Sandra Leta Silberman

Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor

PURPOSE Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. PATIENTS AND METHODS GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. RESULTS Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. CONCLUSION Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study

BACKGROUND Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract characterised by cell-surface expression of the tyrosine kinase KIT (CD117). No effective systemic treatment is available. Imatinib (STI571) inhibits a similar tyrosine kinase, BCR-ABL, leading to responses in chronic myeloid leukaemia, and has also been shown to inhibit KIT. We did a phase I study to identify the dose-limiting toxic effects of imatinib in patients with advanced soft tissue sarcomas including GISTs. METHODS 40 patients (of whom 36 had GISTs) received imatinib at doses of 400 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice daily. Toxic effects and haematological, biochemical, and radiological measurements were assessed during 8 weeks of follow-up. 18Fluorodeoxy-glucose positron-emission tomography (PET) was used for response assessment in one centre. FINDINGS Five patients on 500 mg imatinib twice daily had dose-limiting toxic effects (severe nausea, vomiting, oedema, or rash). Inhibition of tumour growth was seen in all but four patients with GISTs, resulting in 19 confirmed partial responses and six as yet unconfirmed partial responses or more than 20% regressions. 24 of 27 clinically symptomatic patients showed improvement, and 29 of 36 were still on treatment after more than 9 months. PET scan responses predicted subsequent computed tomography responses. INTERPRETATION Imatinib at a dose of 400 mg twice daily is well tolerated during the first 8 weeks, side-effects diminish with continuing treatment, and it has significant activity in patients with advanced GISTs. Our results provide evidence of a role for KIT in GISTs, and show the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers.

18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec).

Imatinib mesylate (Glivec, formerly STI571) is the first effective systemic treatment for gastrointestinal stromal tumours (GISTs). Major changes in tumour volume, however, tend to occur late after the start of treatment. The aim of this study was to evaluate if [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) can be used for the early evaluation of response to imatinib mesylate treatment in soft-tissue sarcomas (STS). 21 patients (17 GIST, 4 other STS) underwent FDG-PET imaging prior to and 8 days after the start of treatment. PET response (European Organization for Research and Treatment (EORTC) guidelines) was observed in 13 GISTs (11 Complete Responders, 2 partial responders. Subsequent computerised tomography (CT) response Response Evaluation Criteria in Solid Tumours (RECIST) was observed in 10 of these patients after a median follow up of 8 weeks. Stable or progressive disease was observed on PET in 8 patients and none of them achieved a response on CT. PET response was also associated with a longer progression-free survival (PFS) (92% versus 12% at 1 year, P=0.00107). We conclude that FDG-PET is an early and sensitive method to evaluate an early response to imatinib treatment.

Management of malignant gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract. Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers. Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques. The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential. GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase. KIT activation seems to be an early tumour-promoting event in pathogenesis. Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy. Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT. Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate. Responses have been durable, and most patients tolerate the drug well at clinically effective doses. Imatinib mesylate is the first effective systemic therapy for advanced GIST.

Imatinib: the first 3 years

Imatinib (Glivec, formerly STI571, Novartis Pharma AG, Basel, Switzerland) potently inhibits several protein tyrosine kinases, including Bcr-Abl, Kit, and the platelet-derived growth factor receptor. Phase I and II studies demonstrated that orally administered imatinib is highly effective and well tolerated in all phases of chronic myeloid leukemia (CML) at doses ranging from 400 to 600 mg. Importantly, preliminary evidence suggests that patients with advanced CML achieving hematologic or major cytogenetic responses to imatinib may have longer survival than those without such responses, whereas chronic phase patients who respond to treatment may have longer times to disease progression. Ongoing and planned studies are focused on optimizing CML treatment with imatinib, evaluating imatinib-based combination therapy, defining additional therapeutic targets and exploring the use of imatinib in children. In particular, results from several combination phase I studies are expected shortly, including an evaluation of combination imatinib-interferon-alpha therapy and imatinib-cytarabine in chronic phase CML, and a phase I study of single-agent imatinib in children with Philadelphia chromosome-positive leukemia is ongoing. A large phase III trial comparing imatinib with standard inferferon alfa plus cytarabine in first-line CML treatment is also ongoing.

Abstract CT314: Interim results from a phase I/II trial of TPI 287, a novel brain penetrable antimicrotubule agent, in combination with bevacizumab for the treatment of recurrent glioblastoma

Background: TPI 287 is a novel anti-microtubule agent designed to evade inactivation and efflux by multiple drug resistance pathways, which enables meaningful penetration of the blood-brain barrier. Preclinical results demonstrate CNS accumulation at pharmacologically relevant concentrations and significant anti-neoplastic activity in a murine model of brain metastases (Fitzgerald, et al Mol Can Ther 2012 11:1959-67). Safety data from clinical trials enrolling over 200 cancer patients have shown TPI 287 to be well tolerated. Based on these data, a dose-escalation phase I/II trial was designed to determine the maximum tolerated dose (MTD) and efficacy of TPI 287 for recurrent glioblastoma (GBM) in combination with the angiogenesis inhibitor bevacizumab. Interim results from the dose escalation portion of this trial are reported. Methods: GBM patients at first or second relapse after failure of standard chemoradiation and without prior exposure to angiogenesis inhibitors are eligible. Standard-of-care bevacizumab is administered at 10 mg/kg as an IV infusion once every 2 weeks. TPI 287 is administered as an IV infusion every 3 weeks. Employing a 3+3 design, dose escalation of TPI 287 is ongoing until determination of MTD, followed by transition to the randomized phase II stage of the trial. MRIs are obtained every six-weeks with response assessment via RANO criteria. Results: As of December 2014, 16 subjects have been enrolled in the first 5 TPI dose-escalation cohorts (140-180 mg/m2). No dose-limiting toxicities have been observed to date. Of 12 patients evaluable for safety, myelosuppression has been the only Grade 3 adverse event attributed to treatment (2 patients). Among the 13 patients evaluable for efficacy, there were 5 confirmed objective responses (1 CR; 4 PR) and 2 responses awaiting confirmation (1 CR; 1 PR). Durability of the confirmed responses has ranged from 5.5 to 8.2+ months. Conclusions: These interim results demonstrate that TPI 287 in combination with bevacizumab is well tolerated. Moreover, efficacy data is promising, with a high rate of durable responses achieved below the MTD. This study also highlights the power of translational studies for evaluating effective cancer therapy. Evolving safety and efficacy results will be presented. Citation Format: Sandra L. Silberman, Samuel Goldlust, L. Burt Nabors, J Paul Duic, Tara Benkers, Nimish Mohile, Donald Picker, Samuel Singer, George Farmer. Interim results from a phase I/II trial of TPI 287, a novel brain penetrable antimicrotubule agent, in combination with bevacizumab for the treatment of recurrent glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT314. doi:10.1158/1538-7445.AM2015-CT314