Supplementary Data from Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure

AIMS:Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.METHODS:The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL).RESULTS:Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related.CONCLUSIONS:Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.

AIMSTwo multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.METHODSThe results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12.RESULTSAt Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12.CONCLUSIONSThese studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

Background: Executive functions (EF) are essential for independence and engagement in complex activities. Neuropsychological and functional evaluations of stroke outcome may be insensitive to subtle EF deficits present in mild stroke (mCVA) despite low NIHSS scores and excellent outcome based on the Barthel Index (BI>95) and Modified Rankin Scale (MRS< 1). We evaluated EF deficits in 25 individuals with first mCVA (admission NIHSS < 5) and 21 matched controls on the Multiple Errands Test-Revised (MET-R). Methods: Inclusion criteria: age > 18 years, first clinical stroke, functional independence (pre-stroke BI >95 and MRS < 1) and community residence at admission and 6 month follow-up. Demographic and clinical information were obtained at acute admission to acute neurology stroke service. Stroke was confirmed by a neurologist and acute imaging reviewed to score stroke lesions and location and white matter disease. Six month follow-up included a neuropsychological test battery, self-reported outcomes by the Stroke Impact Scale (SIS) and Reintegration to Normal Living Scale (RNLI) and the MET-R, a performance test previously used with TBI. The MET-R is a timed test which requires following standard instructions and rules while performing multiple tasks in a real-world environment. Results: Sample mean age was 60 ± 10.8 years; 65% female and 30 % Black, with no significant demographic differences between groups. The mCVA group reported SIS Global Recovery Scores of 68 ± 21.6, Participation Scores of 73.8 ±24.1 and Memory Scores of 77.2 ± 17.5. Differences between controls and the mCVA group were significant for MET-R sub-scores including: Tasks Completed (p<0.0001), Rules Broken (p<0.001), and Performance Efficiency (p <0.002). Poor performance on the MET-R was associated with lower SIS scores and lower life satisfaction and measured by the RNLI. Conclusion: Persons with Persons with mCVA lacking obvious cognitive or motor impairments may be discharged home without rehabilitation or support because currently available measures are inadequate to identify the presence of EF deficits. Subjective complaints of difficulty with cognitively demand activities at follow-up should be evaluated. Rehabilitation can effectively address these deficits.

We evaluated pharmacodynamic changes in tumour perfusion using positron emission tomography (PET) imaging with 15O-water to assess biological response to sunitinib, a multitargeted tyrosine kinase inhibitor.

Abstract Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902–9)

Abstract Purpose: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study. Experimental Design: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis. Results: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40). Conclusions: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings. (Clin Cancer Res 2009;15(18):5869–77)

BACKGROUND:In a randomized, phase 3 trial, sunitinib demonstrated superior efficacy over interferon-alfa as first-line therapy in patients with metastatic clear-cell renal cell carcinoma (RCC). On the basis of outcome data from that trial, the authors developed a nomogram for predicting the probability of 12-month progression-free survival for patients who received sunitinib therapy.METHODS:Three-hundred seventy-five patients who received sunitinib in the phase 3 trial were the subject of the current analysis. Nomogram pretreatment predictor variables included corrected serum calcium levels, the number of metastatic sites, hemoglobin levels, prior nephrectomy, the presence of lung and liver metastases, thrombocytosis, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, and serum levels of alkaline phosphatase and lactate dehydrogenase. Investigator-assessed progression-free survival was the predicted outcome endpoint. Internal validation of the nomogram consisted of quantification of the discrimination with the concordance index and assessment of calibration.RESULTS:One-hundred seventy-four of 375 patients (46%) who received sunitinib achieved an objective response, and the median progression-free survival was 10.8 months (95% confidence interval, 10.6-12.6 months). A nomogram for predicting the probability of 12-month progression-free survival for patients who received sunitinib therapy was constructed on the basis of a Cox regression model from 11 parameters that were determined before treatment. The concordance index was 0.633.CONCLUSIONS:A nomogram was developed from pretreatment clinical features to predict the probability of achieving 12-month progression-free survival with sunitinib therapy for metastatic clear-cell RCC. The authors concluded that independent validation of the nomogram and additional studies to identify tumor-specific prognostic factors are warranted.

10524 Background: SU is an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, FLT3, CSF-1R and RET, approved multinationally for treatment of advanced GIST after IM failure. Interim analysis of a double-blind, PL-controlled phase III trial in this pt population showed a significant difference in OS between pts randomized to SU (50 mg/d administered in 6-wk cycles of 4 wk on treatment, 2 wk off; N=207) or PL (N=105) favoring SU (HR 0.49; P=0.007), without medians having been reached. The study design allowed PL pts to cross over to SU at PD or unblinding of the trial. While efficacy and safety/tolerability continue to be assessed, conventional statistical methods yield biased treatment-effect estimates for mature OS data because of the crossover. Methods: In addition to the log-rank test, Cox model and Kaplan-Meier method, OS was analyzed using the rank-preserving structural failure time (RPSFT) method to account for crossover. Results: Across the entire study (double-blind + open-label phases), 243 pts were randomized to receive SU and 118 pts to receive PL, 104 of whom crossed over to SU. As of Nov. 2007, conventional analysis showed that OS converged in the two treatment groups (SU median 74.7 wk, 95% CI 61.4–85.7; PL 64.9 wk, 45.7–98.4; HR 0.82, P=0.128) as expected, given the crossover design. However, RPSFT analysis yielded an estimated median OS for PL of 36.0 wk (95% CI 25.9–51.0), revealing a significant SU treatment effect (HR 0.46, P<0.0001) comparable to that of the blinded phase. As in the blinded phase, the most common treatment-related AEs throughout the entire study were fatigue, diarrhea, nausea and skin discoloration, mainly grade 1/2; incidences increased slightly with extended SU treatment. The frequencies of hematologic laboratory abnormalities were similar for shorter-term and extended SU treatment. The incidence of cardiac AEs was low with SU across the study (4.3%). Conclusions: Use of RPSFT analysis to account for crossover confirmed the long-term OS benefit provided by SU vs. PL to pts with IM-resistant/intolerant GIST in this phase III study, with implications for other crossover trials. SU demonstrated acceptable, predictable safety with long-term treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc. GlaxoSmithKline, Infinity, MedImmune, Novartis, Pfizer Inc., sanofi-aventis Pfizer Inc. Novartis, Pfizer Inc., PharmaMar, SigmaTau Infinity, Jansen Cilag, Novartis, Pfizer Inc., SigmaTau Infinity, Novartis, Pfizer Inc. Novartis, PharmaMar

PURPOSE:Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC).PATIENTS AND METHODS:Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis.RESULTS:Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during >or= 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions.CONCLUSION:Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.

PURPOSE:Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.PATIENTS AND METHODS:Tumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.RESULTS:Clinical benefit (partial response or stable disease for > or = 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.CONCLUSION:The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

PURPOSE Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients. PATIENTS AND METHODS Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed. RESULTS Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment. CONCLUSION Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.