المؤلفون: Schlumberger, M, Elisei, R, Müller, S, Schöffski, P, Brose, M, Shah, M, Licitra, L, Krajewska, J, Kreissl, MC, Niederle, B, Cohen, EEW, Wirth, L, Ali, H, Clary, DO, Yaron, Y, Mangeshkar, M, Ball, D, Nelkin, B, Sherman, S

المصدر: Annals of Oncology. 28(11)

مصطلحات موضوعية: Cancer, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Aged, Anilides, Carcinoma, Medullary, Diagnostic Imaging, Double-Blind Method, Female, Follow-Up Studies, Humans, International Agencies, Male, Prognosis, Pyridines, Survival Rate, Thyroid Neoplasms, cabozantinib, medullary thyroid cancer, progression-free survival, overall survival, RET M918T, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.Trial registration numberNCT00704730.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/86x359t4Test

المؤلفون: Schöffski, Patrick, Gordon, Michael, Smith, David C, Kurzrock, Razelle, Daud, Adil, Vogelzang, Nicholas J, Lee, Yihua, Scheffold, Christian, Shapiro, Geoffrey I

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Trials and Supportive Activities, Clinical Research, Rare Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Anilides, Antineoplastic Agents, Belgium, Disease Progression, Disease-Free Survival, Drug Administration Schedule, Early Termination of Clinical Trials, Female, Humans, Israel, Kaplan-Meier Estimate, Male, Neoplasms, Protein Kinase Inhibitors, Pyridines, Taiwan, Time Factors, Treatment Outcome, United States, Cabozantinib, Vascular endothelial growth factor receptor, Solid tumour, Objective response rate, Progression-free survival, Randomised discontinuation trial, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: Cabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.Cabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.A total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non-small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III-IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).Clinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.NCT00940225.

الوصول الحر: https://escholarship.org/uc/item/75w037drTest

المؤلفون: Jones, RL, Chawla, SP, Attia, S, Schöffski, P, Gelderblom, H, Chmielowski, B, Le Cesne, A, Van Tine, BA, Trent, JC, Patel, S, Wagner, AJ, Chugh, R, Heyburn, JW, Weil, SC, Wang, W, Viele, K, Maki, RG

المساهمون: Jones, Robin

مصطلحات موضوعية: MORAb-004, endosialin, ontuxizumab, sarcomas, tumor endothelial marker 1 (TEM-1), Adult, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antigens, CD, Neoplasm, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cohort Studies, Deoxycytidine, Docetaxel, Double-Blind Method, Female, Humans, Male, Middle Aged, Progression-Free Survival, Sarcoma, Young Adult

جغرافية الموضوع: United States

الوصف: BACKGROUND: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. METHODS: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. RESULTS: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. CONCLUSIONS: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

وصف الملف: Print-Electronic; 2454; application/pdf

العلاقة: Cancer, 2019, 125 (14), pp. 2445 - 2454; https://repository.icr.ac.uk/handle/internal/5394Test

الإتاحة: https://doi.org/10.1002/cncr.32084Test
https://repository.icr.ac.uk/handle/internal/5394Test

المؤلفون: Kang, Y-K, George, S, Jones, RL, Rutkowski, P, Shen, L, Mir, O, Patel, S, Zhou, Y, von Mehren, M, Hohenberger, P, Villalobos, V, Brahmi, M, Tap, WD, Trent, J, Pantaleo, MA, Schöffski, P, He, K, Hew, P, Newberry, K, Roche, M, Heinrich, MC, Bauer, S

المساهمون: Jones, Robin

مصطلحات موضوعية: Adult, Aged, 80 and over, Antineoplastic Agents, Asia, Australia, Disease Progression, Drug Administration Schedule, Europe, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Humans, Male, Middle Aged, Mutation, North America, Phenylurea Compounds, Progression-Free Survival, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrazoles, Pyridines, Pyrroles, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Triazines

جغرافية الموضوع: United States

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

وصف الملف: Print-Electronic; 3139; application/pdf

العلاقة: Journal of Clinical Oncology, 2021, 39 (28), pp. 3128 - 3139; https://repository.icr.ac.uk/handle/internal/5486Test

الإتاحة: https://doi.org/10.1200/JCO.21.00217Test
https://repository.icr.ac.uk/handle/internal/5486Test

المؤلفون: Elisei, Rossella, Schlumberger, Martin J, Müller, Stefan P, Schöffski, Patrick, Brose, Marcia S, Shah, Manisha H, Licitra, Lisa, Jarzab, Barbara, Medvedev, Viktor, Kreissl, Michael C, Niederle, Bruno, Cohen, Ezra EW, Wirth, Lori J, Ali, Haythem, Hessel, Colin, Yaron, Yifah, Ball, Douglas, Nelkin, Barry, Sherman, Steven I

المصدر: Journal of Clinical Oncology. 31(29)

مصطلحات موضوعية: Cancer, Clinical Trials and Supportive Activities, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Anilides, Calcitonin, Carcinoembryonic Antigen, Carcinoma, Neuroendocrine, Disease-Free Survival, Double-Blind Method, Female, Humans, Male, Middle Aged, Protein Kinase Inhibitors, Pyridines, Thyroid Neoplasms, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and methodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1s59k0fcTest

المؤلفون: Smith, David C, Smith, Matthew R, Sweeney, Christopher, Elfiky, Aymen A, Logothetis, Christopher, Corn, Paul G, Vogelzang, Nicholas J, Small, Eric J, Harzstark, Andrea L, Gordon, Michael S, Vaishampayan, Ulka N, Haas, Naomi B, Spira, Alexander I, Lara, Primo N, Lin, Chia-Chi, Srinivas, Sandy, Sella, Avishay, Schöffski, Patrick, Scheffold, Christian, Weitzman, Aaron L, Hussain, Maha

المصدر: Journal of Clinical Oncology. 31(4)

مصطلحات موضوعية: Urologic Diseases, Clinical Trials and Supportive Activities, Prostate Cancer, Cancer, Aging, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Musculoskeletal, Aged, Aged, 80 and over, Alkaline Phosphatase, Anilides, Antineoplastic Agents, Biomarkers, Tumor, Bone Neoplasms, Bone Remodeling, Collagen Type I, Disease-Free Survival, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Middle Aged, Orchiectomy, Peptides, Prostatic Neoplasms, Pyridines, Receptor Protein-Tyrosine Kinases, Treatment Outcome, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeCabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.Patients and methodsPatients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.ResultsOne hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).ConclusionCabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5kp0s919Test

المؤلفون: Cesne, AL, Bauer, S, Demetri, GD, Han, G, Dezzani, L, Ahmad, Q, Blay, J-Y, Judson, I, Schöffski, P, Aglietta, M, Hohenberger, P, Gelderblom, H

المساهمون: Judson, Ian

مصطلحات موضوعية: Humans, Sarcoma, Neoplasm Metastasis, Sulfonamides, Pyrimidines, Angiogenesis Inhibitors, Antineoplastic Agents, Neoplasm Staging, Treatment Outcome, Survival Analysis, Retrospective Studies, Aged, 80 and over, Middle Aged, Female, Male, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic

الوصف: Background PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.Methods PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.Results A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.Conclusions Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.Trial registration NCT00753688 , first posted September 16, 2008 (registered prospectively).

وصف الملف: Electronic; ?; application/pdf

العلاقة: BMC cancer, 2019, 19 (1), pp. 794 - ?; https://repository.icr.ac.uk/handle/internal/3330Test

الإتاحة: https://doi.org/10.1186/s12885-019-5988-3Test
https://repository.icr.ac.uk/handle/internal/3330Test

المؤلفون: Mateo, J, Olmos, D, Dumez, H, Poondru, S, Samberg, NL, Barr, S, Van Tornout, JM, Jie, F, Sandhu, S, Tan, DS, Moreno, V, LoRusso, PM, Kaye, SB, Schöffski, P

المساهمون: Kaye, Stanley Bernard, Mateo Valderrama, Joaquin

مصطلحات موضوعية: Leukocytes, Mononuclear, Humans, Neoplasms, Imidazoles, Triazines, Multiprotein Complexes, Protein Kinase Inhibitors, Maximum Tolerated Dose, Dose-Response Relationship, Drug, Half-Life, Adult, Aged, Middle Aged, Female, Male, Young Adult, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2

الوصف: Background The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted.Methods Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics.Results One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients.Conclusions OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.

وصف الملف: Print-Electronic; 896; application/pdf

العلاقة: British journal of cancer, 2016, 114 (8), pp. 889 - 896; https://repository.icr.ac.uk/handle/internal/2960Test

الإتاحة: https://doi.org/10.1038/bjc.2016.59Test
https://repository.icr.ac.uk/handle/internal/2960Test

المؤلفون: Reichardt, P, Demetri, GD, Gelderblom, H, Rutkowski, P, Im, SA, Gupta, S, Kang, YK, Schöffski, P, Schuette, J, Soulières, D, Blay, JY, Goldstein, D, Fly, K, Huang, X, Corsaro, M, Lechuga, MJ, Martini, JF, Heinrich, MC

المصدر: urn:ISSN:1471-2407 ; BMC Cancer, 16, 1, 22

مصطلحات موضوعية: Rare Diseases, Orphan Drug, Clinical Trials and Supportive Activities, Clinical Research, Digestive Diseases, Cancer, 6.1 Pharmaceuticals, 6 Evaluation of treatments and therapeutic interventions, Adolescent, Adult, Aged, 80 and over, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Gastrointestinal Stromal Tumors, Genotype, Humans, Indoles, Male, Middle Aged, Mutation, Prognosis, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrroles, Receptor, Platelet-Derived Growth Factor alpha, Sunitinib

الوصف: Background: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-aα (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. Methods: This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ2 test) in the same molecular subgroups. Results: Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20 %) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib ...

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/1959.4/unsworks_39167Test; https://unsworks.unsw.edu.au/bitstreams/0ae25641-8174-4d68-92b7-91587176ab3d/downloadTest; https://doi.org/10.1186/s12885-016-2051-5Test

الإتاحة: https://doi.org/10.1186/s12885-016-2051-5Test
http://hdl.handle.net/1959.4/unsworks_39167Test
https://unsworks.unsw.edu.au/bitstreams/0ae25641-8174-4d68-92b7-91587176ab3d/downloadTest

المؤلفون: Beuselinck, B, Wolter, P, Karadimou, A, Elaidi, R, Dumez, Herlinde, Rogiers, Annick, Van Cann, T, Willems, L, Body, Jean-Jacques, Berkers, J, Van Poppel, H, Lerut, E, Debruyne, P, Paridaens, R, Schöffski, P

المصدر: British Journal of Cancer, 107 (10

مصطلحات موضوعية: Sciences bio-médicales et agricoles, Antineoplastic Combined Chemotherapy Protocols -- adverse effects -- therapeutic use, Bone Density Conservation Agents -- administration & dosage -- adverse effects, Bone Neoplasms -- drug therapy -- pathology -- secondary, Carcinoma, Renal Cell -- drug therapy -- pathology -- secondary, Diphosphonates -- administration & dosage -- adverse effects, Disease-Free Survival, Female, Humans, Indoles -- administration & dosage, Kidney Neoplasms -- drug therapy -- pathology, Male, Middle Aged, Neoplasm Metastasis, Niacinamide -- administration & dosage -- analogs & derivatives, Osteonecrosis -- chemically induced, Phenylurea Compounds -- administration & dosage, Prognosis, Protein Kinase Inhibitors -- administration & dosage, Protein-Tyrosine Kinases -- antagonists & inhibitors, Pyrroles -- administration & dosage, Retrospective Studies, Treatment Outcome, Bisphosphonates, Bone metastases, Osteonecrosis of the jaw, Outcome, Renal cell carcinoma, Targeted therapy

الوصف: The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ). ; Journal Article ; Research Support, Non-U.S. Gov't ; SCOPUS: ar.j ; info:eu-repo/semantics/published

وصف الملف: 1 full-text file(s): application/pdf

العلاقة: uri/info:doi/10.1038/bjc.2012.385; uri/info:pii/bjc2012385; uri/info:pmid/23132391; uri/info:scp/84869225968; https://dipot.ulb.ac.be/dspace/bitstream/2013/143043/3/doi_126664.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/143043Test

الإتاحة: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/143043Test