RÉSUMÉ
Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Crizotinib/usage thérapeutique , Sarcome alvéolaire des parties molles/traitement médicamenteux , Adolescent , Adulte , Sujet âgé , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/génétique , Femelle , Réarrangement des gènes , Humains , Mâle , Adulte d'âge moyen , Survie sans progression , Inhibiteurs de protéines kinases/usage thérapeutique , Sarcome alvéolaire des parties molles/génétique , Sarcome alvéolaire des parties molles/mortalité , Jeune adulteRÉSUMÉ
BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.
Sujet(s)
Ostéonécrose de la mâchoire associée aux biphosphonates/traitement médicamenteux , Agents de maintien de la densité osseuse/effets indésirables , Inhibiteurs de protéines kinases/effets indésirables , Facteur de croissance endothéliale vasculaire de type A/effets indésirables , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Ostéonécrose de la mâchoire associée aux biphosphonates/anatomopathologie , Agents de maintien de la densité osseuse/pharmacologie , Femelle , Humains , Incidence , Mâle , Adulte d'âge moyen , Inhibiteurs de protéines kinases/pharmacologie , Facteur de croissance endothéliale vasculaire de type A/pharmacologie , Jeune adulteRÉSUMÉ
BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.
Sujet(s)
Protéines proto-oncogènes c-met/génétique , Pyrazoles/effets indésirables , Pyrazoles/usage thérapeutique , Pyridines/effets indésirables , Pyridines/usage thérapeutique , Sarcome à cellules claires/traitement médicamenteux , Sarcome à cellules claires/enzymologie , Adolescent , Adulte , Études de cohortes , Crizotinib , Femelle , Réarrangement des gènes , Humains , Hybridation fluorescente in situ , Mâle , Adulte d'âge moyen , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/usage thérapeutique , Protéine EWS de liaison à l'ARN/génétique , Sarcome à cellules claires/génétique , Jeune adulteRÉSUMÉ
BACKGROUND: 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). METHODS: Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk. RESULTS: Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates. CONCLUSION: Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.