Imatinib and solid tumours

Imatinib mesylate (Gleevec, Glivec, Novartis, Basel, Switzerland) is a small molecule inhibitor of the tyrosine kinase c-abl, c-kit and the platelet derived growth factor receptor (PDGFR). Imatinib was developed for the treatment of chronic myeloid leukaemia (CML) but was approved both in Europe and the US fro the treatment of CML and gastrointestinal stromal tumors (GIST). Given its activity against both c-kit and PDGFR kinases and its remarkable safety profile, imatinib has been 'tried' in several solid tumors; results however have often been deceiving. We review the current data regarding the activity of imatinib in solid tumors, including GIST.     

The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.     

Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Ninety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression. RESULTS: Fifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue. CONCLUSION: Bevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.     

Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy

BACKGROUND: Systemic treatment of metastatic melanoma is largely ineffective and alternative approaches are needed. Imatinib mesylate is an oral tyrosine kinase inhibitor that targets bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta, leading to remarkable clinical responses in several cancers. Signal transduction via c-kit, PDGFR-alpha, and PDGFR-beta has been demonstrated in malignant melanoma. METHODS: The primary objective of this Phase II study was to determine the response rate, response duration, and the frequency of 6-month progression-free survival in patients who could receive up to 2 prior therapeutic regimens. Initially, patients received imatinib at at dose of 400 mg twice orally each day. Based on Simon's optimal design, the study allowed entry of 21 patients; if there were > or = 2 objective responses, accrual would then continue to a total of 41 patients. RESULTS: Twenty-six patients were enrolled. Patients experienced 29 episodes of Grade 3 and 2 episodes of Grade 4 toxicity (according to National Cancer Institute common toxicity criteria). No objective clinical responses were noted among the 25 evaluable patients. The median time to progression was 54 days and the median overall survival was 200 days. No patient was free of disease progression at 6 months. Paraffin-embedded tumor specimens from 15 patients were tested for expression of imatinib responsive kinases by immunohistochemistry. Three tumors had moderate and 5 tumors had weak staining for c-kit. Five tumor samples had weak staining for PDGFR-alpha and -beta. CONCLUSIONS: Imatinib is an inactive single agent in metastatic melanoma in a population of predominantely pretreated patients. The levels of c-kit and/or PDGFR-alpha, -beta expression in the current study were lower than previously reported. Alternative treatment strategies remain a priority for patients with advanced melanoma.     

Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.

PURPOSE: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.     

Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis : a Hoosier Oncology Group trial

BACKGROUND: Ovarian tumors frequently express c-Kit and/or platelet-derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). METHODS: Eligible patients had recurrent, platinum-resistant, or refractory EOC that expressed PDGFRalpha or c-kit, as determined by immunohistochemistry. Imatinib mesylate at a dose of 600 mg orally once daily was administered continuously with docetaxel at a dose of 30 mg/m(2) given intravenously once weekly in Weeks 1 through 4 of every 6-week cycle. The primary endpoint was objective response rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-four patients were screened for PDGFRalpha and c-kit expression to enroll 23 patients between December 2003 and October 2005. Four patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (range, 33-76 years). Patients had received a median of 3 prior treatments. The ORR was 21.7% and included 1 complete and 4 partial responses. An additional 3 patients had stable disease for more than 4 months. Expression of PDGFR, c-kit, phosphatase and tensin homolog (PTEN), and phosphorylated protein kinase B (Akt) did not predict response to therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were graded as grade 1 or 2. CONCLUSIONS: The combination imatinib and docetaxel was tolerated in patients with heavily pretreated EOC that expressed c-kit or PDGFRalpha. Few patients had sustained responses or stable disease.     

U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval.

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN-alpha therapy, (b) accelerated phase, and (c) blast crisis. The accelerated approval was accompanied by a postmarketing commitment by Novartis Pharmaceuticals to continue patient follow-up to determine duration of treatment response and survival. The present review, based on a safety and efficacy report submitted on December 20, 2002, summarizes data applicable to the conversion of these three CML indications to full approval status. RESULTS: Chronic phase CML: Five hundred thirty-two chronic phase CML patients who had not benefited from prior IFN therapy were treated at a starting imatinib mesylate dose of 400 mg p.o. qd; dose escalation to 800 mg p.o. qd was allowed. Patients had received a median of 14 months of IFN therapy at doses > or =25 million IU/wk and were all in late chronic phase, with a median time from diagnosis of 32 months. Median duration of imatinib mesylate treatment was 29 months, with 81% of patients treated for > or =24 months (maximum 31.5 months). Initial favorable treatment responses were sustained. An estimated 87.8% of patients who had a major cytogenetic response maintained their response 2 years after their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and the estimated overall survival was 90.8% (95% confidence interval, 88.3-93.2). Accelerated phase CML: Patients enrolled totaled 293: 235 with CML accelerated phase, 48 with relapsed/refractory acute lymphocytic leukemia, 2 with relapsed/refractory acute myelocytic leukemia, and 8 with relapsed/refractory CML in lymphoid blast crisis. Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg/d, taken as 400 mg bid. Efficacy results were improved in patients receiving imatinib mesylate 600 mg qd versus patients receiving 400 mg qd. The median duration of hematologic response was 29 versus 17 months and the estimated 24-month maintained hematologic response rate was 61% versus 42%. The median survival of patients treated with imatinib mesylate 600 mg qd was not reached versus 20.9 months for patients receiving 400 mg qd. Estimated 24-month survival rate was 66% versus 46%. The median survival in the advanced leukemia population (acute lymphocytic leukemia, acute myelocytic leukemia, and lymphoid blast crisis) was only 5 months, and only two patients are still on treatment. Blast crisis CML: A total of 260 patients were recruited. The imatinib mesylate dose was initially 400 mg qd (37 patients) but was subsequently increased to 600 mg qd (223 patients). Patients receiving imatinib mesylate 600 mg qd had a higher hematologic response rate than did patients receiving 400 mg (33% versus 16%). Major cytogenetic responses occurred in 15% of the 260 study patients. The overall median survival was 6.9 months: 7.1 months for patients treated with imatinib mesylate 600 mg and 4.7 months for patients receiving imatinib mesylate 400 mg. Estimated 12-month survival rate for all study patients was 32.1% and estimated 24-month survival rate was 18.3%. Safety: Imatinib mesylate was generally well tolerated, but relatively frequent reports of common toxicity criteria grade 3/4 neutropenia and thrombocytopenia were encountered. The most frequently reported adverse events included gastrointestinal disturbances, edema, rash, and musculoskeletal complaints. These rarely led to discontinuation of therapy. CONCLUSIONS: The results confirm those of the interim analysis and suggest that imatinib mesylate represents an effective therapeutic agent for the treatment of patients with CML in chronic phase after failure of IFN-alpha therapy, in blast crisis, and in accelerated phase.     

Nilotinib: a novel, selective tyrosine kinase inhibitor

The development of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myelogenous leukemia (CML) was based on the discovery that CML stem and progenitor cells overexpress the abnormal fusion protein kinase BCR-ABL. The prototype TKI, imatinib, selectively inhibits BCR-ABL, as well as several other kinases, including stem cell factor receptor (KIT), discoidin domain receptor (DDR), platelet-derived growth factor receptor (PDGFR), and colony-stimulating factor receptor-1 (CSF-1R). Although the management of CML improved dramatically with the introduction of imatinib, not all patients benefit from treatment because of resistance or intolerance. Consequently, research efforts have focused on developing more potent TKIs with the ability to circumvent imatinib resistance. Nilotinib, a second-generation oral TKI, was rationally designed based on the crystal structure of imatinib to be highly active against a wide range of imatinib-resistant BCR-ABL mutants and is approved for the treatment of newly diagnosed or imatinib-resistant or -intolerant CML, and has shown superiority over imatinib in first-line treatment for newly diagnosed CML. Furthermore, the activity of nilotinib against KIT and PDGFRα has led to its evaluation in advanced gastrointestinal stromal tumors (GIST). The purpose of this review is to describe the development of nilotinib, providing a structural explanation for the differential activity of nilotinib and imatinib in GIST. Activity of nilotinib against KIT and PDGFR and emerging evidence of differences in cellular uptake between nilotinib and imatinib are discussed.     

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.     

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia,high-risk myelodysplastic syndrome,and myeloproliferative disorders

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.     

Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium

AimTo explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases.MethodsExploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed.ResultsThirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m²/d over a total of 255 months. Fifteen tumours expressed KIT in ?30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1–2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively).ConclusionsImatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.     

Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202)

BACKGROUND: Imatinib mesylate, an inhibitor of KIT, ABL protein, and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinase, has recently been found to have a dramatic antitumor effect on gastrointestinal stromal tumor (GIST). The aim of this study was to assess the efficacy and safety of imatinib mesylate in Japanese patients with advanced GIST. METHODS: Patients with measurable lesions were enrolled between April 1, 2002, and September 20, 2002, using a design based on previous phase II studies in the United States and the European Union. The diagnosis of GIST was proven histologically with positive immunostaining for KIT (CD117). Imatinib mesylate was administered at a dose of either 400 mg or 600 mg once a day. Pharmacokinetic parameters and mutation analysis of c-kit were also assessed in a subgroup of patients. RESULTS: A total of 74 patients (28 receiving imatinib mesylate at 400 mg/day; 46 receiving 600 mg/day); median age, 56.0 years, were enrolled. No patient had a complete response, 51 patients (69%) had a partial response, and 19 patients (26%) had stable disease. The median progression-free survival time was 96 weeks. The estimated 3-year overall survival (Kaplan-Meier) rate for all patients was 73.6%. The most frequent adverse effects related to the drug were nausea (78%), diarrhea (70%), dermatitis (62%), facial edema (61%), edema of the lower limbs (58%), vomiting (54%), and eyelid edema (51%). Most of the adverse effects were mild and manageable. CONCLUSION: Imatinib mesylate is generally safe and has significant activity in the treatment of advanced GIST in Japanese patients.     

Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling

INTRODUCTION: Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR alpha and beta, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival. METHODS: Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10 microM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay. RESULTS: Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR beta and Akt was detected. CONCLUSIONS: The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients.     

A phase II trial of imatinib in patients with refractory/relapsed myeloma

Although imatinib was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases including c-kit. As pre-clinical data, 126 patients with plasma cell disorders and 19 controls were evaluated for c-kit expression. Patients were eligible for the treatment trial if they had relapsed/refractory myeloma. The primary end-point of the study was response. Of the 145 studied before the trial, c-kit expression was present on the bone marrow plasma cells of control (11%), AL amyloid (53%), MGUS (47%), SMM (67%) and MM (42%) patients. Twenty-three MM patients were enrolled on the therapeutic trial (imatinib 400 mg daily) and 52% had positive c-kit staining. There were no responses. The median duration of treatment was 48 days (range: 12-349). Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imantinib is not an active agent in patients with relapsed or refractory multiple myeloma.     

Phase II Trial of Docetaxal Plus Imatinib Mesylate in the Treatment of Patients With Metastatic Breast Cancer

BackgroundInhibition of the platelet-derived growth factor receptor (PDGFR) might improve the efficacy of chemotherapy by lowering interstitial tumor pressure and allowing increased tumor penetration by cytotoxic agents. In this phase II trial, we added imatinib, a PDGFR inhibitor, to docetaxel in the first-line treatment of women with metastatic breast cancer (MBC).Patients and MethodsWomen with MBC who had received a maximum of 1 previous chemotherapy regimen were eligible for this trial. Initially, patients received oral imatinib 600 mg daily and docetaxel 30 mg/m² on days 1, 8, and 15 of a 28-day cycle. The imatinib dose was lowered from 600 mg to 400 mg daily because of toxicity (primarily gastrointestinal) observed in the first 15 patients. Patients were evaluated for response (Response Evaluation Criteria in Solid Tumors) after 8 weeks of therapy; treatment continued in responding/stable patients until tumor progression or unacceptable toxicity. The primary endpoint was the overall response rate.ResultsThirty-seven patients entered this trial between May 2005 and March 2008. This regimen was relatively poorly tolerated, even after reduction of the imatinib dose, primarily because of gastrointestinal toxicity (nausea, vomiting, and diarrhea). Eight patients (22%) stopped therapy because of toxicity before the 8-week initial evaluation. Six of 37 enrolled patients (16%; 95% CI, 4.3%-28.1%) had partial responses; an additional 4 patients had stable disease for > 6 months. The median progression-free and overall survivals were 9.3 months and 15.4 months, respectively.ConclusionWhen compared with previous results with single-agent docetaxel, the combination of weekly docetaxel plus imatinib was tolerated relatively poorly and produced a low objective response rate. The efficacy of weekly docetaxel is not improved by concurrent administration of imatinib as a PDGFR inhibitor.     

Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study.

PURPOSE: This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases. PATIENTS AND METHODS: In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks. RESULTS: Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles. CONCLUSION: Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.     

CD117 (c-kit) expression in human hepatocellular carcinoma

AimsAlthough various methods of treatment have been tried, treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Expression of the platelet-derived growth factor has been shown in HCC, which may derive from hepatic stem cells that express the c-kit proto-oncogene. Because of the promising results of imatinib and the key role played by c-kit in gastrointestinal stromal tumours and other solid tumours, the aim of this study was to determine the prevalence of c-kit (CD117) overexpression in patients with HCC.Materials and methodsA retrospective study of 258 archival specimens of subjects with histologically confirmed HCC was carried out. Expression of the c-kit proto-oncogene was evaluated by immunohistochemistry using rabbit anti-CD117 antibody A4502.ResultsThe overall percentage of positive immunohistochemical staining of HCCs was 2.3% (6/258).ConclusionsOur results suggest that CD117 is not significantly overexpressed in HCC and there seems to be no role for the use of imatinib.     

伊马替尼治疗晚期脊索瘤患者的临床研究

目的：研究晚期脊索瘤患者口服伊马替尼治疗的临床疗效分析。方法本研究收集2007年6月至2012年6月,在解放军总医院第一附属医院住院治疗的晚期脊索瘤患者63例,其中失访病例24例,我们长期追踪到的39例为可评价患者。患者在接受伊马替尼治疗前通过病理组化检测 PDGFRβ蛋白表达情况,分为低表达组和高表达组。所有患者均口服伊马替尼的剂量为每天400 mg ,每3个月进行1次 CT或 MRI 检查肿瘤生长情况,按照 RECIST 标准评价临床治疗效果,同时比较两组患者对伊马替尼治疗疗效的差别,并以 SPSS13.0作统计分析,P＜0.05具有统计学意义;采用 Kaplan-Meier 法绘制患者生存曲线。结果免疫组化提示高表达PDGFRβ患者为25例,占64.1%,14例低表达患者,占35.9%;在39例可评价患者中,完全缓解（CR）病例为0例（0%）,部分缓解（PR）病例为3例（8%）,病情稳定（SD）患者为27例（69%）,疾病进展（ PD ）病例为9例（23%）;临床获益率为76.9%（ CR%＋PR%＋SD%）;中位无疾病进展期为9个月,中位生存时间为31.2个月。PDGFRβ高表达组临床获益人数为22例（临床获益率88%）,低表达组临床获益人数8例（临床获益率57.1%）;两组患者相比差异有统计学意义,P值为0.0282。结论本研究提示伊马替尼在治疗晚期脊索瘤方面具有抗肿瘤活性,临床获益率较好,同时在 PDGFRβ高表达的患者获得了更好的疗效。     

Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity

Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.     

Imatinib mesylate (Gleevec®) in advanced breast cancer-expressing C-Kit or PDGFR-β: clinical activity and biological correlations

BackgroundNovel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec®) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects.Patients and methodsThirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-β overexpression and none showed c-kit expression.ResultsNo objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-γ production by TCR-activated CD4⁺ T cells.ConclusionImatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.