Background: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are... Show moreBackground: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS.Materials and methods: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome.Results: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively.Conclusions: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare Show less
Gelderblom, H.; Jones, R.L.; Blay, J.Y.; George, S.; Mehren, M. von; Zalcberg, J.R.; ... ; Bauer, S. 2023
PurposeIn the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously... Show morePurposeIn the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL).Patients and methodsPatients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up.ResultsQuestionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days).ConclusionPatients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib. Show less
BackgroundUveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase ... Show moreBackgroundUveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK. MethodWe conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis. ResultsThirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1. ConclusionsConcurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated. Show less
Palmerini, E.; Healey, J.H.; Bernthal, N.M.; Bauer, S.; Schreuder, H.; Leithner, A.; ... ; Sande, M. van de 2023
Background: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial... Show moreBackground: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. Material and Methods: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). Results: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. Conclusion: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088)The TOPP registry is an international prospective study that previously described the impact of diffuse-type tenosynovial giant cell tumor on patient-reported outcomes from a baseline snapshot. This article reports a 2-year follow-up based on treatment strategies and could represent a benchmark for future clinical trials. Show less
Schoeffski, P.; George, S.; Heinrich, M.C.; Zalcberg, J.R.; Bauer, S.; Gelderblom, H.; ... ; Mehren, M. von 2022
Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and... Show moreBackground: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in >= fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. Conclusion: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. Show less
Schoeffski, P.; George, S.; Heinrich, M.C.; Zalcberg, J.R.; Bauer, S.; Gelderblom, H.; ... ; Mehren, M. von 2022
Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVIC‑ TUS phase 3 trial, ripretinib increased median progression-free survival and... Show moreBackground: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVIC‑ TUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥fourth-line advanced GIST. Here, we report prespecifed analysis of quality of life (QoL) as assessed by patientreported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covari‑ ance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO meas‑ ures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically signifcant diferences between treatments (nominal P<0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. Conclusion: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. Show less
PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI... Show morePURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor alpha mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib. Show less
Bernthal, N.M.; Healey, J.H.; Palmerini, E.; Bauer, S.; Schreuder, H.; Leithner, A.; ... ; Sande, M. van de 2022
Background and Objectives: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical... Show moreBackground and Objectives: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up. Methods: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits. Results: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD +/- 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options. Conclusions: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy. Show less
Rohrbach, P.J.; Dingemans, A.E.; Spinhoven, P.; Ginkel, J.R. van; Fokkema, M.; Wilderjans, T.F.; ... ; Furth, E.F. van 2022
Objective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the... Show moreObjective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the effectiveness of Featback, a fully automated online self-help intervention, online expert-patient support and their combination. Method: A randomized controlled trial with a 12-month follow-up period was conducted. Participants aged 16 or older with at least mild eating disorder symptoms were randomized to four conditions: (1) Featback, a fully automated online self-help intervention, (2) chat or email support from a recovered expert patient, (3) Featback with expert-patient support and (4) a waiting list control condition. The intervention period was 8 weeks and there was a total of six online assessments. The main outcome constituted reduction of eating disorder symptoms over time. Results: Three hundred fifty five participants, of whom 43% had never received eating disorder treatment, were randomized. The three active interventions were superior to a waitlist in reducing eating disorder symptoms (d = -0.38), with no significant difference in effectiveness between the three interventions. Participants in conditions with expert-patient support were more satisfied with the intervention. Discussion: Internet-based self-help, expert-patient support and their combination were effective in reducing eating disorder symptoms compared to a waiting list control condition. Guidance improved satisfaction with the internet intervention but not its effectiveness. Low-threshold interventions such as Featback and expert-patient support can reduce eating disorder symptoms and reach the large group of underserved individuals, complementing existing forms of eating disorder treatment. Public significance statement: Individuals with eating-related problems who received (1) a fully automated internet-based intervention, (2) chat and e-mail support by a recovered individual or (3) their combination, experienced stronger reductions in eating disorder symptoms than those who received (4) usual care. Such brief and easy-access interventions play an important role in reaching individuals who are currently not reached by other forms of treatment. Show less
Rohrbach, P.J.; Dingemans, A. E.; Spinhoven, P.; Ginkel, J.R. van; Fokkema, M.; Wildermans, T.F.; ... ; Furth, E.F. van 2022
Objective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the... Show moreObjective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the effectiveness of Featback, a fully automated online self-help intervention, online expert-patient support and their combination.Method: A randomized controlled trial with a 12-month follow-up period was conducted. Participants aged 16 or older with at least mild eating disorder symptoms were randomized to four conditions: (1) Featback, a fully automated online selfhelp intervention, (2) chat or email support from a recovered expert patient, (3) Featback with expert-patient support and (4) a waiting list control condition. The intervention period was 8 weeks and there was a total of six online assessments. The main outcome constituted reduction of eating disorder symptoms over time. Results: Three hundred fifty five participants, of whom 43% had never received eating disorder treatment, were randomized. The three active interventions were superior to a waitlist in reducing eating disorder symptoms (d = -0.38), with no significant difference in effectiveness between the three interventions. Participants in conditions with expert-patient support were more satisfied with the intervention. Discussion: Internet-based self-help, expert-patient support and their combination were effective in reducing eating disorder symptoms compared to a waiting list control condition. Guidance improved satisfaction with the internet intervention but not its effectiveness. Low-threshold interventions such as Featback and expert-patient support can reduce eating disorder symptoms and reach the large group of underserved individuals, complementing existing forms of eating disorder treatment. Public significance statement: Individuals with eating-related problems who received (1) a fully automated internet-based intervention, (2) chat and e-mail support by a recovered individual or (3) their combination, experienced stronger reductions in eating disorder symptoms than those who received (4) usual care. Such brief and easyaccess interventions play an important role in reaching individuals who are currently not reached by other forms of treatment. Show less
PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem... Show morePURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Muller-Schafer method. RESULTS Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years. (c) 2022 by American Society of Clinical Oncology Show less
Objective The primary aim was assessing the cost-effectiveness of an internet-based self-help program, expert-patient support, and the combination of both compared to a care-as-usual condition.... Show moreObjective The primary aim was assessing the cost-effectiveness of an internet-based self-help program, expert-patient support, and the combination of both compared to a care-as-usual condition. Method :An economic evaluation from a societal perspective was conducted alongside a randomized controlled trial. Participants aged 16 or older with at least mild eating disorder symptoms were randomly assigned to four conditions: (1) Featback, an online unguided self-help program, (2) chat or e-mail support from a recovered expert patient, (3) Featback with expert-patient support, and (4) care-as-usual. After a baseline assessment and intervention period of 8 weeks, five online assessments were conducted over 12 months of follow-up. The main result constituted cost-utility acceptability curves with quality-of-life adjusted life years (QALYs) and societal costs over the entire study duration. Results: No significant differences between the conditions were found regarding QALYs, health care costs and societal costs. Nonsignificant differences in QALYs were in favor of the Featback conditions and the lowest societal costs per participant were observed in the Featback only condition (euro16,741) while the highest costs were seen in the care-as-usual condition (euro28,479). The Featback only condition had the highest probability of being efficient compared to the alternatives for all acceptable willingness-to-pay values. Discussion: Featback, an internet-based unguided self-help intervention, was likely to be efficient compared to Featback with guidance from an expert patient, guidance alone and a care-as-usual condition. Results suggest that scalable interventions such as Featback may reduce health care costs and help individuals with eating disorders that are currently not reached by other forms of treatment. Public significance statement: Internet-based interventions for eating disorders might reach individuals in society who currently do not receive appropriate treatment at low costs. Featback, an online automated self-help program for eating disorders, was found to improve quality of life slightly while reducing costs for society, compared to a do-nothing approach. Consequently, implementing internet-based interventions such as Featback likely benefits both individuals suffering from an eating disorder and society as a whole. Show less
Rohrbach, P.J.; Dingemans, A.E.; Furth, E.F. van; Spinhoven, P.; Ginkel, J.R. van; Bauer, S.; Van den Akker‐Van Marle, M.E. 2022
Objective: The primary aim was assessing the cost-effectiveness of an internet-based self-help program, expert-patient support, and the combination of both compared to a care-as-usual condition.... Show moreObjective: The primary aim was assessing the cost-effectiveness of an internet-based self-help program, expert-patient support, and the combination of both compared to a care-as-usual condition. Method: An economic evaluation from a societal perspective was conducted alongside a randomized controlled trial. Participants aged 16 or older with at least mild eating disorder symptoms were randomly assigned to four conditions: (1) Featback, an online unguided self-help program, (2) chat or e-mail support from a recovered expert patient, (3) Featback with expert-patient support, and (4) care-as-usual. After a baseline assessment and intervention period of 8 weeks, five online assessments were conducted over 12 months of follow-up. The main result constituted cost-utility acceptability curves with quality-of-life adjusted life years (QALYs) and societal costs over the entire study duration. Results: No significant differences between the conditions were found regarding QALYs, health care costs and societal costs. Nonsignificant differences in QALYs were in favor of the Featback conditions and the lowest societal costs per participant were observed in the Featback only condition (euro16,741) while the highest costs were seen in the care-as-usual condition (euro 28,479). The Featback only condition had the highest probability of being efficient compared to the alternatives for all acceptable willingness-to-pay values. Discussion: Featback, an internet-based unguided self-help intervention, was likely to be efficient compared to Featback with guidance from an expert patient, guidance alone and a care-as-usual condition. Results suggest that scalable interventions such as Featback may reduce health care costs and help individuals with eating disorders that are currently not reached by other forms of treatment. Public significance statement Internet-based interventions for eating disorders might reach individuals in society who currently do not receive appropriate treatment at low costs. Featback, an online automated self-help program for eating disorders, was found to improve quality of life slightly while reducing costs for society, compared to a do-nothing approach. Consequently, implementing internet-based interventions such as Featback likely benefits both individuals suffering from an eating disorder and society as a whole. Show less
Background: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety,... Show moreBackground: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results: Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8-4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions: The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing. Show less
Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established.... Show morePurpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort.Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival.Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location.Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted. Show less
A. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M.... Show moreA. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M. Montemurro54, B. Morland55, C. Morosi56, E. Palmerini57, M. A. Pantaleo58, R. Piana59, S. Piperno-Neumann60, P. Reichardt61, P. Rutkowski62, A. A. Safwat63, C. Sangalli64, M. Sbaraglia19, S. Scheipl48, P. Schoffski65, S. Sleijfer66, D. Strauss67, K. Sundby Hall13, A. Trama68, M. Unk69, M. A. J. van de Sande70, W. T. A. van der Graaf66,71, W. J. van Houdt72, T. Frebourg73x, R. Ladenstein41z, P. G. Casali2,74z & Show less
Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of... Show morePurpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups.Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed.Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan-Meier PFS analysis (exon 11 , P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo.Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs. Show less
Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established.... Show morePurpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort.Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival.Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location.Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted. Show less
