Sunitinib Arm Research Articles

Efficacy and safety of sunitinib and everolimus as front-line treatment for nonclear cell RCC: A pooled-analysis from randomized trials.

e16069 Background: Non-clear Renal cell carcinoma (non-ccRCC) accounts for about 25% of all RCC and generally is responsible for a poorer outcome in metastatic setting. Optimal treatment for patients with metastatic non-ccRCC has not been established yet; therefore Sunitinib and Everolimus still represent two feasible options as frontline therapy, given the results reported from single-arm trials and expanded access studies. Hence, we provided a pooled analysis from prospective randomized trials to evaluate the benefit and risks of these therapies for patients with metastatic-non-ccRCC. Methods: A systematic search of literature was carried out using Medline, Embase, ESMO and ASCO library with no data restriction up to December 2016, to identify relevant studies on this topic. Eligible studies had to fulfill the following criteria: randomized prospective trial comparing the efficacy of Sunitninb and Everolimus as first line therapy in patients with m-non-ccRCC. Studies excluded: non-randomized prospective trials, subgroup analysis data deriving from randomized prospective trials carried out on metastatic ccRCC population. No language restriction was applied. Data were pooled using RevMan 5.3 software. Results: The literature search identified 29 potential titles and abstracts of whom only 2, recruiting a total of 176 metastatic-non ccRCC patients (Sunitinib: 84, Everolimus: 92), fulfilled our eligible criteria and were included in the pooled analysis. A trend towards better outcome in terms of PFS and OS was reported among patients with non-cc RCC enrolled in Sunitinib arm. Sunitinib vs Everolimus: PFS [HR]:0,83 [0,38-1,78]; OS [HR]: 0,67 [0,37-1,21]. Moreover Sunitinib was associated with more Grade 3-4 adverse events HR: 3.06 [1,60-5,84]. Conclusions: This pooled analysis reported a trend towards favoring Sunitinib versus Everolimus for the first line treatment of patients with metastatic non-ccRCC, although statistical significance was not reached. Sutent was associated with more Grade 3-4 toxicieties. Further prospective randomized phase III trials are required to clarify the better therapeutic option for this subset of patients.

Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma?

AimPazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker. MethodsData from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed. ResultsAnalyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN. ConclusionNeither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study.

BackgroundSunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer.MethodsPatients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life.ResultsEnrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm.ConclusionWhile the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer.

Correlation of PDL1 tumor expression and treatment outcomes in patients with renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors: COMPARZ study analysis.

416 Background: The interaction of PDL1 (B7H1) with its receptor PD-1 on activated T cells contributes to suppression of antitumor immune responses. Tumor PDL1 expression has been associated with poor outcomes in RCC but has not been investigated as a biomarker of response in RCC patients receiving standard vascular endothelial growth factor (VEGF)-targeted therapy. Methods: Formalin-fixed paraffin-embedded tumor samples were collected at baseline from consenting patients enrolled in COMPARZ—a phase lll clinical trial comparing pazopanib and sunitinib as first-line interventions for metastatic RCC (Motzer et al, NEJM 2013). PDL1 expression was evaluated using the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) on the Leica automated immunohistochemistry platform. Additional dual PDL1/CD68 staining was performed on tumor associated macrophages (TAMs). Tumor PDL1 expression was quantified by an H-score (HS). PDL1+ TAMs were assessed semiquantitatively. In addition, intra-tumor CD8+ T cells were quantified morphometrically. The association between PDL1 HS, CD8+T cell counts, and survival was investigated using Kaplan-Meier analysis. Results: HS data were available from 453 of 1110 patients. 64% of patients had negative (HS = 0) PDL1 expression (HS range 0-290), but PDL1 expression was associated with tumours containing higher numbers of infiltrating macrophages. Peripheral CD8+ T cells in the invasive margin surrounding the tumor were also observed. Patients with HS >50 (n = 61, 13%) had significantly shorter overall survival (OS) in both pazopanib (19.7 vs 31.6 mo) and sunitinib (15.3 vs 27.7 mo) arms. In both arms, patients with HS >50 with intratumoral CD8+T cell counts >300 had the shortest OS. Results were similar for progression-free survival and persisted on multivariate analysis. Conclusions: This is the largest report to show that tumors’PDL1 expression and CD8+ T cell counts are associated with treatment outcome in metastatic RCC patients. Increased PDL1, or increased PDL1 plus tumor CD8+ T cell counts, were associated with shorter OS. These findings may have major implications for future trial designs that involve PD-1 inhibitors.

Development and validation of a prognostic nomogram for progression-free and overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib.

405 Background: Pazopanib, an oral multikinase inhibitor, demonstrated noninferiority to sunitinib in patients with aRCC in COMPARZ (NCT00720941), a randomized, phase III trial (NEJM 2013;369:722). The purpose of this study was to develop and validate prognostic nomograms based on outcome data from COMPARZ for predicting the probability of 12-month progression-free survival (PFS) and 30-month overall survival (OS) for aRCC patients who received pazopanib. Methods: Statistical modeling was performed on a dataset consisting of 557 patients from the pazopanib arm of COMPARZ. A Cox proportional hazards regression model was fit using predictors thought to be prognostic. These predictors included neutrophil count, platelet count, LDH, and alkaline phosphatase, all relative to ULN; calcium; albumin; hemoglobin; Karnofsky score; months from diagnosis to treatment; number of metastatic sites; and presence of lung, liver, and bone metastases. Data from patients on the sunitinib arm of COMPARZ and the pazopanib arm of the VEG105192 trial (NCT00334282; J Clin Oncol 2010;28:1061) were used for validation. Missing values were imputed using chained equations. For validation with the VEG105192 dataset, bootstrap-corrected estimates of discrimination and calibration were calculated following 1000 resamples. The Cox model was plotted as a nomogram. Results: Prognostic nomograms were developed and validated for predicting the probability of 12-month PFS and 30-month OS in aRCC patients based on a Cox regression model. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of PFS and OS. The concordance index for 12-month PFS was 0.636 with sunitinib patients and 0.635 for pazopanib patients; the concordance index was 0.692 for 30-month OS (sunitinib patients). When examining the PFS and OS nomograms, albumin, calcium, and LDH levels appeared to be the most influential predictors of outcome. Conclusions: The nomograms predict, with reasonable accuracy, treatment outcomes in patients with aRCC receiving pazopanib, based on their baseline clinical characteristics.

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Double‐blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma

Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC. Patients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6-month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor-2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05). A total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6-month progression rate was 72% versus 64%. The median progression-free survival (PFS) was 2.9 months (range, 0.5 months-32.5 months) versus 2.7 months (range, 0.8 months -65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months-22 months). The current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6-month progression rate. Open-label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib.

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

Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients 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). Early 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%). OS 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.

Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer

Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.

Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma.

9031 Background: Uveal melanoma (UM) is a rare cancer with a propensity for metastasis. There are no effective systemic therapies for metastatic UM, although dacarbazine is commonly used in practice. Sunitinib is a tyrosine kinase inhibitor with activity against several targets including c-Kit and VEGF receptors, both of which have been implicated in the pathogenesis of UM. Methods: In this randomized multicentre, phase II study (SUAVE), patients (pts) with metastatic UM, ECOG PS 0-2, and no prior systemic therapy for advanced disease, were randomized 1:1 to sunitinib (50mg daily for 28 days, followed by a 14 day break), or dacarbazine (1000 mg/m2once every 21 days). Crossover was permitted on progression. The primary endpoint was PFS; secondary endpoints included response rate and OS. A sample size of 124 was planned, with a power of 0.9 to detect an increase in 3 month PFS from 0.2 to 0.4 (HR: 0.563) and a one-sided alpha of 0.05. A preplanned futility analysis was performed after 50% of events, and recruitment stopped early, due to low conditional power (0.17% under current trend). Presentation of results was approved by DMC. Results: 74 pts from 12 centres were randomized over 24 months. Overall response rates of 0% and 8% were observed in the sunitinib and dacarbazine arms; while stable disease was observed in 24% of pts on sunitinib, and 11% on dacarbazine. PFS and OS were not improved with sunitinib (see Table). 11 pts in the sunitinib arm and 23 in the dacarbazine arm underwent crossover on progression. No unexpected AEs were observed, and no deaths due to toxicity occurred. Conclusions: In these preliminary results sunitinib did not have significant clinical activity in metastatic UM. This trial is one of the largest undertaken in metastatic UM and demonstrates that timely recruitment to collaborative multicentre randomized trials is achievable in this rare disease. Clinical trial information: 75033520. [Table: see text]

Impact of tyrosine kinase inhibitors and cytoreductive nephrectomy in patients with metastatic renal cell carcinoma

Until recently, the standard of care for metastatic renal cell carcinoma (mRCC) has been cytoreductive nephrectomy (CN) followed by systemic immunotherapy in the form of interferon-α (IFN-α). As of 2007, there was a paradigm shift; a prospective randomized trial comparing sunitinib versus IFN-α in patients with mRCC showed superior progression-free survival in the sunitinib arm,1 and more recently, an update on this trial was published showing prolonged overall survival in patients treated with sunitinib compared with IFN-α (median survival 26.4 v. 21.8 mo).2 Patients in the IFN-α arm had longer overall survival than was previously published, in part owing to the crossover in patients who used a tyrosine kinase inhibitor (TKI) after treatment with IFN-α failed. In general, patients enrolled in phase-III trials are selected for good performance status and lack of clinically important comorbidities and, as such, may not always represent the general patient population. Warren and colleagues3 aimed to evaluate the effect of TKIs (compared with IFN-α) on survival in patients with mRCC in the “real world” clinical practice setting. The authors confirmed the benefits of TKIs compared with IFN-α in these patients. Overall survival rates for patients treated with IFN-α were inferior compared with those treated with TKIs as first-line and second-line therapy (10.0 v. 15.8 and 19.5 mo, respectively). Presently, it is widely accepted that CN remains an integral aspect in the management of patients with mRCC. This practice was based on 2 prospective randomized trials that evaluated CN in patients with mRCC who were treated with immunotherapy and demonstrated a significant survival benefit in patients who underwent CN.4,5 However, both trials were not able to provide mechanistic insight for the survival benefit conferred by CN. Several biological hypotheses have been proposed, supporting the theory that immunosuppressive activity is reversed after CN owing to resection of the primary tumour. Whether or not the benefit of CN persists in the TKI era is unclear as there is no level-1 evidence evaluating the role of CN in patients treated with TKIs. In contrast, it would be unrealistic to expect a repeat phase-III trial to revalidate the benefits of CN for each novel class of agents that show efficacy in the treatment of mRCC. As such, many urological and medical oncologists have embraced CN even in the TKI era by extrapolating the data from the studies that used immunotherapy as systemic therapy. Interestingly, Warren and colleagues showed that prior nephrectomy was independently associated with improved survival in patients treated with TKIs. Although I support the role of CN in patients with mRCC treated with TKIs, one has to be careful when assessing the therapeutic impact of CN in a retrospective series because of confounding variables with having or not having CN before systemic therapy. Lastly, one should also note that the previous evidence supporting the use of CN was largely based on patients with mRCC of clear cell histology. When we examined the M.D. Anderson experience treating patients with mRCC (n = 606), the outcome of patients treated with CN and systemic therapy for mRCC with nonclear cell histology was dismal compared with patients with clear cell histology (median survival 9.7 v. 20.3 mo).6 This raises yet another concern of whether or not patients who have mRCC with nonclear cell histology should be treated with systemic therapy alone without an upfront CN.

Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial

This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC). Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed. In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm. Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy

Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

FDA Approval Summary: Sunitinib for the Treatment of Progressive Well-Differentiated Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent®; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies.

Complete Longitudinal Analyses of the Randomized, Placebo-Controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor following Imatinib Failure

To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

e14621 Background: No randomized trial has compared everolimus (EVE) and sunitinib (SUN) for treatment of advanced pancreatic neuroendocrine tumors (pNET). This study indirectly compared overall survival (OS) with EVE vs. placebo (PBO), and OS and progression-free survival (PFS) with EVE vs. SUN. Methods: Individual patient data were used from the RADIANT-3 trial of EVE 10 mg/day vs. PBO (cutoff: April 2010); published summary data were used from the A6181111 trial of SUN 37.5 mg/day vs. PBO (cutoff: June 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to A6181111 exclusion criteria and weighted to match A6181111 baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for EVE vs. the PBO arm from A6181111 (which had access to SUN after progression or early stopping) and vs. the SUN arm. PFS was also compared. Analyses did not adjust for early stopping of A6181111, which may bias towards longer PFS and OS with SUN vs. PBO. Results: 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 missing baseline data) and all 171 patients in A6181111 were included. RADIANT-3 patients differed from A6181111 patients in baseline performance status, prior use of somatostatin analogues, and prior use of systemic chemotherapy before matching. After matching, all baseline characteristics were well-balanced between trials. EVE was associated with significantly prolonged OS vs. PBO in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04), corresponding to a 1-year number needed to treat of 8.3 patients to prevent 1 death. OS and PFS were longer, but not statistically different, with EVE vs. SUN (HR for death = 0.81, 95%CI=0.49-1.31, HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with significantly prolonged OS compared to placebo. OS and PFS were longer, but not statistically different, with everolimus compared to sunitinib.

Characterizing fatigue associated with sunitinib (SU) in patients (pts) with metastatic renal cell carcinoma (mRCC).

6092 Background: Fatigue is common in cancer pts and associated with use of tyrosine kinase inhibitors (TKIs) such as SU. Limited data exist on the time pattern of fatigue with TKI therapy. Methods: Data from treatment-naïve mRCC pts in SU arms of two clinical trials were analyzed retrospectively. Study 1; 375 pts were randomized to SU 50 mg/d on a 4 weeks-on-2-weeks-off schedule (Schedule 4/2), for up to 30 cycles. Study 2; pts were randomized to SU 50 mg/d Schedule 4/2 (Group 1; n=146) or 37.5 mg/d continuous daily dosing (CDD; Group 2; n=146). In both trials, fatigue was measured with the question to pts: “I feel fatigued” over the past week (5-point rating scale, not at all-very much), and with the provider-rated Common Terminology Criteria for Adverse Events (CTCAE). In addition to descriptive profiles, Study 1 used two modeling approaches; repeated measures model (M1), with time as a categorical predictor; and random intercept-slope model (M2), with time as a continuous predictor. Study 2 calculated mean absolute values of within-cycle rate of change (from one assessment to the next) through the first 6 treatment cycles. Results: In Study 1, representing fatigue across cycles, M1 showed that the initial increase in patient-reported fatigue was worst during Cycle 1; mean values at all subsequent cycles were numerically better. For CTCAE fatigue, M1 showed that all but one of the pair-wise comparisons of the cycle means were not significantly different. M2 showed that the overall trend for patient-reported fatigue and CTCAE fatigue was not statistically different from zero. In Study 2, the mean absolute rate of change for fatigue during 6 treatment cycles was greater for Group 1 (4/2) compared to Group 2 (CDD): 0.042 vs. 0.032, respectively; P=0.003, t-test. Conclusions: In Study 1, pts reported notable fatigue in Cycle 1, which improved or stabilized, thereafter. In Study 2, Schedule 4/2 was associated with more within-cycle fluctuation in fatigue. These findings illustrate how SU-associated fatigue occurs early in therapy and continues with more within-cycle fluctuation associated with 4/2 dosing. This may help patient-clinician communications and interventions that support maintaining effective therapy.

Sunitinib Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer: A Phase III Trial

Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC. Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm. In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.

Abstract 1903: In vitro and in vivo characterization of sunitinib resistance in renal cancer models

Abstract Background. Resistance to TK inhibitors such as sunitinib and sorafenib can rapidly develop through multiple mechanisms, including angiogenic growth factors redundancy or switches in signaling pathways, leading to an acceleration of tumor growth after treatment failure and an increased aggressiveness. The aim of the present study was to investigate, in vitro and in vivo, the molecular mechanisms of acquired resistance to sunitinib in renal cell carcinoma (RCC) models. Materials and Methods: CAKI1 (VHL+) and 786-0 (VHL-) renal carcinoma cells were exposed to stepwise increasing doses of sunitinib for &amp;gt;6 months. Invasiveness of cells was determined by Matrigel invasion assay. Genes and protein expressions were assessed by qRT-PCR and western blot. For in vivo experiments, CAKI1 cells were xenografted in nude mice and treated continuously with 60 mg/kg oral sunitinib until progression. Results. CAKI-Suni and 786-Suni cells treated for an extensive period of time displayed a 2-fold IC50 increase compared to parental cells. Several changes in gene expressions were detected in these cells Protracted exposure to sunitinib led to a &amp;gt;3-fold increase of ErbB3 and CDH1 mRNA expression in CAKI-Suni and 786-Suni cells compared to the parental CAKI1 and 786-0 cells. Resistance to sunitinib was also associated with AKT and ERK activation. In addition, CAKI-Suni cell line was at least 3 times more invasive than its parental counterpart. To compare these in vitro modifications to the ones observed after the development of an in vivo resistance to sunitinib, nude mice bearing CAKI1 xenografts were treated with 60 mg/kg/day oral sunitinib until progression. Sunitinib induced a significant tumor growth retardation with a median PFS of 59 days in the sunitinib arm compare to 22 days in the placebo arm (p&amp;lt;0.0001). After 35 days of treatment several tumors became progressive under sunitinib. IHC analysis of tumor tissues revealed a decrease in necrosis and an increase in the number of blood vessels in the sunitinib-resistant tumors compared to the sunitinib-controlled tumors. In the relapsed tumors, we observed a 2-fold increase in mRNA expression of VEGFA, CXCR4, CA-IX and HIF1A and a 4-fold decrease expression of E-cadherin (CDH1). Resistance to sunitinib was also associated with an increase in CXCR4, vimentin and ErbB3 protein levels. Conclusions. Long term exposure to sunitinib induced significant changes in gene expression, invasion properties and survival signaling pathways in RCC tumors. Both in vitro and in vivo data suggest a possible role of the epithelial-to-mesenchymal transition in the relapse in RCC tumors treated by sunitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1903. doi:1538-7445.AM2012-1903

Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

237 Background: Everolimus and sunitinib are approved in the US and EU for treating advanced pancreatic neuroendocrine tumors (pNET). No randomized trial has directly compared these treatments for pNET. This study indirectly compared overall survival (OS) with everolimus vs. 1) placebo and 2) sunitinib. Methods: Individual patient data were used from the RADIANT-3 trial of everolimus 10 mg/day vs. placebo (cutoff: April 4, 2010); published summary data were used from the A6181111 trial of sunitinib 37.5 mg/day vs. placebo (cutoff: June 1, 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to exclusion criteria used in A6181111 and then re-weighted to match A6181111 in terms of baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for everolimus in RADIANT-3 vs. 1) the placebo arm in A6181111, which had access to sunitinib after early stopping, and 2) the sunitinib arm in A6181111. Progression-free survival (PFS) was also assessed, but was confounded by early stopping of A6181111. Results: Analyses included 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 with missing baseline data) and all 171 patients in A6181111. Before matching, patients in RADIANT-3 had better performance status, more prior use of somatostatin analogues and less prior use of systemic chemotherapy. After matching, these and all other baseline characteristics were well-balanced between trials. Everolimus was associated with prolonged OS vs. placebo in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04). No statistically significant difference was observed with everolimus vs. sunitinib in OS (HR for death = 0.81, 95%CI=0.49-1.31) or in PFS (HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with prolonged OS compared to treatment with placebo.