Originally published as JCO Early Release 10.1200/JCO.2005.02.2194 on November 28 2005
Journal of Clinical Oncology, Vol 24, No 1 (January 1), 2006: pp. 25-35
© 2006 American Society of Clinical Oncology.
Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer
Sandrine Faivre,
Catherine Delbaldo,
Karina Vera,
Caroline Robert,
Stéphanie Lozahic,
Nathalie Lassau,
Carlo Bello,
Samuel Deprimo,
Nicoletta Brega,
Giorgio Massimini,
Jean-Pierre Armand,
Paul Scigalla,
Eric Raymond
From the Department of Medicine, Gustave-Roussy Institute, Villejuif, France; and SU11248 Working Group, Pfizer Co, Rome, Italy and New York, NY
Address reprint requests to Eric Raymond, MD, PhD, Head of the Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du Général Leclerc, Clichy, France; e-mail: eric.raymond{at}bjn.aphp.fr
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ABSTRACT
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PURPOSE: To establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies.
PATIENTS AND METHODS: Sunitinib was given orally for 4 weeks every 6 weeks.
RESULTS: Twenty-eight patients received doses ranging from 15 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses  75 mg/d were reversible grade 3 fatigue, grade 3 hypertension, and grade 2 bullous skin toxicity. Therefore, the recommended dose was 50 mg/d. At this dose, the main adverse effects were sore mouth, edema, and thrombocytopenia. Hair discoloration and yellow coloration of the skin were observed at doses 50 mg/d. Pharmacokinetic data indicate that potentially active target plasma concentrations 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing. Six objective responses were observed in three renal cell carcinomas, one neuroendocrine tumor, one stromal tumor, and one unknown primary adenocarcinoma patient. At higher doses ( 75 mg/d), tumor responses were often associated with reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula.
CONCLUSION: At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.
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INTRODUCTION
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Tyrosine kinase receptors, including platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors, and vascular endothelial growth factor receptors (VEGFRs) and their ligands, have been shown to play important roles in tumor growth and angiogenesis.1 Inhibition of VEGF signaling through the use of antibodies2-4 or VEGFR antagonists has demonstrated potent antitumor effects that might be used to circumvent resistance to classical anticancer agents.5-7 Recently, the humanized anti-VEGF monoclonal bevacizumab antibody in combination with chemotherapy was associated with an increased survival in patients with advanced colon cancer.8
Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY; Fig 1) is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib has been identified as a potent inhibitor of VEGFR-1, VEGFR-2, fetal liver tyrosine kinase receptor 3 (FLT3), KIT (stem-cell factor [SCF] receptor), PDGFR , and PDGFRß in both biochemical and cellular assays.9,10 In vitro, sunitinib inhibited growth of cell lines driven by VEGF, SCF, and PDGF and induced apoptosis of human umbilical vein endothelial cells.10 In vivo, sunitinib caused bone marrow depletion and effects in the pancreas in rats and monkeys, as well as adrenal toxicity in rat (microhemorrhage). In monkeys, a slight increase in arterial blood pressure and QT interval were reported at higher doses (investigator brochure). Sunitinib exhibited dose- and time-dependent antitumor activity in mice, potently repressing the growth of a broad variety of human tumor xenografts.10-14
In vitro metabolism studies demonstrated that sunitinib was primarily metabolized by cytochrome CYP3A4, resulting in formation of a major, pharmacologically active N-desethyl metabolite, SU012662. This metabolite was shown to be equipotent to the parent compound in biochemical tyrosine kinase and cellular proliferation assays, acting toward VEGFR, PDGFR, and KIT.15 SU012662 was the major plasma metabolite in mice, rats, and monkeys in vivo. SU012487 (an N-oxide metabolite) was the major metabolite in dog but was infrequently observed in human. Radiolabeled orally administrated sunitinib in preclinical species was primarily excreted in the feces (rat, > 71%; monkey, > 84%; investigator brochure). Pharmacokinetic/pharmacodynamic data from animal studies showed that target plasma concentrations of sunitinib plus SU012662 capable of inhibiting PDGFR-ß and VEGFR-2 phosphorylation were established in the range of 50 to 100 ng/mL.9-12 Interestingly, those data were consistent with those observed in patients with acute myeloid leukemia in whom exposure to sunitinib led to a sustained inhibition of FLT3 phosphorylation in blast cells.16 Although initial studies were planned to provide continuous administration, the 4-week-on, 2-week-off schedule was selected at the request of the health authorities to allow patients to recover from potential bone marrow and adrenal toxicity observed in animal models.
On the basis of the promising preclinical antitumor activity, safety data in animals, and early results in phase I clinical trial in patients with acute myeloid leukemia,17 this phase I dose-escalation study was undertaken to determine the recommended dose, tolerability, basic pharmacokinetics, and antitumor effects of sunitinib given orally daily for 4-week-on, 2-week-off schedule in patients with advanced solid malignancies.
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PATIENTS AND METHODS
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Eligibility Criteria
Patients with histologically proven advanced solid malignancy for which no other therapy was possible, with an Eastern Cooperative Oncology Group performance status  2, were included in the study. Eligible patients were women (postmenopausal, surgically sterile, or using effective contraception) or men 18 years of age with adequate bone marrow, liver, and renal function (hemoglobin level 10 g/dL, absolute neutrophil count 1.5 x 109/L, platelet count 75 x 109/L, serum transaminases < 2.5 times the upper limit of normal [ULN], bilirubin < 1.5 x ULN, serum creatinine < 1.5 x ULN, or creatinine clearance > 40 mL/min). Patients were not eligible if they had failed to recover from toxicity of previous chemotherapy, radiotherapy, or immunotherapy or had received any anticancer agent within 4 weeks, including investigational agents, chemotherapy (within 6 weeks for nitrosoureas or mitomycin), immunotherapy, biologic or hormonal therapy, or surgery. Other exclusion criteria included a history of any malignancy other than in situ carcinoma of the cervix or basal-cell carcinoma of the skin, known CNS metastases, or prior cardiovascular disease or diabetes mellitus. Written informed consent was obtained from all patients, and approval from our institutional review boards was obtained.
Pretreatment and Follow-Up Examinations
Complete medical history, physical examination, Eastern Cooperative Oncology Group performance status, CBC with differential and platelet count, biochemical profile (including electrolytes, renal, and hepatic function, coagulation, cortisol, pancreatic amylase, and lipase), urinalyses and ECGs (12-lead ECGs or 24-hour holter) were recorded before starting treatment and repeated on days 2, 4, 7, 10, 13, 16, 19, 22, 25, and 28 during the first cycle of therapy (cortisol on days 2, 10, 22, and 28), then weekly thereafter. ECG and/or 24-hour holter were collected on day 28 in subsequent cycles. A 12-lead ECG and a chest x-ray were obtained within 14 days before receiving sunitinib and repeated every 4 weeks. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Tumors were measured by computed tomography/magnetic resonance imaging scans 4 weeks before starting sunitinib, after 6 weeks, then every third cycle, and at study discontinuation. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors guidelines.
Drug Administration
Sunitinib was supplied as capsules of 25 and 50 mg for oral administration. Sunitinib was given continuously for 4 weeks followed by 2 weeks off treatment. This 6-week time period was defined as a treatment cycle.
Dose Escalation Procedure
Based on animal toxicology and pharmacokinetic data, the starting oral dose of sunitinib was 30 mg/m2 every 2 days (15 mg/m2/d). This study was designed with predetermined dose levels. According to the classical design of phase I studies, the body-surface area (BSA) dosing was initially used. At the time of the study, only 25-mg and 50-mg capsules were available, and therefore the total dose was rounded up to the nearest 25 mg according to BSA. During the course of the study, pharmacokinetic analysis revealed that variability in exposure was not reduced by normalizing for BSA (see Pharmacokinetic Analysis). Analysis of toxicity and data were subsequently presented according to flat dosing corresponding to 50 mg/d (30 mg/m2), 75 to 100 mg/d (42 mg/m2), and 100 to 150 mg/d (59 mg/m2). Hematologic dose-limiting toxicity (DLT) was defined as at least a grade 4 hematologic toxicity or grade 3 thrombocytopenia accompanied by a grade 3 or greater hemorrhage. Nonhematologic DLTs were defined as any grade 3 or greater adverse event that was considered related to the study drug except nausea and vomiting that responded to antiemetic therapy.
Doses were escalated based on occurrence of DLT at cycle 1. If no DLT was seen in three patients during the first cycle, the dose was increased to the next level. If DLT was observed during the first cycle in one patient at any dose level, three additional patients were recruited to that dose level for a total of six patients, with dose escalation proceeding if two of six patients exhibited DLT. If DLT was observed in two of three or three of six patients at any dose level, additional patients were recruited to that dose level for a total of at least nine patients. If DLT was observed in three or more patients, the maximum-tolerated dose (MTD) had been exceeded, and additional patients were recruited to expand the dose level immediately below MTD for a total of at least nine patients. The MTD was defined as the dose level at which less than 33% of the patients would experience DLT at cycle 1.
Treatment could not be delayed for more than 2 weeks for the patient to recover from toxicities. Dose reduction to the next lower dose level was allowed in response to unacceptable toxicity if the patient exhibited evidence of clinical benefit. If unacceptable toxicity occurred after this dose reduction, treatment was stopped.
Bioanalytical Method
Blood samples (3 mL each) for determination of sunitinib and SU012662 plasma levels were collected on day 1 and 28 of each cycle, before dosing and hourly at 1 to 8 hours and at 10, 12, and 18 (or 20) hours after dosing. Steady-state level samples were also collected on days 4, 7, 10, 13, 16, 19, 22, and 25. Blood samples were centrifuged at 4°C for 10 minutes, plasma was separated and split in two 1.5-mL Nalgene cryovials (Nalgene, Rochester, NY) and stored at –80°C protected from light until analysis. Similar to previous publications,17 mean plasma concentrations of sunitinib and SU012662 were determined using liquid chromatography-tandem mass spectrometry (LC-MS-MS), with a lower limit of detection of 0.099 ng/mL for sunitinib and 0.088 ng/mL for SU012662.
Blood samples for determination of plasma levels of VEGF and soluble VEGFR were collected predose and 6 hours postdose on day 1 and 28. Samples were centrifuged (3,500 rpm for 5 minutes) and plasma was isolated and frozen at –20°C until analysis. VEGF/soluble VEGFR concentrations were determined by enzyme-linked immunosorbent assay according to the manufacturer's instructions (R&D Systems, Minneapolis, MN). Analysis was performed using two ways of analysis of variance (SAS, SAS Institute, Cary, NC).
Pharmacokinetic Analyses
Concentration-versus-time data for sunitinib and SU012662 were analyzed using a noncompartmental analytic technique. Peak concentration, half-life, area under the concentration-time curve (AUCt), clearance, and steady-state volume of distribution were calculated. The oral clearance was calculated on day 28 only for sunitinib, calculated as dose/AUC0-24 for patients who received a daily dose regimen. Dose represented the dose of sunitinib free base. Sums of sunitinib plus SU012662 AUCs (AUC sum) were calculated (without adjusting for modest differences in molecular weight). To preliminarily assess the proportionality of exposure with dose, an exponential regression model was used to describe the relationship between peak concentration, AUC, and AUC sum versus dose. Software packages used for this study were Statistical Analysis System (SAS Institute, Cary, NC) version 6.12 and WINNonlin version 3.2 (PharSight Corp, Mountain View, CA).
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RESULTS
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General
Twenty-eight patients were enrolled between June 2001 and September 2003 (Table 1). Twenty-seven patients received at least 4 weeks of sunitinib treatment and were assessable for toxicity (one patient was included but was not considered assessable because of an early tumor progression).
No DLT was observed at starting doses of 30 mg/m2 every other day, which corresponded to 50 or 100 mg every other day (three patients; Table 2). Among the first three patients treated at the second dose-level of 50 mg/d, one patient developed grade 3 edema of the limbs and face. Because the three additional patients who were therefore enrolled did not develop DLT, dose escalation proceeded to 75 to 100 mg/d. None of those three patients receiving 75 mg/d experienced DLTs during cycle 1, and dose escalation proceeded to 100 to 150 mg/d. At this later dose, reversible grade 3 hypertension was observed in one patient and grade 3 asthenia was reported in the other two patients (one patient receiving 100 mg/d and another 150 mg/d). Therefore, the MTD had been exceeded, and nine additional patients were enrolled at the dose of 75 mg/d. Five of 12 patients treated at 75 to 100 mg/d (11 patients receiving a total of 75 mg/d and one patient receiving 100 mg/d) developed DLT at cycle 1 (grade 3 asthenia in three patients, grade 3 hypertension in one patient, and tumor necrosis in one patient [described herein]). Four of the patients receiving a total dose of 75 mg/d at cycle 1 were dose-reduced and treated at 50 mg/d without DLT. Because more than 33% of patients receiving 75 mg/d experienced DLTs at cycle 1, the next lower dose of 50 mg/d was further evaluated by entering three additional patients. Among a total of nine patients who received 50 mg/d, two patients developed DLT: grade 3 edema and grade 4 peripheral thrombocytopenia. Thrombocytopenia was associated with the presence of normal well-differentiated megacaryocytes in bone marrow aspiration, no activation of coagulation, and grade 2 hemolytic anemia with schizocytes, beta 2-microglobulin, and lactate dehydrogenase elevation, suggesting a microangiopathy.
Overall Safety After Repeated Cycles
Grade 3 to 4 adverse events per patient and per cycle are summarized in Table 3. Asthenia was the most frequent grade 3 to 4 toxicity at doses 50 mg/d. Asthenia appeared progressively from grade 1 during the first 2 weeks and worsened slightly to grade 3 to 4 during weeks 3 and 4 of each cycle. It was associated with an increased length of rest period during daytime and sleepiness at night. Asthenia was fully reversible during the 2-week-off period of each cycle. Grade 3 to 4 asthenia occurred in six of 12 patients at 75 to 100 mg/d but was restricted to two of nine patients at the recommended dose of 50 mg/d. Age and performance status at study entry did not predict asthenia, and this event was not associated with neurologic symptoms or tumor progression. Grade 3 to 4 nausea and vomiting were infrequently reported.
Hypertension was observed in a total of five patients and required antihypertensive treatment (grade 3 to 4) in two patients treated at doses 75 mg/d. Hypertension usually occurred after 3 to 4 weeks of treatment. After normalization of blood pressure, antihypertensive therapy was maintained during the 2 weeks-off period with twice weekly monitoring. At the recommended dose of 50 mg/d, only one patient presented grade 1 to 2 elevated blood pressure. Careful cardiac monitoring occurred and no cardiac adverse event was reported.
Hematologic toxicity, consisting mostly of thrombocytopenia and neutropenia, resolved during the 2 weeks off in most cases and recurred in subsequent cycles with the same dose.
Skin toxicity typically occurred after 3 to 4 weeks of treatment. Grade 2 reversible symmetric palm and sole acral erythemas (Figs 2A, 2B, 2C) were observed in five of 28 patients at doses 75 mg/d. Rapidly healing painful bullous lesions (cycles 1 to 3 in five patients), predominantly located on the lateral aspect of the fingers, showed endothelial cell modifications in dermal capillaries with capillary dilation, endothelial cell distention/apoptosis, and vascular fibrinoid necrosis (Fig 2D) in biopsy. In addition, skin adjacent to a bullous lesion showed an intraepidermal cleavage with dispersed necrotic keratinocytes without inflammatory infiltrate. Immunostaining for KIT, PDGFR, and PDGFRß showed no difference between areas of normal skin and bullous lesions (data not shown). Grade 1 to 2 edema was predominant on the eyelids but without weight increase; dry skin, stomatitis, and sore mouth were also frequently reported. Two patients had grade 1 to 2 bipolar erosions consisting of stomatitis with perianal and penile erosions. Histologic examination of the perianal lesion showed a dermal leukocytoclastic vasculitis and superficial epidermis erosions; bacterial and viral cultures were negative.
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Fig 2. Sunitinib skin toxicity consisted of (A) painful periungual erythema, (B) bullous lesions on the fingers, (C) plantar areas with erythema that consisted of hyperacanthosis, intraepidermal cleavage, and (D) microscopic examination.
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Minor Skin Effects
Yellow skin coloration appeared after 1 week of treatment in patients receiving 50 mg/d of sunitinib and increased in intensity at the highest doses. Transient skin coloration was associated with a yellow coloration of urine due to the excretion of the drug and metabolites.
Various degrees of hair depigmentation (gray coloration) occurred in 18 of 28 patients who received doses 50 mg/d of sunitinib (Figs 3A through 3D). Hair depigmentation was visible after 5 to 6 weeks (2 to 3 weeks in men with facial hair) of treatment, and this was reversible 2 to 3 weeks after treatment discontinuation. In some patients, successions of depigmented and normally pigmented bands correlated with on and off periods of treatment (Fig 3E). Scalp skin biopsies of two patients showed that hair follicles associated melanocytes were still present. No alopecia was observed.
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Fig 3. Sunitinib-induced hair depigmentation. In patients with (A) no gray hair before treatment; (B) facial hair; (C) eyelashes; (D) hair will progressively grow discolored under exposure to sunitinib; and (E) hair discoloration was reversible during the washout period.
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Asymptomatic subungual splinter hemorrhages (consisting of a mass of blood in a layer of squamous cells adherent to the undersurface of the nail; Fig 4) were found in seven patients, associated with acral erythema in six patients.
Pharmacokinetic and Pharmacodynamic Analysis
Pharmacokinetic parameters of sunitinib and its major metabolite SU012662 are summarized in Tables 4 and 5. Overall, sunitinib displayed a long half-life and a large volume of distribution with moderate interpatient variability. Trough plasma concentrations of sunitinib and SU012662 increased with increasing dose (Fig 5A). However, AUC values increased less than proportionally with doses. Accumulation ratios of sunitinib were greater than one with detectable trough drug levels, suggesting drug accumulation over time. At the recommended dose, the maximum plasma concentration occurred approximately 5 hours after administration and half-life ranged from 41 to 86 hours. Doses of 50 mg/d led to plasma concentration ranging from 50 to 100 ng/mL. Most patients with DLT had combined (sunitinib plus SU012662) trough plasma concentrations 100 ng/mL (Fig 5B).
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Fig 5. Trough plasma levels of (A) sunitinib (SU11248) and (B) its metabolite SU012662; (C) combined (SU11248 + SU012662) through plasma levels in individual patients treated with sunitinib at increasing doses.
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To assess the need for dosing based on BSA, a simulation was performed in which observed values for AUC sum based on the 30, 42, and 59 mg/m2/d doses were adjusted to reflect fixed doses of sunitinib of 50, 75 to 100, and 100 to 150 mg, respectively. Simulated AUC sum values were approximated based on the actual AUC sum and the actual dose (in milligrams) each patient received during cycle 1. The degrees of variability between BSA-normalized and fixed dosing were comparable at days 1 and 28 for both sunitinib (R2 range, 0.002 to 0.12) and SU012662 (R2 range, 0.0004 to 0.085), and no or minimal improvement in variability would be expected from normalizing the dose based on BSA.
VEGF concentrations increased slightly during the first month of treatment with sunitinib (Fig 6A). This was associated with a decrease in the mean sVEGFR-2 level in plasma in our trial (Fig 6B).
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Fig 6. Vascular endothelial growth factor (VEGF) concentrations (A) tend to increase after 28 days of treatment with sunitinib (SU11248), whereas; (B) sVEGFR2 concentrations decrease. Spots represent individual patient data with means (•–) and standard deviation (two-sided P values comparing data at days 1 and 28 at 24 hours are .04 and < .001 for VEGF and sVEGFR2, respectively).
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Antitumor Effects
Among 22 assessable patients, sunitinib induced tumor shrinkage and tumor necrosis. As shown in Table 6, six patients had objective responses: four prolonged partial responses and two cases of more than 90% central tumor necrosis with viable cells in peripheral areas on postoperative pathologic specimens. Responses were observed in three patients with local and/or lung metastasis of renal cell carcinomas (lasting 28, 36, and 54 weeks), in one patient with bulky peritoneal recurrences of a neuroendocrine tumor (lasting 21 weeks) and in one patient with lung metastases of an adenocarcinoma of unknown primary, and one patient with a peritoneal recurrence of an imatinib mesylate resistant gastrointestinal stromal tumor (GIST; Fig 7). In addition, five patients (with renal cell carcinoma, cervical carcinoma, and a neuroendocrine tumor) developed long-lasting minor responses and tumor stabilization.
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Fig 7. Computed tomography scans showing objective responses in patients treated with sunitinib. (A, B) Baseline and post-treatment scans of patients with lung metastasis from renal cell carcinoma; (C, D) peritoneal recurrence of rectal neuroendocrine tumor; and (E, F) lung metastasis of carcinoma of unknown primary showing objective responses.
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Six patients developed evidence of tumor necrosis that led to tumor cavitations in four patients with further development of fistula in two patients (local recurrences of a cervical and neuroendocrine tumor in irradiated areas), lethal peritoneal hemorrhage in one patient (peritoneal recurrence of GIST), and infection of necrotic area in the lung in another patient (lung metastasis of undifferentiated carcinoma of nasopharyngeal type). High-frequency ultrasound Doppler echography18 performed in these six patients revealed that intratumoral vessels progressively disappeared after 1 week of treatment, with an increase of necrosis in the central areas of tumors (Fig 8). Consistent with evidence of antitumor activity and necrosis, lactate dehydrogenase levels increased during cycle 1 in several patients.
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Fig 8. Antivascular effects of sunitinib. (A) Baseline; (B) 1 week after treatment; (C) 2 weeks after treatment; (D) 4 weeks after treatment. Arrows indicate areas of necrosis and vascularization. As short as 1 week of treatment with sunitinib reduces the number of vessels in tumors as measured with high-frequency ultrasound echography.
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DISCUSSION
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Multitarget signaling inhibitors have recently been proposed as a new paradigm to enlarge the spectrum of activity of targeting agents. In this study, asthenia and hypertension were found to be the main DLTs of sunitinib at doses 75 mg/d. The occurrence of DLTs was associated with combined trough sunitinib/SU012662 plasma levels more than 100 ng/mL. Based on safety data from patients entered at the 50 mg/d dose level and those nine patients treated at higher doses and subsequently dose-reduced to 50 mg/d, this dose of 50 mg/d for 4 weeks every 6 weeks was recommended for further phase II trials. AUC sum values obtained using BSA-normalized and fixed dosing were found to be comparable, suggesting that normalizing the dose based on BSA would not improve variability. Fixed dosing on a milligram basis was therefore considered appropriate for phase II studies.
The adverse-event profile of sunitinib in our study was consistent with observations in other phase I trials in patients with acute myeloid leukemia and solid tumors exploring alternative schedules.16,17 Hypertension and asthenia have been observed with several other inhibitors of VEGF and VEGFRs.3,4,7 Other adverse events were skin toxicity, including dry skin, edema, and hand-foot syndromes with/without bullous lesions, observed only at doses 75 mg/d. The most consistent histologic changes were dermal vascular modifications with slight endothelial changes in grade 1 to 2 hand-foot syndromes and more pronounced vascular alterations with scattered keratinocyte necrosis and intraepidermal cleavage in grade 3 hand-foot syndromes and peribullous lesions. Sunitinib induces endothelial cell apoptosis in vitro and in animal tumor models,18 and pathologic changes observed in this study suggest that dermal vessel alteration and apoptosis might be due to direct anti-VEGFR and/or -PDGFR effects of sunitinib on dermal endothelial cells. Consistent with the effects of sunitinib on dermal endothelial cells, asymptomatic subungual splinter hemorrhages was observed in several patients,19 associated in one case with thrombocytopenia suggesting microangiopathy. Thrombosis has been reported in several other trials of drugs that target VEGF and VEGFRs20,21 and was observed in two patients in this study. A recent study showed that exposure to SU5416, another multitargeted tyrosine kinase inhibitor that blocks VEGFR, increased the susceptibility of endothelial cells to damages by cisplatin and gemcitabine.22 Taken together, these results reinforce the hypothesis suggesting that VEGF plays a role as a protection factor for endothelial cells.
Reversible hair depigmentation was observed with sunitinib at 50 mg/d. Persistence of melanocytes associated with hair follicles indicated that sunitinib did not affect the migration and survival of melanocytes. It is known that hair pigmentation is dependent on modulation of tyrosinase-related protein 1 genes and tyrosinase, related to KIT signaling pathway.23-25 Blocking KIT/PDGFR with imatinib mesylate induced skin depigmentation,26 but paradoxically caused hair repigmentation.27 Therefore, the graying effects of sunitinib may be related to multiple signaling pathways inhibition, including KIT, PDGFR, and VEGFR.28,29 Interestingly, gray hair might be regarded as a potential surrogate marker to monitor sunitinib observance and biologic effects.
Although tumor evaluation was not the primary objective of this study, objective responses (four partial responses and two stable diseases with intratumoral necrosis) were observed at doses of sunitinib 50 mg/d. These responses occurred in patients with highly vascularized tumors (such as renal and digestive neuroendocrine tumors). In patients with stable disease and intratumoral necrosis, cytoreductive surgery provided pathologic confirmation of more than 90% tumor necrosis, and they were reclassified as pathologic responses to sunitinib. A similar feature was previously reported in patients with GIST being treated with imatinib mesylate, showing prolonged stable diseases with tumor necrosis and/or early inhibition of intratumoral metabolic activity as measured using [18F]fluorodeoxyglucose positron-emission tomography.30 In another study, sunitinib was shown to rapidly inhibit the uptake of glucose using [18F]fluorodeoxyglucose positron emission tomography in patients with GIST31 as well as other malignancies.32
In this study, tumor necrosis could result in fistula formation, infection, eventually associated with lactate dehydrogenase elevation and rapid disappearance of intratumoral blood flow using ultrasound. Necrosis was also reported with bevacizumab treatment in patients with lung cancer.33 The necrosis induced by bevacizumab and sunitinib underlines the important role of VEGF/VEGFR signaling in the maintenance of tumor vasculature. Future studies may consider including prospective imaging techniques, such as high frequency ultrasound, to monitor tumor density.
In conclusion, based on evidence of antitumor activity, phase II trials have been initiated in patients with renal cell carcinoma, neuroendocrine tumors, and GIST resistant to imatinib mesylate.34 Considering the good safety profile at the recommended dose, other schedules are currently being investigated using 2-week-on, 2-week-off, and continuous sunitinib administration.
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Authors' Disclosures of Potential Conflicts of Interest
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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
| Authors |
Employment |
Leadership |
Consultant |
Stock |
Honoraria |
Research Funds |
Testimony |
Other |
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| Carlo Bello |
Pfizer (N/R) |
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| Samuel Deprimo |
Pfizer (N/R) |
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| Nicoletta Brega |
Pzifer (N/R) |
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| Giorgio Massimini |
Pfizer (N/R) |
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| Paul Scigalla |
Pfizer (N/R) |
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Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
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Author Contributions
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| Conception and design: Sandrine Faivre, Eric Raymond
Financial support: Carlo Bello, Samuel Deprimo, Nicoletta Brega, Giorgio Massimini, Paul Scigalla
Administrative support: Carlo Bello, Samuel Deprimo, Nicoletta Brega, Giorgio Massimini, Eric Raymond, Paul Scigalla
Provision of study materials or patients: Sandrine Faivre, Catherine Delbaldo, Karina Vera, Caroline Robert, Nathalie Lassau, Carlo Bello, Jean Pierre Armand, Eric Raymond, Paul Scigalla
Collection and assembly of data: Sandrine Faivre, Catherine Delbaldo, Karina Vega, Stéphanie Lozahic, Jean Pierre Armand, Eric Raymond
Data analysis and interpretation: Sandrine Faivre, Catherine Delbaldo, Karina Vera, Stéphanie Lozahic, Eric Raymond
Manuscript writing: Sandrine Faivre, Eric Raymond
Final approval of manuscript: Sandrine Faivre, Catherine Delbaldo, Karina Vera, Caroline Robert, Nathalie Lassau, Carlo Bello, Nicoletta Brega, Jean Pierre Armand, Eric Raymond
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Acknowledgment
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We thank the nurses of the GARD unit for their contribution to the pharmacokinetic sampling of this study; and Siham Djelloul-Ceballos, William Sargent, and Marie-Pierre Chevalier from Pfizer Inc, for their critical reading of the manuscript.
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NOTES
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S.F. and C.D. contributed equally to this work.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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REFERENCES
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Submitted April 4, 2005;
accepted September 22, 2005.
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TOP
ABSTRACT
INTRODUCTION
