Silvana Lanzalone

Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial

PURPOSEnOpen-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer.nnnPATIENTS AND METHODSnPatients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS).nnnRESULTSnEarly trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%).nnnCONCLUSIONnOS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study

BACKGROUNDnHepatocellular carcinoma (HCC) tumour spread is partly dependent on neoangiogenesis. In this open-label, multicentre, phase II trial done in Europe and Asia, sunitinib, a multitargeted tyrosine-kinase inhibitor with anti-angiogenic properties, was assessed in patients with advanced unresectable HCC.nnnMETHODSnBetween February and July, 2006, eligible patients were enrolled and treated with repeated cycles of oral sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off treatment). The primary endpoint of this Simon two-stage phase II trial was objective response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, with an expected response rate of 15%. This trial is registered with ClinicalTrials.gov, number NCT00247676.nnnFINDINGSnOf 37 patients enrolled, one (2.7%) patient experienced a confirmed partial response, giving an overall objective response rate of 2.7% (95% CI 0.1-14.2); on the basis of this, the trial did not proceed to the second stage. 13 (35%) of 37 patients achieved stable disease for over 3 months. Commonly observed grade 3 and 4 adverse events included thrombocytopenia (14 of 37; 37.8%), neutropenia (nine of 37; 24.3%), asthenia (five of 37; 13.5%), hand-foot syndrome (four of 37; 10.8%), and anaemia (four of 37; 10.8%). There were four deaths among the 37 patients (10.8%) that were possibly related to treatment.nnnINTERPRETATIONnSunitinib showed pronounced toxicities at a dose of 50 mg/day in patients with unresectable HCC. The response rate was low, and the study did not meet the primary endpoint based on RECIST criteria.nnnFUNDINGnPfizer Oncology.

Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study

PURPOSEnTo determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated.nnnMETHODSnPatients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m(2) days 1, 8) and cisplatin (80 mg/m(2) day 1).nnnRESULTSnA total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses.nnnCONCLUSIONSnThe MTD was identified as sunitinib 37.5mg (Schedule 2/1), gemcitabine 1250 mg/m(2), and cisplatin 80 mg/m(2), with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination.

Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib

BackgroundSeveral proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.MethodsPatients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).ResultsAt the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.ConclusionsBaseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.Trial registrationClinicalTrials.gov: NCT00247676

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250u2009mg twice daily; 3u2009week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. Trial registration number Phase 2 trial (NCT00932451); Results.

Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer

BackgroundnIn clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes.nnnPatients and methodsnData were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively.nnnResultsnOf 11xa0081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (nu2009=u2009700/1246), 55% (nu2009=u2009725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (nu2009=u200925/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, Pu2009=u20090.054; PFS, Pu2009=u20090.17).nnnConclusionsnPatients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Abstract CT117: Evaluation of the effect of crizotinib (CRZ) on the QT interval in patients with ALK-positive non-small cell lung cancer (NSCLC)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAnnBackground: CRZ is an oral tyrosine kinase inhibitor approved for the treatment of ALK-positive NSCLC at a starting dose of 250 mg BID. An ECG substudy was conducted to evaluate and quantitate any potential impact of CRZ on corrected QT interval (QTc). This ECG substudy enrolled patients with ALK-positive advanced NSCLC at selected sites from the phase III trial PROFILE 1007 and the phase II trial PROFILE 1005.nnMethods: All patients enrolled in the ECG substudy received CRZ 250 mg BID orally on a continuous basis. Triplicate 12-lead ECG measurements, approximately 2 minutes apart, were collected after a fast of at least 1 hour at predose, 4 and 8 hours following morning CRZ dosing on Day 1 of Cycle 1, and predose, 2, 4, 6 and 8 hours following morning CRZ dosing on Day 1 of Cycle 2 (1 Cycle = 21 days). All ECG tracings from this substudy were sent to an independent ECG laboratory for blinded manual interval measurements. Plasma PK samples for CRZ and its metabolite, PF-06260182, were collected at respective times immediately following each ECG measurement. ECG endpoints included QT interval corrected for heart rate (HR) using Fridericias (QTcF) (primary endpoint) and Bazetts (QTcB) formulas and a model-based study-specific correction factor (QTcS), PR interval, RR interval, and QRS complex. Categorical analysis was conducted for all QTc endpoints. ANOVA was performed for QTcF and QTcS, the QTc with the most appropriate HR correction. These analyses were performed using the ECG Evaluable Population (EEP), defined as all treated patients with an adequate baseline assessment and at least 1 adequate ECG measurement on Cycle 2 Day 1 (at CRZ steady state). A pharmacokinetic/pharmacodynamic analysis was performed using the ECG-PK matched dataset.nnResults: A total of 65 patients were enrolled in the ECG study, and 52 were in the EEP. ANOVA revealed that all upper limits of the 90% confidence intervals for the least squares mean changes from baseline in QTcF at all Cycle 2 Day 1 time points were <20 ms. The largest LS mean change from baseline was an increase of 12.3 ms, reported at 6 hours post morning dose on Cycle 2 Day 1. No patients had a maximum QTc ≥500 ms and 1 (1.9%) patient had a QTc increase from baseline of ≥60 ms. Consistently with previous findings, mean steady state predose (Ctrough) and maximum plasma concentrations (Cmax) of CRZ were 271 ng/mL and 345 ng/mL, respectively, and mean steady state Ctrough and Cmax of metabolite PF-06260812 were 86.7 ng/mL and 107 ng/mL, respectively. A relationship was observed between CRZ plasma concentration and QTc. HR decreased with increasing CRZ plasma concentration, as reported previously in other studies.nnConclusions: Based on ANOVA results from this substudy, a large QTc effect (≥ 20 ms) by CRZ can be excluded however a smaller increase in QTc cannot be ruled out. Periodic ECGs monitoring should be considered for patients who have a history of QTc prolongation or who are taking medications that prolong QT.nnCitation Format: Weiwei Tan, Keith D. Wilner, Silvana Lanzalone, Anna Polli, Matthew L. Zierhut, Dana Nickens, Kenneth J. OByrne, Fiona H. Blackhall, Alice T. Shaw, Ravi Salgia, Jesus Correl Jaime, Dong-Wan Kim. Evaluation of the effect of crizotinib (CRZ) on the QT interval in patients with ALK-positive non-small cell lung cancer (NSCLC). [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 CT117. doi:10.1158/1538-7445.AM2015-CT117