Search

Purpose:To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).Patients and Methods:Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.Results:At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.Conclusions:The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

Supplementary Data from Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Purpose: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA). Patients and Methods: Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent. Results: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified. Conclusions: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

Purpose: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. Patients and Methods: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted. Results: In all, 286 patients (sunitinib, n = 142; placebo, n = 144) were genotyped. Longer DFS [HR; 95% confidence interval (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44; 95% CI, 0.21–0.91; P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46; 95% CI, 0.23–0.90; P = 0.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30–0.94; P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P ≤ 0.05), and A/A versus C/C with sunitinib (P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P = 0.038) and combined (P = 0.006) groups. Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.

Background: An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. Methods: The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. Results: Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. Conclusions: Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.

Background Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting. Materials and Methods A retrospective analysis was performed on data from sunitinib-treated patients (n = 375) in the pivotal phase III trial of sunitinib versus interferon-α as first-line treatment for mRCC. Objective response rates (ORRs) were determined from independently reviewed radiologic assessments. The Kaplan–Meier method was used to estimate median progression-free survival (PFS) and median overall survival (OS) according to patient risk group. Results Median PFS (95% confidence interval [CI]) was 14.1 (13.4-17.1), 10.7 (10.5-12.5), 2.4 (1.1-4.7), and 10.6 (8.1-10.9) months in sunitinib-treated patients in the IMDC favorable (n = 134), intermediate (n = 205), poor (n = 34), and intermediate + poor (n = 239) risk groups, respectively. Median OS (95% CI) was 23.0 (19.8-27.8), 5.1 (4.3-9.9), and 20.3 (16.8-23.0) months in sunitinib-treated patients in IMDC intermediate, poor, and intermediate + poor risk groups, respectively, and was not reached in the favorable risk group (>50% of patients were alive at data cutoff). ORRs (95% CI) was 53.0% (44.2%-61.7%), 33.7% (27.2%-40.6%), 11.8% (3.3%-27.5%), and 30.5% (24.8%-36.8%) in sunitinib-treated patients in IMDC favorable, intermediate, poor, and intermediate + poor risk groups, respectively. Conclusion Results of this retrospective analysis show differences in patient outcomes for PFS, OS, and ORR on the basis of IMDC prognostic risk group assignment for patients with mRCC.

BACKGROUND The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. METHODS Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management. RESULTS At final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each. CONCLUSIONS This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure. Cancer 2015;121:1405–1413. © 2015 American Cancer Society.

Lessons Learned The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached). Conclusion The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Purpose Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients and Methods 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). Results 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%). Conclusion 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.

Background Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. Methods This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ2 test) in the same molecular subgroups. Results Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20 %) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39–0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment. Conclusions This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status. Trial registration NCT01459757. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2051-5) contains supplementary material, which is available to authorized users.

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.

Summary Background Hepatocellular 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. Methods Between 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. Findings Of 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. Interpretation Sunitinib 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. Funding Pfizer Oncology.

J Randolph Hecht,1 Edith P Mitchell,2 Takayuki Yoshino,3 Manfred Welslau,4 Xun Lin,5 Edna Chow Maneval,6 Jolanda Paolini,7 Maria Jose Lechuga,7 Albrecht Kretzschmar8 1David Geffen School of Medicine at UCLA, Santa Monica, CA, 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, USA; 3National Cancer Center Hospital East, Chiba, Japan; 4Onkologische Praxis Klausmann/Welslau, Aschaffenburg, Germany; 5Pfizer Oncology, La Jolla, 6Seragon Pharmaceuticals, San Diego, CA, USA; 7Pfizer Oncology, Milan, Italy; 8Klinikum St Georg, Leipzig, Germany Background: Sunitinib 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. Methods: Patients 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. Results: Enrollment 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. Conclusion: While 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. Keywords: antiangiogenesis, bevacizumab, combination therapy, metastatic colorectal cancer, oxaliplatin, sunitinib

Background Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention. Methods The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel–Cox test. Results Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P

Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in patients (pts) with loco-regional high-risk renal cell carcinoma (HR=0.76, 95% CI: 0.59-0.98; P=0.03; median[m] DFS, 6.8 vs 5.6 years). Here, we report the results of a retrospective exploratory molecular biomarker analysis using nephrectomy biospecimens from the S-TRAC trial. Materials and Methods: Formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. Biomarker quantification was done by automated image analysis of the regions of interest (ROI). The analysis algorithm utilized an immunoscore approach applied to ROI, reflecting assessment of both the center and invasive margin of tumors (for PD-L1 and CD8 staining). DFS was compared between biomarker stratum by < median vs ≥ median values of a particular IHC parameter using Kaplan-Meier (K-M) analysis. Receiver Operating Characteristics (ROC) curves were generated to further assess the potential clinical utility of biomarkers for which significant (P < 0.05) results were obtained in K-M analysis. Results: In total, 191/615 (101, SU and 90, PBO) pts in the intent-to-treat population were included for IHC analysis. Baseline characteristics were similar in the subpopulations with and without IHC data. Shorter DFS was observed in the PBO group for pts with PD-L1+ vs PD-L1- tumors, although not statistically significant (HR=1.75; 95% CI: 0.89-3.46; P=0.103). In pts with PD-L1+ tumors, DFS was numerically longer for SU vs PBO (mDFS=6.17 vs 2.67 years) (HR=0.58; 95% CI: 0.26-1.29; P=0.175). In the SU group, pts with CD8+ T-cell density ≥ median (cutoff=269.5 CD8+ cells/mm2) had longer DFS (mDFS=not reached [NR]; 95% CI: 6.83-NR) than pts with CD8+ T-cell density < median (mDFS=3.47 years; 95% CI: 1.73-NR), and the difference was statistically significant (HR=0.40, 95% CI: 0.20-0.81; P=0.009), while CD8+ T-cell density showed no significant difference in DFS for PBO pts (HR=0.80, 95% CI: 0.42-1.50; P=0.484). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively, and the optimal cutoff was 222.22 cells/mm2 with an area under ROC curve of 0.622. Conclusions: Increased density of CD8+ T-cells in tumor tissue was associated with longer DFS in SU-randomized pts but not PBO, suggesting this may be predictive of treatment effect. Further validation in an independent cohort is warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic RCC should be further explored. Citation Format: Daniel J. George, Jean-Francois Martini, Yen-Hwa Chang, Michael Staehler, Jan Breza, Jean-Jacques Patard, Robert J. Motzer, Ahmed Magheli, Bernard Escudier, Giacomo Carteni, Paola Gerletti, Sherry Li, Michelle Casey, Brigitte Laguerre, Hardev S. Pandha, Allan J. Pantuck, Anup Patel, Maria Lechuga, Alain Ravaud. Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1771. doi:10.1158/1538-7445.AM2017-1771

Purpose 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 and Methods 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. Results 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. Conclusion 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.

This phase I study evaluated sunitinib plus modified FOLFOX6 (mFOLFOX6: 5-fluorouracil, leucovorin and oxaliplatin) in Japanese patients with treatment-naïve metastatic colorectal cancer.Sunitinib was administered orally (37.5 mg/day, 4 weeks on, 2 weeks off [Schedule 4/2; arm A] or 50 mg/day, 2 weeks on, 2 weeks off [Schedule 2/2; arm B]) with mFOLFOX6.In arms A/B, respectively (n=6 each): median relative dose intensity was 50.4%/89.1% for sunitinib and 39.2-69.8%/73.0-80.5% for mFOLFOX6 components. Most adverse events were grade 1/2. The most frequent grade 3/4 adverse events were neutropenia, thrombocytopenia, and leukopenia. No significant drug-drug interactions were detected. Four patients had objective responses in each arm.Sunitinib plus mFOLFOX6 had acceptable tolerability, with the Schedule 2/2 combination being generally more manageable than the Schedule 4/2. Based on two global trials and the present study, sunitinib on Schedule 2/2 combined with chemotherapy may be considered, if further first-line trials are planned.

This phase II, open‐label, single‐arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment‐naïve unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo‐leucovorin 200 mg/m(2) + irinotecan 180 mg/m(2), followed by 5‐fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) 46‐h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression‐free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy‐one patients started a median of 3 (range 1–11) sunitinib cycles (median relative dose intensity

NCT00141193/ www.clinicaltrials.gov ) were studied to determine effi cacy and safety at a year 5 assessment. METHODS: In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colo- rectal adenomas removed within 3 months of the study ' s initiation were assessed after ~ 3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratifi ed by cardioprotective aspirin use and randomized to receive orally 400 mg celecoxib (933 subjects) or placebo (628 subjects) once daily. Effi cacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment. RESULTS: At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically signifi cantly lower in the celecoxib group (51.4 % ) than in the placebo group (57.5 % ; P < 0.001). Similarly, the cumulative rate of new advanced adenomas was signifi cantly lower in the celecoxib group (10.0 % ) than in the placebo group (13.8 % ; P = 0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0 % ) was 1.66 times more likely to have new adenomas than the placebo group (16.3 % ; P < 0.0001). Similarly, the percentage of patients with new advanced adenomas was signifi cantly higher in the celecoxib group (5.0 % ) than in the placebo group (3.8 % ) ( P = 0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95 % confi dence interval (CI) 1.01 - 2.73), selected renal / hypertension events (RR 1.35; 95 % CI 1.09 - 1.68), and general vascular (RR 1.34; 95 % CI 1.08 - 1.68) and cardiac disorders (RR 1.59; 95 % CI 1.12 - 2.26) were higher in those taking celecoxib than in those on placebo. CONCLUSIONS: The year 5 cumulative measures of the incidence of new and advanced adenomas were signifi cantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were sig- nifi cantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxyge- nase-2 inhibition. Consistent with what has been previously reported, increased risk of renal / hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Summary Purpose. This phase II, open-label, multicenter study assessed the oral, multitargeted, tyrosine kinase inhibitor sunitinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma who had received prior chemotherapy. Experimental design. Patients received sunitinib 50 mg/day on Schedule 4/2 (4 weeks on treatment, followed by 2 weeks off treatment). The primary endpoint was objective response rate; secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, safety and tolerability, and quality of life. Results. Of 78 patients enrolled, most had gastric adenocarcinoma (93.6%) and metastatic disease (93.6%). All were evaluable for safety and efficacy. Two patients (2.6%) had partial responses and 25 patients (32.1%) had a best response of stable disease for ≥6 weeks. Median PFS was 2.3 months (95% confidence interval [CI], 1.6–2.6 months) and median OS was 6.8 months (95% CI, 4.4–9.6 months). Grade ≥3 thrombocytopenia and neutropenia were reported in 34.6% and 29.4% of patients, respectively, and the most common non-hematologic adverse events were fatigue, anorexia, nausea, diarrhea, and stomatitis. Pharmacokinetics of sunitinib and its active metabolite were consistent with previous reports. There were no marked associations between baseline soluble protein levels, or changes from baseline, and measures of clinical outcome. Conclusions. The progression-delaying effect and manageable toxicity observed with sunitinib in this study suggest that although single-agent sunitinib has insufficient clinical value as second-line treatment for advanced gastric cancer, its role in combination with chemotherapy merits further study.

We thank Dr Cen for his thoughtful comments about our work.1,2 He suggests combining covariates from the Adenoma Prevention With Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials into a single Cox model and using the resulting hazard ratio to estimate the overall effect of celecoxib on cardiovascular end points. This approach treats the variable trial (APC or PreSAP) as 1 ingredient in a stew. We believe in maintaining the integrity of the ingredients as long as possible to allow the flavor of each trial to retain its unique contribution. …

Background Androgen deprivation therapy (ADT) is the standard treatment of hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. Methods Patients (pts) with HSMPC were randomly assigned to either arm A (ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was overall survival (OS). The planned number of pts was 378 to detect an improvement in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 (two-sided test). Secondary endpoints were biological progression-free survival (PFS) and clinical PFS. Data on toxicity and quality of life have been previously presented. Results From October 2004 to December 2008, 385pts were included. Baseline characteristics were well balanced between the two arms. Median age was 63 years (43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% developed metastases after local treatment failure. Median number of D cycles was 8 (range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] (0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 [95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference between the two arms. At the cut-off time, 65% of pts from the ADT arm had received docetaxel since they developed castrate-resistant prostate cancer. Conclusion Combining docetaxel and ADT improves PFS over ADT alone in pts with HSMPC. However, no difference in OS was observed between the two arms. Disclosure G. Gravis: I have expert testimony to disclose: Sanofi Aventis, uncompensated. K. Fizazi: Participation to advisory boards and speaker for Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other authors have declared no conflicts of interest.

4000 Background: The oral multitargeted tyrosine kinase inhibitor Su had antitumor activity in phase II HCC trials, leading to a phase III open-label trial comparing the efficacy and safety of Su with So. Methods: Patients (pts) with advanced HCC, Child-Pugh A, ECOG PS 0/1 and no prior systemic chemotherapy were stratified by geographic region, prior TACE and tumor invasion. Pts were randomized 1:1 to Su 37.5 mg/day or So 400 mg BID. The primary endpoint was overall survival (OS; 1-sided log-rank test; α=0.025, 90% power) with 600 pts/arm required in this superiority/non-inferiority trial design. Secondary endpoints were progression-free survival (PFS), time to progression (TTP) and safety. Efficacy and futility boundaries were set using the Lan-DeMets and O’Brien–Fleming methods for interim analyses. Results: 1,073 pts were randomized (Su 529/So 544) from July 2008 to May 2010. An Independent Data Monitoring Committee stopped the trial early for futility and safety concerns. Pts were notified. Su discont...

Introduction: SU is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. In a phase III mCRC study, adding SU to FOLFIRI did not improve progression-free survival (PFS) vs. FOLFIRI/placebo. Potential correlations were investigated between germline genotype and safety/efficacy endpoints among patients (pts) in this trial. Methods: Blood sample donation for genotype analysis was optional. Selection of genes and polymorphisms was based on prior reported associations. Twenty-one single-nucleotide polymorphisms (SNPs) in 10 genes (VEGF-A, VEGFR-2, CYP1A1, ABCG2, ABCB1, ABCC2, MTHFR, UGT1A1, FLT1 and FLT3) were analyzed by TaqMan allelic discrimination assay or fragment analysis, using DNA isolated from peripheral blood samples. All 21 polymorphisms were analyzed for associations with efficacy (PFS; overall survival [OS]) and selected safety endpoints. Results were adjusted for multiple testing of SNPs in linkage disequilibrium. Results: Genotyping was performed in 139/768 pts (18%). Age and gender were similar between genotyped and non-genotyped pts, but the genotyped subset had fewer non-Caucasians (13% vs. 39%; Fisher's exact P Conclusions: Presence of the T allele in the ABCC2 gene at rs717620 was associated with increased risk of grade 3/4 diarrhea in a small number of Caucasian pts receiving FOLFIRI/placebo. No significant associations were identified between genotype and safety/efficacy endpoints in pts who received SU/FOLFIRI. As OS was superior in genotyped vs. non-genotyped pts, correlative findings may not be extrapolated beyond the genotyped subset. Further analysis of baseline characteristics is underway in the genotyped group to investigate this difference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2011-289

4593 Background: Sunitinib malate (SU) is a multikinase inhibitor with antitumor activity in patients (pts) with HCC (Faivre et al, ASCO 2007). To assess potential biomarkers of SU response, we inv...

3546 Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor ( [Table: see text]

18057 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.

Background Several 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. Methods Patients 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). Results At 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. Conclusions Baseline 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 registration ClinicalTrials.gov: NCT00247676