had familial adenomatous polyposis, metabolic bone disease, or history of significant pulmonary disease. Tegavivint was administered IV and dosed weekly (three weeks on, one week off) for up to two years. Results: A total of 17 patients with a median age of 41 years (range 18-66 years) were enrolled in six dose levels from 0.5 mg/kg to 5 mg/kg. The median time from initial desmoid diagnosis to study treatment was 2.1 years with a median of one prior systemic treatment (range 0-6). Prior radiation and/or surgical resection occurred in 42% (n=7). No dose-limiting toxicities were observed and the MTD was not determined. The RP2D was declared at 5 mg/kg based on achieving pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Tegavivint exposure (AUC and Cmax) correlated with total dose administered. Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included fatigue (71%), nausea (35%), headache (35%), decreased appetite (24%) and dysgeusia (24%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, ALT increased, and headache occurred in 4 separate patients. No grade 4-5 adverse events were observed. One serious adverse event of Grade 2 infusion site extravasation occurred. Median time on study was 11.8 months, with a median relative dose intensity of 97%; one patient remains on study. Three (18%) partial responses (WHO criteria) were observed at 1, 4 and 5 mg/kg with a median duration of response of 329 days and all responses were ongoing. The clinical benefit rate was 82% (n = 14). Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 adverse events and no Grade 3 TRAEs occurring in more than one patient. The preliminary objective response rate of 18% in progressive desmoid tumors warrants continued research in the ongoing dose expansion portion of the study at the 5 mg/kg RP2D. Citation Format: Lee Cranmer, Albiruni A. RAZAK, Ravin Ratan, Edwin Choy, Suzanne George, David Liebner, David Stenehjem, Mrinal Gounder. A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT185.

6513 Background: Pt recruitment receives well-deserved attention, but pt retention is also important for trial interpretability and generalizability. We report on trends and predictive factors for withdrawal of pt consent, defined as pt cessation from trial participation for reasons not mandated in the protocol. Methods: Alliance phase II/III trials that enrolled pts during 2013 – 2019 were included. All pts had ≥2 years (yrs) of follow-up. Primary outcome was withdrawn consent (yes; no) within 2 yrs of enrollment. Pt factors included year of enrollment, age, race, ethnicity, and gender. Trial factors included randomization, use of placebo, and use of radiation. Univariable (Uni) and full multivariable (MV) logistic regression models (including all factors from Uni setting) with a Bonferroni p-value correction (p 10%) trial categories included 22% experimental therapeutics or rare tumors, 12% gastrointestinal, 12% genitourinary, 12% neuro-oncology and 10% symptom intervention. 78% of trials were randomized, 22% placebo-controlled and 14% used radiation. 1060 (9%) pts withdrew consent within 2 yr of enrollment (range,5.7% -9.8%) during 2013-2019. In Uni models, all trial and pt factors significantly predicted pt withdrawal except age, race, and gender (See table). In MV models, pts of Hispanic origin, and >75 yrs were more likely to withdraw. Trials using radiation had less likelihood of pt withdrawal. Placebo-controlled randomized trials had higher likelihood of withdrawal. Conclusions: Both trial and pt factors contribute to higher rates of pt withdrawal from clinical trials. Understanding these factors will enable investigators to focus on pt education and optimization of trial design to improve pt retention and the overall clinical trial plan. Support: U10CA180821, U10CA180882 [Table: see text]

11509 Background: uLMS is an aggressive sarcoma subtype of smooth muscle origin. Chemotherapy provides limited benefit for advanced disease. 18-25% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. uLMS exhibits high levels of replicative stress. These findings prompted a phase 2 study of O+T in pretreated uLMS where O+T demonstrated activity: ORR 27%, mPFS 6.9 mos (Ingham M. et. al. ASCO 2021: #11506) Methods: NCI protocol #10250 is a single-arm, multicenter, phase 2 trial evaluating O+T in advanced uLMS pts with progression on ≥1 prior line. Pre-treatment (Pre) and on-treatment (On) biopsies were collected from 22 pts. In prespecified analysis, we evaluated for a relationship between clinical outcomes and HR gene alterations by whole exome sequencing (WES), SLFN11/MGMT expression by RNAseq, and RAD51 foci formation (functional assay). HRD scores were calculated from WES using scarHRD. Gene expression was evaluated using a Spearman rank-order correlation analysis to identify genes associated with PFS (p < 0.01) and overexpressed in sensitive (S: PFS > 240d) or resistant (R: PFS < 240d) pts. Gene set enrichment analysis (GSEA) was performed (q = FDR-adjusted p value). Pts with available results: WES/RNAseq (16), Pre HRD score (13), Pre RAD51 foci (12). Results: 31% (5/16) pts had a mutation (Mut) or homozygous deletion (Hd) in the HR panel: ATRX Mut (2), ATR Mut, PALB2 Hd, RAD51B Hd. Pts with PALB2 and RAD51B Hd had longest PFS on study. Recurrent alterations also occurred in TP53 (56%) and RB1 (19%). Median HRD score in Pre samples was 51 (range 36-66) and 10/13 had HRD scores ≥ 42. Pre and On SLFN11 and MGMT RNA expression were not correlated with ORR/PFS. 6/13 Pre samples were HR-deficient by the RAD51 foci assay. Of pts with PFS ≥ 200d, 4/6 were HR-deficient. In Pre samples, 81 genes were overexpressed in S pts and 73 in R pts. In On samples, 146 genes were overexpressed in S pts and 127 in R pts. In On samples, GSEA identified the epithelial-mesenchymal transition enriched in S pts (q = 3.38e-7) and cell cycle pathways (E2F targets, G2M checkpoint) in R pts (q = 7.43e-4). Only 2 genes, CXCL10 and PCDH15, were differentially expressed between paired Pre and On samples (both increased in On). Gene expression signatures for replicative stress showed borderline association with worse PFS. Conclusions: Most uLMS tumors exhibit HR defects as measured by HRD scores. A subset of pts with greater benefit from O+T were identified by WES for HR genes and the RAD51 assay. There was no correlation between SLFN11 and MGMT expression and outcomes. GSEA identified pathways differentially expressed in S and R pts in On samples. O+T induced CXCL10 which has been associated with T-cell trafficking to tumors. A randomized phase 3 trial of O+T versus investigator’s choice is planned. These results provide insight into which pts may benefit most from this novel drug combination. Clinical trial information: NCT03880019.

11523 Background: Desmoid tumors are known to have increased nuclear β-catenin levels. Tegavivint selectively disrupts the interaction of β-catenin and TBL1/ TBLR1, resulting in specific degradation of nuclear β-catenin. The primary objectives of this study were to determine the maximum tolerated dose (MTD), safety, and preliminary efficacy of tegavivint in patients (pts) with desmoid tumors. Methods: This study ( NCT03459469) utilized an accelerated dose escalation schema for the first two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D) of tegavivint, followed by a dose expansion phase. The study included adult pts with sporadic desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery, or symptomatic), unresectable, and measurable via WHO criteria. Tegavivint was administered IV weekly (three weeks on, one week off) up to two years. Results: 24 pts were enrolled. Dose escalation enrolled 17 pts in six dose levels from 0.5 - 5 mg/kg. In dose expansion, 7 additional pts were enrolled. Dose expansion cohort also included 6 pts in dose escalation that were escalated to RP2D and 3 pts treated at RP2D in dose escalation (n = 16 total). Median age was 43 years (18-66). Median time from diagnosis was 3.1 years with median of one prior systemic treatment (range 0-6). Median time on study was 9.4 months; 3 pts remain on study at data cut-off. No dose-limiting toxicities were observed; MTD was not determined. RP2D was declared at 5 mg/kg based on pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts included fatigue (71%), headache (38%), nausea (33%), constipation (21%), decreased appetite (21%), and dysgeusia (21%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, increased ALT, diarrhea, and headache occurred in 5 separate pts. There were no grade 4-5 adverse events (AEs). One serious AE of Grade 2 extravasation occurred. Objective response rate (ORR) of 17% across all dose levels and 25% at RP2D (WHO and RECIST criteria) were observed. Median duration of response was 8.1 months (range 6 to 11.8 months) with all responses ongoing. The 9-month progression free survival rate was 76% (95% CI: 54 - 90%) among all pts and 79% (95% CI: 51 – 93%) among those treated at RP2D. Patient reported outcomes and correlative science will be included in the presentation. Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 AEs and no serious toxicity associated with WNT inhibition. The ORR of 25% at the RP2D warrants continued development of tegavivint in desmoid tumors. Clinical trial information: NCT03459469.

11512 Background: GPR20 is selectively and abundantly expressed in GISTs, the most common sarcoma of digestive tract. DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). The target drug-to-antibody ratio is ̃8. The DXd payload, when released, inhibits topoisomerase I and induces cell apoptosis. Methods: This study conducted in the US and Japan was designed to include a dose-escalation (Part 1) and a dose-expansion (Part 2) in adult pts with advanced GIST (NCT04276415). Part 1 evaluated safety, tolerability, efficacy, and pharmacokinetics (PK) to determine the maximum-tolerated dose (MTD) and/or recommended dose for expansion. Key eligibility criteria included ECOG PS of 0 or 1, measurable disease per RECIST v1.1, and adequate bone marrow, hepatic, and renal function. DS-6157a was administered every 3 weeks as monotherapy. Pts had tumor assessments per RECIST 1.1 every 6 weeks (wks) for 36 wks, then every 9 wks thereafter. Results: At data cutoff, 34 pts were available for full analysis: median treatment duration was 9.9 wks (range, 3-56 wks) and 5 pts (14.7%) were ongoing; median age 60.5 years (y) (range, 29-81 y); 19 pts (56%) were male; 47% of pts were Asian and 47% were white. Baseline GPR20 expression was highly prevalent, and dose-dependent PK exposure was confirmed within the range of dose levels. The MTD was 6.4 mg/kg. One pt with SDH-deficient GIST with both SDH B and NF1 mutations, had a confirmed PR with shrinkage of -75%; 18 pts (53%) experienced stable disease and 10 pts (29%) experienced progressive disease as best response. Median progression-free survival across all dose levels was 3.6 months (95% CI, 1.6, 6.9). Treatment-emergent AEs (TEAEs) occurred in all pts and treatment-related TEAEs (TRAEs) in 32 pts (94%). The most common (≥25%) all-grade (Gr) TEAEs were nausea (82%), decreased appetite (59%), fatigue (47%), anemia (44%), constipation (38%), decreased platelets (35%), and vomiting (32%). Gr ≥3 TRAEs occurred in 14 pts (41%); the most common were decreased platelets (21%) and anemia (18%). Serious TEAEs (SAEs) occurred in 9 pts (27%) and related SAEs in 4 pts (12%). Related Gr 4 SAEs in 2 pts included abnormal hepatic function, neutropenia, thrombocytopenia and leukopenia. There was 1 treatment related death (hepatic failure). Further investigations are on-going to understand the modest clinical efficacy observed. The study did not proceed to Part 2, because the data from Part 1 did not meet efficacy targets. Conclusions: DS-6157a was generally well tolerated with early signs of moderate clinical activity. While there were no objective responses in pts with KIT-mutant GIST, tumor shrinkage was observed in all 4 pts with KIT wild-type GIST treated at different doses, including a confirmed PR at the MTD in a pt with SDH-deficient GIST with both SDH B and NF1 mutations. Clinical trial information: NCT04276415.

TPS11592 Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age > 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.