Suzanne George

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

BACKGROUND No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib

BACKGROUND Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. METHODS We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinibs effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. FINDINGS Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. INTERPRETATION Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.

Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase Inhibitors

PURPOSE While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST. METHODS We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease). RESULTS Disease status before surgery was associated with surgical result (P < .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). CONCLUSION Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.

Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors

Context Sunitinib, a tyrosine kinase inhibitor, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Contribution In a series of imatinib-resistant patients treated with sunitinib for gastrointestinal stromal tumors, 36% developed hypothyroidism during the course of treatment. Incidence of hypothyroidism increased progressively with duration of treatment. Implications Disruption of specific cellular signaling pathways by kinase inhibitors that are intended to interfere with malignant cell growth may have profound and unanticipated metabolic consequences. Patients receiving kinase inhibitors should be closely monitored for the occurrence of adverse effects on other organ systems. The Editors Tyrosine kinase inhibitors are beneficial for the treatment of numerous malignant conditions. Although each small molecule is modeled to block the activity of selected kinase signaling enzymes, it is increasingly evident that many have overlapping effects on several kinase pathways. Sunitinib malate (Sutent [previously known as SU11248], Pfizer, Inc., New York, New York), a multitargeted small-molecule tyrosine kinase inhibitor with proven antitumor activity against gastrointestinal stromal tumors and renal cell carcinoma, has recently been approved in the United States and Europe for treatment of patients with metastatic or surgically unresectable disease (14). Although the drug is usually well tolerated, patient-reported fatigue noted during clinical trials led to the monitoring of serum thyroid-stimulating hormone (TSH) concentrations to rule out primary hypothyroidism. After the identification of 2 index case-patients who developed primary hypothyroidism, we expanded our observations in patients receiving sunitinib therapy to further define this association. Index case-patient 1, a 39-year-old woman, presented with lower gastrointestinal bleeding and was found to have a gastrointestinal stromal tumor of the stomach wall with several liver metastases. Following surgery to resect the bleeding lesion, she was treated with imatinib mesylate. Within months, serial imaging confirmed disease progression. Imatinib was withdrawn, and she enrolled in a phase I/II clinical study investigating the safety and efficacy of sunitinib. She received sunitinib in repeated 4-week cycles (50 mg/d for 2 weeks, followed by a 2-week washout phase). At initiation of therapy, the patient had an Eastern Cooperative Oncology Group performance status of zero and had no cold intolerance, constipation, fatigue, or other signs of hypothyroidism. Baseline serum TSH concentration was 1.6 mU/L (normal range, 0.5 to 5.0 mU/L). The patient was treated with sunitinib for more than 1 year and had normal serum TSH concentration during this time, except 1 value of 8.8 mU/L at 38 weeks of therapy (Figure 1). During the 60th week of sunitinib therapy, she reported progressive fatigue, confusion, and cold intolerance. Physical examination was notable for myxedema. The results of thyroid function testing showed a serum TSH value of 288 mU/L. l-Thyroxine was administered, and a normal TSH value was achieved, resulting in resolution of symptoms. Figure 1. Biochemical findings of thyroid dysfunction in a patient treated with sunitinib for recurrence of gastrointestinal stromal tumor. The figure depicts sequential thyroid-stimulating hormone (TSH) measurements during 2 years of sunitinib therapy. l-Thyroxine therapy was initiated at week 74. At 92 weeks, the patient was referred from the oncology program to the Division of Endocrinology for consultation at the Brigham and Womens Hospital, Boston, Massachusetts. At that time, the patient appeared clinically euthyroid, and results of thyroid function tests were normal while she was receiving 150 g of l-thyroxine per day. Her thyroid was not palpable, and results on neck ultrasonography showed minimal thyroid tissue. Index case-patient 2, a 38-year-old woman, presented with a metastatic gastrointestinal stromal tumor. She had previously been treated with imatinib for 18 months before developing refractory disease. Imatinib was withdrawn, and the patient began receiving sunitinib in repeated 6-week cycles (50 mg/d for 4 weeks, followed by a 2-week washout period) at a different cancer center. After she developed diarrhea and fatigue, her dose was reduced to 37.5 mg/d. Following 24 weeks of sunitinib therapy, she noted heart palpitations, heat intolerance, dysphagia, and anterior neck pain lasting several weeks. After approximately 30 weeks of therapy, the patient developed progressive fatigue, cold intolerance, hoarseness, and constipation. These symptoms were initially attributed to direct effects of sunitinib in conjunction with systemic effects of her tumor. After 51 weeks of sunitinib therapy, she was referred to the Dana Farber Cancer Institute, Boston, Massachusetts, and her persistent symptoms suggesting hypothyroidism prompted an endocrine consultation. She was extremely hypothyroid, with dry skin, nonpitting edema, absence of palpable thyroid tissue, and delayed relaxation of deep tendon reflexes. The results of a neck ultrasonography showed no visible thyroid tissue (Figure 2). Her TSH level was 101 mU/L; serum thyroxine concentration was 21 nmol/L (1.6 g/dL) (normal range, 64 to 142 nmol/L [5 to 11 g/dL]), her thyroid hormone binding ratio was 0.48 (normal range, 0.8 to 1.2), her free thyroxine index was 0.8 (normal range, 5 to 11), and her thyroid peroxidase antibody was 17.6 U/mL (normal range, 0 to 20 U/mL). The patient was treated with l-thyroxine, 88 g/d, resulting in complete resolution of her symptoms. On the basis of these initial findings in 2 patients receiving sunitinib, we sought to prospectively evaluate thyroid function in patients enrolled in a phase I/II study investigating sunitinib as a treatment for patients with imatinib-resistant gastrointestinal stromal tumors at the Dana Farber Cancer Institute. Methods Patients Between April 2002 and December 2004, 79 patients were treated in a phase I/II trial investigating sunitinib therapy for the treatment of imatinib-resistant gastrointestinal stromal tumors. Most received 50 mg of sunitinib per day in repeated 4- or 6-week cycles, each consisting of 2 to 4 weeks of sunitinib followed by 2 weeks with no therapy. Patients enrolled in this study had stopped receiving imatinib therapy at least 14 days before starting sunitinib therapy. Between April 2002 and September 2002, thyroid function tests were performed only if there was a clinical suspicion of hypothyroidism. Beginning in October 2002, the study protocol was modified to include measurements of serum TSH at the beginning of each sunitinib treatment cycle. In December 2004, the Endocrinology Division began collaborative evaluation of this population. Serum TSH values were available for 69 of 79 patients (87%), 20 of whom were excluded from primary analysis because of abnormal thyroid function or l-thyroxine therapy preceding initiation of sunitinib or because baseline data were not available. Of these 20 patients, 8 patients were receiving l-thyroxine therapy at study entry (6 had begun l-thyroxine therapy before either imatinib or sunitinib therapy, and 3 patients were first tested for thyroid function after treatment with 5 cycles of sunitinib; 9 other patients had abnormal baseline thyroid function (7 had elevated TSH concentrations, and 2 had suppressed TSH concentrations). Seven additional patients with normal baseline thyroid function received sunitinib therapy for less than 3 cycles because of progressive disease or drug intolerance and were also excluded. No participants received medications known to cause thyroid dysfunction, such as iodinated compounds, lithium, or interferon. Thus, we evaluated results in 42 patients with normal baseline thyroid function treated with sunitinib for at least 3 cycles. These 42 patients were treated for a median of 37 weeks (range, 10 to 167 weeks). Biochemical Evaluation and Treatment Patients were screened for thyroid dysfunction by monitoring serum TSH concentration (5, 6). A TSH concentration greater than 5.0 mU/L was considered abnormal. Patients with substantial increases in TSH were further evaluated, and treatment with l-thyroxine was initiated as indicated. Role of the Funding Source The phase I/II trial of sunitinib was funded in part by Pfizer, Inc., and the results of the trial have been reported elsewhere. There was no separate industry funding source for this investigation, and funding played no role in the collection, analysis, and interpretation of these data or in the decision to submit this paper for publication. The institutional review board of the Dana Farber Cancer Institute granted permission to perform these investigations. Results During the phase I/II trial of sunitinib, 15 of 42 (36%) patients developed hypothyroidism after an average of 50 weeks of therapy (range, 12 to 94 weeks) (Table). Of these, 9 had TSH concentrations more than 20 mU/L (mean maximal serum TSH concentration, 100 mU/L) and 6 had TSH concentrations between 7.0 and 20 mU/L. Seven additional patients (17%) had at least 1 TSH concentration between 5.0 and 7.0 mU/L while receiving sunitinib that subsequently normalized. Four patients developed TSH suppression while receiving sunitinib but discontinued the study protocol before repeated thyroid function studies could be performed. In summary, abnormal serum TSH values were documented in 26 of 42 (62%) patients receiving sunitinib. Eastern Cooperative Oncology Group functional status was similar in patients with normal thyroid function and in those who were hypothyroid, suggesting that acute illness did not selectively influence thyroid function in affected patients. Table. Serum Thyroid-Stimulating Hormone Concentrations in 15 Patients Who Developed Hypothyroidism during Sunitinib Therapy for the Treatment of Gastrointestinal Stromal Tumors Six of the 15 (40%

Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure

AIMS To assess the antitumour activity, safety, pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour (GIST) and to assess morning dosing versus evening dosing. PATIENTS AND METHODS In this open-label phase II study, patients were randomised to receive morning or evening dosing of sunitinib 37.5mg/day. The primary end-point was clinical benefit rate (CBR; percent complete responses+partial responses [PRs]+stable disease [SD] 24 weeks). Secondary end-points included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters and plasma biomarker levels. RESULTS Sixty of 61 planned patients received treatment (30 per dosing group); 26 completed the study. Overall, the CBR was 53% (95% exact CI, 40-66): eight patients (13%) achieved objective PRs; 24 (40%) achieved SD 24 weeks. Median PFS was 34 weeks (95% CI, 24-49); median OS was 107 weeks (95% CI, 72 - not yet calculable). Most adverse events (AEs) were of grade 1 or 2 in severity, and were manageable through dose modification or standard interventions. No new AEs were apparent compared with the approved intermittent dosing schedule. Antitumour activity and safety were generally similar with morning and evening dosing. Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles. Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS. CONCLUSION For patients with imatinib-resistant/intolerant GIST, continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety.

Meta-analysis of Vascular and Neoplastic Events Associated with Tamoxifen

OBJECTIVE: Tamoxifen reduces the risk of developing breast cancer but also affects the risks of certain vascular and neoplastic events. Our purpose was to estimate the effects of tamoxifen on potentially life-threatening vascular and neoplastic outcomes.DESIGN: Random effects meta-analysis of published randomized controlled trials.PATIENTS: Participants in all trials in which a treatment arm that included tamoxifen was compared to a similar control arm. Breast cancer risk reduction and treatment trials were included.INTERVENTIONS: Tamoxifen at variable dose and duration.MEASUREMENTS AND MAIN RESULTS: Thirty-two trials (52,929 patients) reported one or more outcomes of interest. Tamoxifen was associated with significantly increased risks of endometrial cancer (relative risk [RR] 2.70; 95% CI, 1.94 to 3.75), gastrointestinal cancers (RR 1.31; 95% CI, 1.01 to 1.69), strokes (RR 1.49; 95% CI, 1.16 to 1.90), and pulmonary emboli (RR 1.88; 95% CI, 1.77 to 3.01). Tamoxifen had no effect on secondary malignancies other than endometrial and gastrointestinal cancers (RR 0.96; 95% CI, 0.81 to 1.13). In contrast, tamoxifen significantly decreased myocardial infarction deaths (RR 0.62; 95% CI, 0.41 to 0.93) and was associated with a statistically insignificant decrease in myocardial infarction incidence (RR 0.90; 95% CI, 0.66 to 1.23). Postmenopausal women had greater risk increases for neoplastic outcomes.CONCLUSIONS: This meta-analysis of randomized trials found tamoxifen use to be significantly associated with several neoplastic and vascular outcomes. Consideration of tamoxifen use requires balance of potential benefits and risks.

Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas

PURPOSE To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. PATIENTS AND METHODS A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [(18)F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. CONCLUSION Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.

Efficacy and Safety of Regorafenib in Patients With Metastatic and/or Unresectable GI Stromal Tumor After Failure of Imatinib and Sunitinib: A Multicenter Phase II Trial

PURPOSE Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. PATIENTS AND METHODS Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. RESULTS From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. CONCLUSION Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib

The oral multitargeted kinase inhibitors (MTKI) sunitinib (SU11248, Sutent; Pfizer, New York) and sorafenib (BAY 43-9006, Nexavar; Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) are increasingly used to treat malignant solid tumors. These small-molecule agents inhibit signaling through receptor tyrosine kinases such as vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and c-KIT, among others (1). In the kidney, glomerular podocytes express VEGF and glomerular endothelial cells express VEGF receptors. Podocyte-specific deletion of a single VEGF allele causes proteinuria and capillary endotheliosis in rodents, and disrupted glomerular VEGF signaling is strongly implicated in the pathogenesis of human preeclampsia (2–4).

Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors

Purpose: Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG2 anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated. Experimental Design: Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1. Results: No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17–300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab. Conclusions: Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.