Publications by authors named "Suzanne George"

129 Publications

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Epidemiology, Regional Health Council, Biomedical Research Institute of Murcia-Arrixaca, Murcia University, Murcia, Spain.

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.
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http://dx.doi.org/10.1002/cncr.33618DOI Listing
April 2021

Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data.

BMC Cancer 2021 Mar 19;21(1):291. Epub 2021 Mar 19.

Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: Avapritinib, 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).

Methods: This 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.

Results: Fifty-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.

Conclusions: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.

Trial Registration: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .
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http://dx.doi.org/10.1186/s12885-021-08013-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976710PMC
March 2021

Imprecision About Body Mechanics When Child Witnesses Are Questioned About Sexual Abuse.

J Interpers Violence 2021 Mar 9:886260521997941. Epub 2021 Mar 9.

University of Southern California, Los Angeles, CA, USA.

In child sexual abuse cases, a central part of the child's testimony is their description of the abuse episode. However, it is often difficult for children to describe the body mechanics of abuse, and miscommunications are likely to occur. In the present study, we examined questions about the mechanics of abuse in trial transcripts ( = 63) to identify sources of miscommunication ( = 130) between attorneys and children (5-12 years old, age at trial = 9.44,  = 1.97). We found that both attorneys and children used imprecise language, which led to miscommunication. Specifically, the imprecise use of sexual terminology and the word "touch," polarity items, broad open-ended questions, anaphora and elliptical questions, and "how" questions led to imprecision in attorneys' questions. Imprecise attorney questions often elicited underinformative answers from children, including misinterpretations of the grain size (i.e., level of detail) requested. In response to these underinformative answers, attorneys at times asked highly focused and leading questions, which led to further miscommunications. Implications and recommendations for future research on how best to elicit details about the mechanics of abuse from children are discussed.
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http://dx.doi.org/10.1177/0886260521997941DOI Listing
March 2021

Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-In-Class Antibody-Drug Conjugate.

Cancer Discov 2021 Feb 12. Epub 2021 Feb 12.

Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKIs), which eventually lead to 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-TK target in GIST, developed new GPR20 immunohistochemistry, assessed GPR20 expression in cell lines, PDXs & clinical samples from 2 institutes (USA & 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. Pre-clinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients with resistance, refractory, or intolerance to approved TKIs.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1434DOI Listing
February 2021

Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement.

Clin Cancer Res 2021 May 9;27(9):2394-2399. Epub 2021 Feb 9.

American Society of Clinical Oncology, Alexandria, Virginia.

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 () 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- 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 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..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3852DOI Listing
May 2021

Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial.

Eur J Cancer 2021 Mar 16;145:132-142. Epub 2021 Jan 16.

Department of Medical Oncology, University Hospital Essen, Sarcoma Center, University of Duisburg-Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1016/j.ejca.2020.12.008DOI Listing
March 2021

Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.

Oncologist 2021 04 1;26(4):e639-e649. Epub 2021 Feb 1.

Fox Chase Cancer Center, Philadelphia, Pennsylvania, 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.
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http://dx.doi.org/10.1002/onco.13674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018324PMC
April 2021

Protocol for the methamphetamine approach-avoidance training (MAAT) trial, a randomised controlled trial of personalised approach bias modification for methamphetamine use disorder.

Trials 2021 Jan 6;22(1):21. Epub 2021 Jan 6.

Monash Addiction Research Centre, Eastern Health Clinical School, Monash University, Melbourne, Australia.

Background: Globally, methamphetamine use has increased in prevalence in recent years. In Australia, there has been a dramatic increase in numbers of people seeking treatment, including residential rehabilitation, for methamphetamine use disorder (MUD). While residential rehabilitation is more effective for MUD than withdrawal treatment (i.e. "detoxification") alone, relapse rates remain high, with approximately half of rehabilitation clients using methamphetamine within 3 months of rehabilitation. "Approach bias modification" (ABM) is a computerised cognitive training approach that aims to dampen automatically triggered impulses to approach drugs and drug-related stimuli. ABM has been demonstrated to reduce alcohol relapse rates, but no randomised controlled trials of ABM for MUD have yet been conducted. We aim to test whether a novel "personalised" form of ABM, delivered during rehabilitation, reduces post-treatment methamphetamine use, relative to a sham-training control condition. Secondary outcomes will include dependence symptoms, cravings, and approach bias.

Methods: We aim to recruit 100 participants attending residential rehabilitation for MUD at 3 sites in the Melbourne metropolitan area. Participants will complete baseline measures of methamphetamine use, craving, dependence severity, and approach bias before being randomised to receiving 6 sessions of ABM or "sham" training. In the active condition, ABM will be personalised for each participant, using those methamphetamine images that they rate as most relevant to their recent methods of methamphetamine use as "avoidance" images and using positive images representing their goals or healthy sources of pleasure as "approach" images. Approach bias and craving will be re-assessed following completion of training, and methamphetamine use, dependence, and craving will be assessed 4 weeks and 3 months following discharge from residential treatment.

Discussion: This study is the first randomised controlled trial of ABM for MUD and also the first ABM study to test using a personalised set of both approach and avoid images for ABM training. If effective, the low cost and easy implementation of ABM means it could be widely implemented as a standard part of MUD treatment.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12620000072910. Registered on 30 January 2020 (prospectively registered): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378804&isReview=true.
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http://dx.doi.org/10.1186/s13063-020-04927-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788914PMC
January 2021

NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021.

J Natl Compr Canc Netw 2020 12 2;18(12):1604-1612. Epub 2020 Dec 2.

28UCSF Helen Diller Family Comprehensive Cancer Center; and.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.
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http://dx.doi.org/10.6004/jnccn.2020.0058DOI Listing
December 2020

Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib.

J Clin Oncol 2020 10 17;38(28):3294-3303. Epub 2020 Aug 17.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

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 and 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.
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http://dx.doi.org/10.1200/JCO.20.00522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526717PMC
October 2020

Superior Vena Cava Syndrome associated with recurrent uterine adenosarcoma.

Gynecol Oncol Rep 2020 Aug 22;33:100613. Epub 2020 Jul 22.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

•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.
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http://dx.doi.org/10.1016/j.gore.2020.100613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393396PMC
August 2020

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial.

Lancet Oncol 2020 07;21(7):935-946

Dana-Farber Cancer Institute, Boston, MA, USA.

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.
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http://dx.doi.org/10.1016/S1470-2045(20)30269-2DOI Listing
July 2020

Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade.

Clin Cancer Res 2020 Oct 29;26(19):5078-5085. Epub 2020 Jun 29.

Department of Medical Oncology, Sarcoma Center, Dana-Farber Cancer Institute, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1706DOI Listing
October 2020

Oncogenic Gene-Expression Programs in Leiomyosarcoma and Characterization of Conventional, Inflammatory, and Uterogenic Subtypes.

Mol Cancer Res 2020 09 9;18(9):1302-1314. Epub 2020 Jun 9.

Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Leiomyosarcoma (LMS) is a mesenchymal neoplasm with complex copy-number alterations and characteristic loss of tumor suppressor genes without known recurrent activating mutations. Clinical management of advanced LMS relies on chemotherapy and complementary palliative approaches, and research efforts to date have had limited success identifying clinically actionable biomarkers or targeted therapeutic vulnerabilities. To explore the biological underpinning of LMS, we evaluated gene-expression patterns of this disease in comparison with diverse sarcomas, nonmesenchymal neoplasms, and normal myogenic tissues. We identified a recurrent gene-expression program in LMS, with evidence of oncogenic evolution of an underlying smooth-muscle lineage-derived program characterized by activation of E2F1 and downstream effectors. Recurrently amplified or highly expressed genes in LMS were identified, including IGF1R and genes involved in retinoid signaling pathways. Though the majority of expressed transcripts were conserved across LMS samples, three separate subtypes were identified that were enriched for muscle-associated transcripts (conventional LMS), immune markers (inflammatory LMS), or a uterine-like gene-expression program (uterogenic LMS). Each of these subtypes expresses a unique subset of genes that may be useful in the management of LMS: IGF1R was enriched in conventional LMS, worse disease-specific survival was observed in inflammatory LMS, and prolactin was elaborated by uterogenic LMS. These results extend our understanding of LMS biology and identify several strategies and challenges for further translational investigation. IMPLICATIONS: LMS has a recurrent oncogenic transcriptional program and consists of molecular subtypes with biological and possible clinical implications.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484251PMC
September 2020

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2020 07 5;21(7):923-934. Epub 2020 Jun 5.

Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.

Methods: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.

Findings: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep).

Interpretation: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments.

Funding: Deciphera Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(20)30168-6DOI Listing
July 2020

Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.

Br J Cancer 2020 04 9;122(8):1158-1165. Epub 2020 Mar 9.

University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.

Background: The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.

Methods: This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.

Results: Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.

Conclusions: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.

Trial Registration Number: NCT01468688.
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http://dx.doi.org/10.1038/s41416-020-0769-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156686PMC
April 2020

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors.

BMC Cancer 2020 Feb 5;20(1):99. Epub 2020 Feb 5.

Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.

Methods: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).

Results: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.

Conclusions: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
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http://dx.doi.org/10.1186/s12885-020-6597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003348PMC
February 2020

A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas.

Eur J Cancer 2020 02 31;126:21-32. Epub 2019 Dec 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Chemotherapy objective response rates (ORRs) in metastatic soft tissue sarcoma (STS) are typically 20-40% with median progression-free survival (PFS) less than 6 months. Lurbinectedin is a new anticancer agent under investigation. The primary objective of this three-arm, phase II study was to determine the disease control rate (DCR = ORR + stable disease [SD]) at 24 weeks of lurbinectedin alone or with chemotherapy in STS. Eligible patients included adults with ≤2 prior cytotoxic therapies. Study cohorts were: stratum A (StrA; anthracycline-naive), lurbinectedin/doxorubicin; stratum B (StrB; prior anthracycline), lurbinectedin/gemcitabine; stratum C (StrC; prior anthracycline/gemcitabine) lurbinectedin monotherapy. Each stratum was analysed separately by Simon two-stage design. Forty-two patients were accrued (StrA = 20, StrB = 10, StrC = 12) including leiomyosarcoma [LMS] (n = 20), synovial sarcoma [SS](n = 4), malignant peripheral nerve sheath tumour (n = 3) and other STS histologies (n = 15). For StrA there were seven partial responses (PR) plus one stable disease (SD) at 24 weeks. For StrB, two patients met the 24-week DCR including one PR (leiomyosarcoma) and one SD (desmoplastic small round cell tumour [DSRCT]). StrB did not continue to the second stage. In StrC, no patients met the primary end-point. Median progression-free survival (PFS) was: StrA = 4.2 months (90% CI 1.4-7.8), StrB = 1.7 months (90% confidence interval (CI) 1.0-7.4), and StrC = 1.3 months (90% CI 1.1-3.0). Lurbinectedin as a single agent or with chemotherapy was well tolerated with haematologic adverse events (AE's) as the most common toxicity. There were no treatment-related deaths. The combination of lurbinectedin/doxorubicin reached the DCR end-point with seven PR and one patient with SD (ORR 35.0%, 24-week DCR 40.0%). Evidence of drug benefit was seen in leiomyosarcoma, dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), synovial sarcoma (SS), and desmoplastic small round cell tumour (DSRCT). TRIAL REGISTRATION: clinicaltrials.gov; NCT02448537.
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http://dx.doi.org/10.1016/j.ejca.2019.10.021DOI Listing
February 2020

Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study.

Clin Cancer Res 2020 04 2;26(8):1837-1845. Epub 2019 Dec 2.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of , or uncommonly . Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST.

Patients And Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results.

Results: Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively.

Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856429PMC
April 2020

Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib.

Future Oncol 2020 Jan 22;16(1):4251-4264. Epub 2019 Nov 22.

Portland VA Health Care System & OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in and . Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.
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http://dx.doi.org/10.2217/fon-2019-0633DOI Listing
January 2020

Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors.

Clin Cancer Res 2019 12 30;25(24):7287-7293. Epub 2019 Aug 30.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted.

Patients And Methods: Phase Ib study investigating continuous treatment with cycles of sunitinib (3 days) followed by regorafenib (4 days) in patients with tyrosine kinase inhibitor (TKI)-refractory GIST. A 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and droplet digital PCR (ddPCR).

Results: Of the 14 patients enrolled, 2 experienced dose-limiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5 mg/day and regorafenib 120 mg/day was the RP2D. Treatment was well-tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in 4 patients, and median progression-free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11 of 12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination.

Conclusions: Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in patients with GIST.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2150DOI Listing
December 2019

Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

Clin Cancer Res 2019 08 4;25(16):5135-5142. Epub 2019 Jun 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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 ( = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma ( = 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341441PMC
August 2019

Correction: Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

Br J Cancer 2019 Jul;121(3):281

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.

The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.
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http://dx.doi.org/10.1038/s41416-019-0487-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738067PMC
July 2019

Developments in Systemic Therapy for Soft Tissue and Bone Sarcomas.

Authors:
Suzanne George

J Natl Compr Canc Netw 2019 05;17(5.5):625-628

The past year has led to significant changes in systemic therapies used to treat soft tissue sarcomas, mainly dominated by the removal of the recently approved drug olaratumab as part of combination therapy with doxorubicin from the NCCN Guidelines for Soft Tissue Sarcoma, according to Dr. Suzanne George. Several histology-specific drugs have entered the space, including pazopanib and pembrolizumab, the latter of which was approved as a category 2B recommendation for alveolar soft part sarcoma, highlighting the rather limited role of immunotherapy in sarcomas. Dr. George also discussed updated data for sorafenib in the treatment of desmoid tumors, as well as the importance of larotrectinib in TRK fusion-positive tumors.
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http://dx.doi.org/10.6004/jnccn.2019.5020DOI Listing
May 2019

Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.

JCO Precis Oncol 2019 24;2019. Epub 2019 Jan 24.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.

Purpose: Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease.

Patients And Methods: Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS). Sequencing reads were aligned to the human genome and CNAs identified in cell-free DNA and tumor DNA by ichorCNA software to determine the presence of ctDNA. Clinical data were reviewed to assess disease burden and clinicopathologic features.

Results: We identified LMS ctDNA in eleven of sixteen patients (69%) with disease progression and total tumor burden over 5 cm. Sixteen patients with stable disease or low disease burden at the time of blood draw were found to have no detectable ctDNA. Higher ctDNA fraction of total cell-free DNA was associated with increasing tumor size and disease progression. Conserved CNAs were found between primary tumors and ctDNA in each case, and recurrent CNAs were found across LMS samples. ctDNA levels declined following resection of progressive disease in one case and became detectable upon disease relapse in another individual patient.

Conclusion: These results suggest that ctDNA, assayed by a widely available sequencing approach, may be useful as a biomarker for a subset of uterine and extrauterine LMS. Higher levels of ctDNA correlate with tumor size and disease progression. Liquid biopsies may assist in guiding treatment decisions, monitoring response to systemic therapy, surveying for disease recurrence and differentiating benign and malignant smooth muscle tumors.
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http://dx.doi.org/10.1200/PO.18.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380497PMC
January 2019

Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

Br J Cancer 2019 03 22;120(6):612-620. Epub 2019 Feb 22.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41416-019-0389-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462042PMC
March 2019

Characteristics of mismatch repair deficiency in sarcomas.

Mod Pathol 2019 07 14;32(7):977-987. Epub 2019 Feb 14.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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 < 0.001). However, in comparison to mismatch repair-deficient carcinomas, mismatch repair-deficient sarcomas showed a lower tumor mutation burden (median 28 versus 16, p = 0.006) and a significantly greater degree of chromosomal instability. Among mismatch repair-deficient sarcomas, PD-L1 was variably expressed on tumor-associated macrophages but not on tumor cells. Three patients received pembrolizumab: two progressed and one has stable disease with five months follow-up. Mismatch repair deficiency in histologically classifiable sarcomas is rare (1%) and is more common in unclassified sarcomas (10%). Additional study is required to determine the predictive role of mismatch repair-deficiency in sarcomas for immunotherapy.
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http://dx.doi.org/10.1038/s41379-019-0202-3DOI Listing
July 2019

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy.

Sarcoma 2018 24;2018:2068517. Epub 2018 Oct 24.

MD Anderson Cancer Center, Sarcoma Medical Oncology, 1400 Holcombe Blvd, Unit 450, Houston, TX 77030, USA.

Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m intravenously at 10 mg/m/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54-3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma.
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http://dx.doi.org/10.1155/2018/2068517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220374PMC
October 2018

Low Levels of Evidence for Neoadjuvant Chemotherapy to Treat Soft-Tissue Sarcoma.

JAMA Oncol 2018 09;4(9):1169-1170

Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaoncol.2018.1403DOI Listing
September 2018