Publications by authors named "Margaret von Mehren"

147 Publications

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 Jan 15;145:132-142. Epub 2021 Jan 15.

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
January 2021

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

Oncologist 2021 Jan 16. Epub 2021 Jan 16.

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
January 2021

Deciding on the duration of adjuvant therapy in gastrointestinal stromal tumor.

Expert Rev Anticancer Ther 2020 Dec 23:1-9. Epub 2020 Dec 23.

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

: The benefit of the tyrosine kinase inhibitor (TKI) imatinib mesylate in metastatic Gastrointestinal Stromal Tumors (GIST) leads to improved progression-free survival (PFS) and overall survival (OS). Clinical trials of adjuvant imatinib have provided data on the utility in management of primary GIST. There still remains uncertainty regarding the optimal duration of therapy. : Here, we review the literature on the pivotal clinical trials evaluating adjuvant imatinib: ACOSOG Z9000/Z9001, EORTC 62024, Scandinavian Sarcoma Group XVIII, and PERSIST-5. The data from these studies that were analyzed included the patient population, length of therapy, and outcomes. : Clinical trial data demonstrate that adjuvant imatinib delays recurrence and appears to improve survival when taken for 3 years in high-risk patients; treatment for 5 years has been found to be safe, although difficult for patients to maintain adherence. These studies all incorporated slightly different patient populations based upon eligibility criteria for risk of recurrence, but support the use in patients with intermediate to high risk of disease recurrence. Data from these studies does not support treating those with low risk of recurrence or imatinib-insensitive mutations.
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http://dx.doi.org/10.1080/14737140.2021.1863149DOI Listing
December 2020

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

JCI Insight 2021 Jan 25;6(2). Epub 2021 Jan 25.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
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http://dx.doi.org/10.1172/jci.insight.143474DOI Listing
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.

29National Comprehensive Cancer Network.

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

Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

Cancer 2021 Mar 18;127(5):729-738. Epub 2020 Nov 18.

Sarcoma Service, Departments of Surgery and Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes.

Methods: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared.

Results: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma.

Conclusions: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated.
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http://dx.doi.org/10.1002/cncr.33323DOI Listing
March 2021

Ripretinib for advanced gastrointestinal stromal tumours - Authors' reply.

Lancet Oncol 2020 09;21(9):e415

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

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http://dx.doi.org/10.1016/S1470-2045(20)30479-4DOI Listing
September 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

Treatment Patterns and Distance to Treatment Facility for Soft Tissue Sarcoma of the Extremity.

J Surg Res 2020 Dec 13;256:492-501. Epub 2020 Aug 13.

Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: The impact that distance traveled to receive treatment has on treatments and outcomes among patients with soft tissue sarcoma (STS) of the extremity has yet to be thoroughly investigated.

Methods: Information on patients treated for STS of the extremity between 2006 and 2015 was obtained from the National Cancer Database. Patients were stratified into two groups based on median distance traveled to receive treatment. Chi-square tests assessed associations between categorical variables and distance to treatment. Kaplan-Meier survival estimates and Cox regression were used to estimate survival.

Results: The sample included 21,763 patients. The mean age was 59.3 y, 54.6% were men, and 83.2% were white. The median distance traveled to the treating facility was 15.6 miles. Compared with patients who traveled <15 miles, those who traveled ≥15 miles were more likely to have undifferentiated rather than well-differentiated tumors (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.10-1.37), and stage II rather than stage I disease (OR, 1.14; 95% CI, 1.04-1.24). They were also more likely to undergo limb-sparing resection (OR, 1.58; 95% CI, 1.39-1.79) or amputation (OR, 1.72; 95% CI, 1.44-2.07) rather than no surgery and less likely to have positive margins (OR, 0.86; 95% CI, 0.79-0.93). There was no difference in the risk of death between patients who traveled ≥15 miles and those who did not (hazard ratio, 1.00; 95% CI, 0.94-1.07).

Conclusions: Although clinical characteristics and treatments may differ based on distance traveled, survival appears equivalent. Further research into reasons why greater distance traveled is associated with more advanced disease, but comparable survival is warranted.
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http://dx.doi.org/10.1016/j.jss.2020.07.019DOI Listing
December 2020

Clinical Trials in the Age of Pandemics.

J Natl Compr Canc Netw 2020 Aug;18(8):1008-1011

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http://dx.doi.org/10.6004/jnccn.2020.7588DOI Listing
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

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

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

Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin.

Cancer 2019 Dec 10;125(24):4435-4441. Epub 2019 Sep 10.

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

Background: The results of the randomized, phase 3 ET743-SAR-3007 trial demonstrated that trabectedin had a significantly longer progression-free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24-hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient-reported outcomes based on first infusion site of care.

Methods: Patients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m ) or dacarbazine (1 g/m over 20-120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient-reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion.

Results: Of the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter-related complications was similar between groups (16% vs 15%).

Conclusions: Although the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.
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http://dx.doi.org/10.1002/cncr.32462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916570PMC
December 2019

Retroperitoneal Sarcomas: Does Laterality Matter?

J Surg Res 2019 12 3;244:34-41. Epub 2019 Jul 3.

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Background: Sarcomas are malignant tumors of connective tissue that can vary widely in etiology. Parameters such as grade, extent of resection, and tumor integrity have been shown to affect prognosis. Our principal aim was to examine associations between the laterality of retroperitoneal sarcomas and tumor characteristics, treatment, and patient outcomes.

Materials And Methods: We performed a retrospective study of patients treated at our tertiary referral center with a diagnosis of primary retroperitoneal sarcoma who underwent tumor resection. Categorical variables were compared using the chi-square test, whereas continuous variables were compared using one-way analysis of variance. Cox regression was used to estimate the risk of death.

Results: Data from 106 patients were analyzed. A greater proportion of bilateral or midline tumors were leiomyosarcomas (P = 0.02), whereas right-sided tumors were more likely to be liposarcoma (P = 0.02). There was no significant relationship between laterality and tumor grade or stage. Two-thirds of patients had at least one contiguous organ resected (n = 68, 65.4%). Patients with nephrectomy during sarcoma resection were more likely to have right-sided disease (P = 0.02). Splenectomy and pancreatectomy were associated with left-sided disease (P < 0.01; P < 0.01), and pancreaticoduodenectomies with bilateral or midline disease (P < 0.001). Adjusting for age, sex, race, grade, stage, histology, and treatment, there was no increased risk of death or recurrence based on laterality.

Conclusions: Although laterality did not seem to have a measurable relationship with patient outcomes or survival, there was a significant association between laterality, tumor histology, and resection of contiguous organs. These preliminary findings warrant further investigation.
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http://dx.doi.org/10.1016/j.jss.2019.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815680PMC
December 2019

Honing in on Subtypes to Guide More Individualized Treatment of Soft Tissue Sarcoma.

Oncology (Williston Park) 2019 06;33(6):212-4, 216

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June 2019

Soft tissue sarcoma of the extremity: Characterizing symptom duration and outcomes.

Surg Oncol 2019 Jun 21;29:190-195. Epub 2019 May 21.

Fox Chase Cancer Center, Department of Surgery, 333 Cottman Ave, Philadelphia, PA, 19111, United States.

Background: We sought to investigate how the interval between symptom onset and diagnosis of soft tissue sarcoma (STS) of the extremity was associated with survival.

Methods: Patients treated for extremity STS years 2006-2015 were stratified by symptom duration: at least two, six or twelve months between symptom onset and diagnosis. Chi-square tests compared patient and tumor-related characteristics based on symptom duration. Survival analysis included Cox regression and Kaplan-Meier estimates.

Results: Of 113 patients included, mean age was 56.7 years, 52.2% were male, and 75.2% were white. Median tumor size was 75 mm, 48.7% were grade 3, and 38.1% were stage I. With symptom duration of either at least 6 or 12 months, a greater proportion of patients who experienced the specified symptom duration had lower grade tumors (p < 0.01 and p = 0.01, respectively) and lower stage disease (p < 0.01 and p = 0.02, respectively) than those who did not. Among all patients, survival estimates were similar between those who experienced a symptom duration of 2 (p = 0.12), 6 (p = 0.18) or 12 (p = 0.61) months and those who did not.

Conclusion: Patients with extremity STS who tolerated a longer symptom duration had less advanced disease. Reasons for prolonged symptom duration and methods to address these factors warrant further investigation.
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http://dx.doi.org/10.1016/j.suronc.2019.05.016DOI Listing
June 2019

Overall survival and histology-specific subgroup analyses from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

Cancer 2019 08 7;125(15):2610-2620. Epub 2019 Jun 7.

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

Background: We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously-treated patients with liposarcoma/leiomyosarcoma (LPS/LMS).

Methods: Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression-free survival, objective response rate, safety, and patient-reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented.

Results: At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post-study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively).

Conclusion: The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin.
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http://dx.doi.org/10.1002/cncr.32117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771856PMC
August 2019

Adjuvant Chemotherapy in Uterine Leiomyosarcoma: Trends and Factors Impacting Usage.

Sarcoma 2019 10;2019:3561501. Epub 2019 Feb 10.

Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Objectives: The benefit of adjuvant chemotherapy in patients with localized uterine leiomyosarcoma (LMS) remains unclear due to a lack of randomized studies and data only from small retrospective series to rely on. We sought to identify factors associated with the administration of chemotherapy and to determine the trends in the usage of adjuvant chemotherapy in patients with nonmetastatic uterine LMS.

Methods: Patients diagnosed with nonmetastatic uterine LMS between 2004 and 2014 were identified from the National Cancer Database (NCDB). Multiple regression was used to determine factors with a significant impact on patient receipt of chemotherapy. Kaplan-Meier curves and the Cox model were used to determine the effect of adjuvant chemotherapy on overall survival (OS).

Results: 2,732 uterine LMS patients were identified. Patients older than 65 were less likely to receive chemotherapy than their younger counterparts. Patients with stage I or stage II cancer were less likely to receive chemotherapy, whereas individuals with positive regional lymph nodes and those who had received radiation were more likely. In this cohort, adjuvant chemotherapy had no significant impact on OS (HR, 1.04; 95% CI, 0.90-1.22; =0.5768). However, administration of chemotherapy significantly increased from 2004 to 2014 ( < 0.0001).

Conclusions: Expected tumor characteristics such as higher stage of tumor were associated with receipt of chemotherapy. Although adjuvant chemotherapy demonstrated no benefit over observation on OS in patients with nonmetastatic LMS, the number of patients being treated with chemotherapy continued to increase from 2004 to 2014.
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http://dx.doi.org/10.1155/2019/3561501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387708PMC
February 2019

Advances and Challenges on Management of Gastrointestinal Stromal Tumors.

Front Oncol 2018 7;8:135. Epub 2018 May 7.

Hematology, Oncology and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.

Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal and account for over 5,000 newly diagnosed cases in the United States. The discovery of activated and mutations and introduction of imatinib revolutionized the treatment strategy and opened up the new era of target therapy for solid tumors. Although surgery remains the primary modality of treatment for curative purpose, almost half of the patients experienced disease recurrence. Tailoring (neo)-adjuvant treatment with imatinib is ongoing to meet the need for an effective therapy. Currently, two drugs (sunitinib and regorafenib) have obtained Food and Drug Administration approval for GISTs after imatinib failure. However, most of the patients eventually progress due to primary or secondary resistance. Deeper understanding of the molecular mechanisms will guide us to develop personalized strategies in the future. Discussion in this review includes current standard management and the most recent advances and multiple ongoing clinical trials with different approaches. This review will provide further steps to be taken to conquer refractory disease.
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http://dx.doi.org/10.3389/fonc.2018.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949718PMC
May 2018

Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 05;16(5):536-563

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for STS provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumors, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations.
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http://dx.doi.org/10.6004/jnccn.2018.0025DOI Listing
May 2018

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib.

JAMA Oncol 2018 06;4(6):814-820

Department of Internal Medicine, University of Michigan, Ann Arbor.

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients.

Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib.

Design, Setting, And Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017.

Interventions: Dasatinib, 70 mg orally twice daily.

Main Outcomes And Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment.

Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18.

Conclusions And Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.
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http://dx.doi.org/10.1001/jamaoncol.2018.0601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145709PMC
June 2018

Granular cell tumor experience at a comprehensive cancer center.

J Surg Res 2018 06 9;226:1-7. Epub 2018 Feb 9.

Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Background: Granular cell tumors (GCTs) are rare lesions occurring almost anywhere in the body. Multiple case reports have been published. However, there are very few large-scale studies regarding GCT. The aim of this study was to define characteristics, treatment patterns and outcomes of patients with GCT.

Methods: An institutional review board-approved retrospective chart review was performed. Descriptive statistics, chi-square analyses, and Kaplan-Meier survival estimates were produced.

Results: Fifty patients were treated for GCT at our institution between 1992 and 2015. The median age was 47 y; 62% of patients were female and 64% were whites. Median tumor size was 0.8 cm. Four percent of patients had malignant tumors, 10.0% had atypical tumors, and 86.0% had benign tumors. The most frequent location of tumors was the gastrointestinal tract (n = 30; 60%), followed by skin/subcutaneous tissues (n = 19; 38%), then respiratory tract (n = 1; 2%). Most patients underwent surgical excision or endoscopic removal of their tumors without prior biopsy. Three patients (6%) had multifocal tumors; they were more likely to experience recurrence than patients with unifocal tumors (33.3% versus 10.6%, respectively; P = 0.05). Six patients (12.0%) experienced recurrence, with a median time to recurrence of 13.5 mo. Overall cancer-specific 5-y survival was 98.0%. Overall recurrence-free 5-y survival was 86.4%. Patients with atypical tumors had a lower recurrence-free 5-y survival rate than those with benign tumors (75.0% versus 89.7%, respectively; P = 0.04).

Conclusions: Patients with GCT fair well, particularly when tumors are benign. Patients with multifocal tumors are more likely to experience recurrence and should be closely monitored.
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http://dx.doi.org/10.1016/j.jss.2018.01.027DOI Listing
June 2018

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Int J Mol Sci 2018 Mar 4;19(3). Epub 2018 Mar 4.

"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy.

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha () gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.
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http://dx.doi.org/10.3390/ijms19030732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877593PMC
March 2018

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Jan;16(1):66-97

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
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http://dx.doi.org/10.6004/jnccn.2018.0001DOI Listing
January 2018

Gastrointestinal Stromal Tumors.

J Clin Oncol 2018 01 8;36(2):136-143. Epub 2017 Dec 8.

Margaret von Mehren, Fox Chase Cancer Center, Philadelphia, PA; and Heikki Joensuu, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

GI stromal tumors (GISTs) are neoplasms with a varying malignancy potential ranging from virtually indolent tumors to rapidly progressing cancers. GISTs occur throughout the intestinal tract, and most harbor an activating mutation in either KIT or platelet-derived growth factor A ( PDGFRA). Diagnosis is made using immunohistochemistry, but molecular testing with mutation analysis is paramount for selection of appropriate therapy. Most small GISTs are cured with surgery. Tyrosine kinase inhibitor (TKI) therapy has led to substantial improvements in survival, both for patients with localized GIST and those with advanced disease. Adjuvant therapy with imatinib benefits patients with a high risk of recurrence, with studies suggesting most benefit with at least 3 years of therapy. Neoadjuvant imatinib therapy should be considered for patients requiring extensive surgery, aiming at shrinking the tumor to allow organ preservation and less extensive surgery. The following three TKIs have been approved for the management of advanced disease: imatinib, sunitinib, and regorafenib; imatinib is usually the best tolerated of the three and the standard first-line treatment. TKIs benefit the majority of patients with advanced GIST but have no or limited efficacy in patients with the PDGFRA D842V mutation or patients with GIST lacking KIT and PDGFRA mutations. Surgery, the mainstay of primary tumor management, also plays a role in the advanced disease setting for selected patients, as do some other approaches such as palliative radiation therapy. Research continues to identify novel therapies, in particular effective agents to treat TKI-refractory disease.
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http://dx.doi.org/10.1200/JCO.2017.74.9705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553810PMC
January 2018

Emerging drugs for the treatment of gastrointestinal stromal tumour.

Expert Opin Emerg Drugs 2017 12 18;22(4):317-329. Epub 2017 Dec 18.

b Director of Sarcoma Oncology, Associate Director for Clinical Research , Fox Chase Cancer Center , Philadelphia , PA , USA.

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.
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http://dx.doi.org/10.1080/14728214.2017.1411479DOI Listing
December 2017

Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial.

Invest New Drugs 2018 06 27;36(3):476-486. Epub 2017 Nov 27.

Fox Chase Cancer Center, Philadelphia, PA, USA.

Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m. In Study #3007, the trabectedin group received 1.5 mg/m by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUC: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.
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http://dx.doi.org/10.1007/s10637-017-0546-9DOI Listing
June 2018

Distress and Financial Distress in Adults With Cancer: An Age-Based Analysis.

J Natl Compr Canc Netw 2017 10;15(10):1224-1233

From Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.

Although financial distress is commonly recognized in patients with cancer, it may be more prevalent in younger adults. This study sought to evaluate disparities in overall and financial distress in patients with cancer as a function of age. This was a single-center cross-sectional study of patients with solid malignancies requiring cancer therapy. The patient questionnaire included demographics, financial concerns, and measures of overall and financial distress. Data analyses compared patients in 3 age groups: young (<50 years), middle-aged (50-64 years), and elderly (≥65 years). The cohort included 119 patients (median age, 62 years; 52% female; 84% white; 100% insured; 36% income ≥$75,000). Significant financial concerns included paying rent/mortgage (=.003) and buying food (=.032). Impact of Event Scale (IES) results revealed significant distress in 73% young, 64% middle-aged, and 44% elderly patients. The mean Distress Thermometer (DT) score was 6.1 (standard deviation [SD], 2.9) for young patients, 5.4 (SD, 2.6) for middle-aged, and 4.4 (SD, 3.3) for elderly patients. Young patients were more likely than elderly patients to have a higher IES distress score (=.016) and DT score (=.048). The mean InCharge score was lowest (indicating greatest financial distress) in the young group and progressed with age: 5.0 (SD, 1.9), 5.7 (SD, 2.7), and 7.4 (SD, 1.9), respectively (<.001). Multivariable analyses revealed that the relationship between financial distress and overall distress was strongest in the middle-age group; as the DT increased by 1 point, the InCharge scores decreased by 0.52 (<.001). Overall and financial distress are more common in young and middle-aged patients with cancer. There are several factors, including employment, insurance, access to paid sick leave, children, and education, that affect younger and middle-aged adults and are less of a potential stressor for elderly individuals.
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http://dx.doi.org/10.6004/jnccn.2017.0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569506PMC
October 2017