Selective Inhibitor Of VEGF Receptors Research Articles

A Surprising Outcome of Metastatic Pheochromocytoma Misdiagnosed as Renal Cell Carcinoma: A Case Report

Background: Metastatic pheochromocytomas are rare neuroendocrine tumors that carry a poor prognosis. There are no curative treatments; however, current therapeutic strategies to control tumor burden include surgery, radiation, ablative therapy, chemoembolization, and systemic therapies. We describe an interesting case of a patient with metastatic pheochromocytoma misdiagnosed as renal cell carcinoma (RCC) started on axitinib and pembrolizumab, who achieved a partial response to treatment, despite lack of approved indications for these therapies in metastatic pheochromocytoma. Clinical Case: A 64-year-old man presented to the emergency department (ED) with uncontrolled hypertension and severe headache. A 12 cm left-sided pheochromocytoma was diagnosed 11 years ago, which was surgically resected via adrenalectomy. After surgery, the patient was followed in the endocrine clinic for five years with pheochromocytoma serum biochemical markers and declared free of disease. 2 months before hospital admission, he was worked-up for flank pain and at that time, CT abdomen showed a 3 cm mass in the liver and exophytic solid mass measuring 4.2 cm off the left kidney. Subsequently, a CT guided biopsy of the left renal mass was performed and revealed grade II renal cell carcinoma (RCC). He was referred to oncology and was started on a combination of IV pembrolizumab, an immune checkpoint inhibitor against PD-1/PD-L1, and oral axitinib, a selective VEGF receptor inhibitor. He received 3 cycles of immunotherapy treatment; however, he became significantly hypertensive with intermittent headaches, so he was started on atenolol 25 mg once daily. Despite this, he continued to have uncontrolled hypertension, worsening headaches, and flushing, which prompted him to undergo evaluation in the ED. On arrival, BP was 210/90. Labs were remarkable for Hgb 17.2, WBC count of 17.1, and glucose of 178 mg/dL. CT head was negative for any acute intracranial process. Due to suspected recurrence of pheochromocytoma, atenolol was stopped, adrenal workup was conducted, and the patient was started on doxazosin. Urine metanephrines came back elevated at 1097 (RR: 55-320 μg/24 hrs), urine norepinephrine of 260 (RR: 14-120 μg/24 hrs), and urine normetanephrine of 3305 (RR: 114-865 μg/24 hrs). Re-evaluation of pathology opinion was obtained, which indicated that biopsy stained positive for chromogranin A and synaptophysin markers, consistent with metastatic pheochromocytoma. FDG PET/CT was performed following discharge, which revealed the left renal mass decreased to 2.4 cm and the liver mass shrunk to 1.5 cm. Conclusion: To our knowledge, this is the first case report outside of a clinical trial highlighting partial response to axitinib and pembrolizumab in metastatic pheochromocytoma. Emerging preliminary phase II clinical trial data are currently investigating these medications as future treatment modalities.

Patients with metastatic renal cell carcinoma who have benefit from axitinib dose titration: Analysis from a randomized, double-blind, axitinib dose titration phase II study.

438 Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from axitinib titration. Methods: Patients received axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and < 24 months who were randomized to axitinib titration and subsequently, multivariate analysis for baseline characteristics was conducted to investigate effect of interaction with axitinib titration. Results: Fifty-six patients underwent axitinib titration with 53 evaluable for this analysis. Thirty-three patients had an OS ≥ 24 months and had significantly fewer metastatic sites (≤2, ≥3: 52/48% vs. 10/90%), compared to the 20 patients with OS < 24 months. In addition, a lower percentage of patients with OS ≥ 24 months had lymph node metastasis (45 vs. 75%), liver metastasis (15 vs. 45%), duration from diagnosis to treatment <1 year (36 vs. 85%), and baseline hemoglobin (Hb) < LLN (lower limit of normal) (33 vs. 75%), compared to the patients with OS < 24 months. In multivariate analysis in total of 112 patients who were randomized to axitinib or placebo titration, duration from diagnosis and baseline Hb were significantly associated with favorable OS with axitinib titration (p<0.1). Conclusions: Duration from diagnosis and baseline Hb are associated with favorable OS with axitinib titration. Clinical trial information: NCT00835978.

Abstract A24: Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial

Abstract Purpose: Tivozanib (T), is a potent oral selective inhibitor of VEGF receptors 1, 2, and 3. Bevacizumab (B) is an antibody targeting VEGF A mediated signaling. The randomized, open label phase 2 BATON-CRC (Biomarker Assessment of Tivozanib in ONcology), trial compared the progression free survival (PFS) and safety of T + mFOLFOX6 vs. B + mFOLFOX6 in mCRC patients. Data from the pre-specified interim analysis demonstrated futility for superiority; however the addition of T to mFOLFOX6 resulted in comparable PFS (9.4 vs 10.7 months, p=0.706), overall response rate (45.2% vs 43.2%, p=0.718), and safety to B + mFOLFOX6 and resulted in discontinuation of the study. At the time of the interim analysis (September, 2013) 62 patients out of 163 progressed to generate a PFS event and none of the pre-specified biomarkers demonstrated statistically significant association with PFS (ESMO 2014). At the close of the study (February, 2014), there were 91 PFS events out of 164 patients with baseline serum samples. The final analysis included the updated events which led to the observation that serum NRP1 may be a predictive biomarker for T. Serum NRP1, a pre-specified biomarker in BATON CRC, is associated with improved PFS and overall survival (OS) in multiple T studies in renal cell carcinoma (RCC). This strong association and clinical benefit in RCC prompted a post-hoc analysis of the final BATON-CRC PFS data to examine the differential association between base line serum NRP1 levels and outcomes in the two arms. Methods: Similar to the RCC trials, baseline serum from patients in BATON-CRC had NRP1 quantified using the Myriad RBM ELISA assay. The median NRP1 level from this dataset was used to define the cut off for NRP1 high and NRP1 low. A Cox proportional hazard model was used to assess the association between serum NRP1 levels and PFS. Results: In BATON-CRC, 265 patients were enrolled and randomized 2:1 to T + mFOLFOX6 (n = 177) or B + mFOLFOX6 (n = 88). A total of 164 baseline serum samples (T, n = 109 and B, n = 55) were available for NRP1 analysis. In both the T and B arms, patients with NRP1 low showed an improved PFS vs patients with NRP1 high; for T HR (95% CI): 0.224 [0.120, 0.42], p=3.56e-7 and for B HR [95% CI]: 0.487 [0.237, 1.00], p=0.046) supporting the value of NRP1 as a potential prognostic marker for angiogenesis inhibitors. T treated NRP1 low patients demonstrated a statistically significantly improvement in PFS vs B, PFS =17.9 vs 11.2 mos (multivariate analysis stratified for cancer origin, metastatic sites, LDH levels HR [95% CI]: 0.325 [0.147, 0.717], p=0.005). In NRP1 high patients, there was no difference in PFS between the two arms (HR (95% CI): 0.889 [0.639, 1.980], p=0.683). The interaction p-value is 0.027. Conclusions: The data suggest that NRP1 might be a predictive biomarker of T PFS benefit over B in combination with mFOLFOX 6 in advanced CRC. This finding needs to be further validated in another prospective trial. The differential activity observed with T vs B, in NRP1 low patients is potentially due to the broader VEGF pathway inhibitory activity of T. Citation Format: Al Benson, III, Andrew K. Krivoshik, Chip Van Sant, Jeno Gyuris, Bin Feng. Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A24.

A phase 1 trial of a potent and selective VEGF receptor inhibitor, apatinib, in patients with advanced solid tumors.

2525 Background: VEGF-mediated signaling pathways are critical to tumor growth. Apatinib mesylate is a novel, oral angiogenesis inhibitor that potently and selectively inhibits vascular endothelial...

Randomised Study of Axitinib (Axi) Plus Best Supportive Care (Bsc) Versus Placebo (Pbo) Plus Bsc in Patients with Advanced Hepatocellular Carcinoma (Hcc) Following Prior Antiangiogenic Therapy

ABSTRACT Aim: The efficacy and safety of Axi, a potent and selective inhibitor of VEGF receptors 1-3, was evaluated in a global, randomised, double-blind phase II clinical trial in patients (pts) with locally advanced or metastatic HCC. Methods: Eligible pts progressed on or were intolerant to 1 prior antiangiogenic therapy and had ECOG performance status 0 or 1. Pts were randomised 2:1 to receive Axi + BSC or Pbo + BSC at a starting dose of 5 mg twice daily and stratified by tumour invasion (presence vs absence of extrahepatic spread and/or vascular invasion) and geographic region (Asia vs non-Asia). Primary end point was OS and secondary end points included ORR, PFS and safety. The study had 80% power to detect an improvement in median OS (mOS) from 5.0 to 8.3 mo with Axi + BSC, corresponding to a HR 0.60 (1-sided a = 0.025). Results: Two hundred two pts (134 Axi vs 68 Pbo), predominantly of Asian origin (63 vs 62%), were randomised. Baseline pt characteristics and stratification factors were well balanced between the Axi vs Pbo arms. All pts were in Child-Pugh A category and 76% of pts in both arms had tumour invasion. mOS with Axi was 12.7 mo (95% CI: 10.2, 14.9) vs 9.7 mo (95% CI: 5.9, 11.8) with Pbo and was not statistically significant (HR 0.870; 95% CI: 0.620, 1.222; 1-sided stratified P = 0.211). Investigator-assessed median PFS (mPFS) with Axi was 3.6 mo vs 1.9 mo with Pbo and was statistically significant (HR 0.618; 95% CI: 0.438, 0.871; P = 0.004). ORR was 9.7% with Axi vs 2.9% with Pbo (P = 0.083). More pts discontinued due to AE with Axi vs Pbo (23 vs 13%). Most common all causality AEs (Axi vs Pbo, % of pts) were diarrhoea (54 vs 12%), hypertension (54 vs 13%), decreased appetite (47 vs 21%), fatigue (35 vs 26%), abdominal pain (34 vs 21%), hand-foot syndrome (34 vs 6%), weight decrease (27 vs 3%), nausea (26 vs 10%), dysphonia and hypothyroidism (25 vs 0% each). Conclusions: Axi + BSC did not demonstrate statistically significant improvement in mOS but improved mPFS compared to Pbo + BSC in pts with advanced HCC who received prior antiangiogenic therapy. Safety profile with Axi was consistent with earlier clinical trials and no new safety signal was detected. Disclosure: Y. Kang: I have been a consultant for Pfizer Inc and Bayer Healthcare Pharmaceuticals; J. Park: I am (was) a member of Consultancy/Advisory Board of Taiho Pharmaceutical, Bayer Healthcare Pharmaceuticals, and Roche, and received honorarium from Taiho Pharmaceutical and research funding from Bayer Healthcare Pharmaceuticals; S.L. Chan: I received research funding from Pfizer Inc.; J. Tang and O. Valota: I am employed by and own stock in Pfizer; D. Chakrabarti: is an employee of and owns stock in Pfizer.All other authors have declared no conflicts of interest.

Axitinib as first-line therapy in metastatic renal cell carcinoma

Axitinib is a highly potent and selective VEGF receptor inhibitor. Previous trials suggested a significant advantage of axitinib versus sorafenib in progression-free survival (PFS) of patients with metastatic renal cell carcinoma (RCC) treated with prior cytokine therapy. Recently an important negative study was reported, which evaluated the PFS with axitinib and with sorafenib in treatment-naive metastatic RCC. This study was underpowered but conveyed an important message on the limit of current VEGF signal targeted drugs as a first-line therapy. In the future, more emphasis should be put on arrangement of dosing and scheduling of drugs already approved as well as development of new agents targeting novel molecules in this disease.

Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism

Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. Material and methodsWe examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n=43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. ResultsHuman colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000pg/ml within 48h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. ConclusionsOur findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is independent of its primary function in the induction of angiogenesis.

Abstract B1: Dual mTORC1/mTORC2 inhibition limits tumor growth, VEGF production and vascular regrowth

Abstract Inhibitors of VEGF signaling target tumor angiogenesis and inhibit tumor growth; however, the effects of antiangiogenic therapy are often transient. Cessation of treatment or dose interruption can induce rapid regrowth of tumor vessels and tumor relapse. Preclinical studies have demonstrated that upon withdrawal of VEGFR inhibitors, tumor vessels can rapidly repopulate the tumor on the tracks of the empty basement membrane sleeves (1,2). This rapid vessel regrowth is mediated, at least in part, by the interaction of VEGF produced by the tumor and VEGF receptors expressed on endothelial cells. Neutralization of the VEGF ligand combined with VEGFR inhibition may provide more complete VEGF signaling blockade, however the combination of bevacizumb, a monoclonal antibody to VEGF ligand, and sunitinib, a mulitkinase/pan-VEGFR inhibitor, has resulted in significant clinical toxicity (3). As an alternative approach, we reasoned that inhibition of VEGF production would decelerate the regrowth of tumor vessels following VEGFR inhibition. We sought to reduce VEGF production in the tumor by targeting the mechanism for VEGF translation using a selective inhibitor of mTOR. The mTOR kinase is a critical signaling hub which regulates multiple cellular networks including cap-dependent translation. The translation of many cellular growth factors, including VEGF isoforms, is regulated by the 4E-BP1 complex, which is in turn regulated by mTOR. ATP-competitive, selective inhibitors of mTORC1/mTORC2, OXA-01 and OSI-027 (ASP4786) can attenuate 4E-BP1 phosphorylation more completely than rapamycin, an allosteric inhibitor of mTORC1. In RIP-TAg mouse pancreatic tumors, OXA-01 dramatically reduced VEGF production whereas rapamycin, was less effective. Interestingly, OXA-01-mediated reduction in VEGF was associated with decreased vessel growth and normalization of the vascular architecture, but not vascular regression. In contrast, treatment with a selective inhibitor of VEGF receptors, OSI-930, resulted in substantial vascular regression but no decrease in tumor VEGF levels. Upon discontinuation of OSI-930 tumor vessels rapidly regrew, and this regrowth was diminished by OXA-01 treatment but not with rapamycin. Another key mTORC2 activity is regulation of the Akt signaling cascade, a central mediator of cellular survival. Inhibition of mTORC1/mTORC2 with OXA-01 induced tumor cell apoptosis in vivo, and this was enhanced when combined with the VEGFR inhibitor, OSI-930. In order to explore the clinical feasibility of this total VEGF blockade approach, we tested the combination of OSI-027, an mTORC1/mTORC2 inhibitor in clinical trials, and sunitinib, an approved multikinase/VEGFR2 inhibitor, in human tumor xenografts. The combination decreased the growth of human tumor xenografts to a greater degree than either single agent. Together these data demonstrate one mechanism for co-targeting angiogenic ligand production as well as inhibition of VEGFR signaling to provide maximal blockade of VEGF signaling and to limit vessel regrowth after cessation of the VEGFR inhibitor.

Axitinib inhibition of [18F] fluorothymidine (FLT) uptake in patients (pts) with colorectal cancer (CRC): Implications for cytotoxic chemotherapy combinations.

3591 Background: Axitinib is an oral, potent, and selective inhibitor of VEGF receptors (VEGFR) 1, 2, and 3. Clinical trials of VEGFR inhibitors in combination with cytotoxic chemotherapies have yet to yield positive results. Inhibition of cancer cell proliferation by VEGFR inhibitors may be antagonizing cytotoxic chemotherapy. This serial FLT-PET imaging study was performed to determine whether continuous dosing of axitinib inhibits FLT uptake and whether a 3- or 7-day drug holiday could reverse the FLT uptake inhibition. Methods: Pts with CRC or other GI cancers with suitable lesions were enrolled. Axitinib 7 mg (cohort 1) or 10 mg (cohort 2) twice daily (BID) starting dose was administered continuously for 7 days, then interrupted for ≥7 days. Dynamic and whole-body FLT-PET/CT scans were obtained at baseline, at the end of 7 days of continuous axitinib BID dosing, and then 3 and 7 days after axitinib interruption. Kinetic parameters calculated included the Patlak influx constant (Kpatlak) and changes in standardized uptake values (SUVmax, SUVmean). For liver lesions, SUVmean was used. Results: A total of 19 pts were enrolled, 3 and 16 into Cohorts 1 and 2, respectively. 15 had CRC and 4 had other GI cancers; 14 were male, and median age was 56 yrs. Serial FLT-PET data were available for 18 pts: 6 with lung, 5 with liver, 3 with lymph node, 2 with abdominal wall, and 2 with pelvic lesions. Following an initial 7 days of continuous axitinib, tumor FLT uptake (mean DSUV) changed by –46.0% (95% CI: –31.8%, –60.2%) from baseline. Then, after 3 days of axitinib holiday, tumor FLT uptake increased from nadir by +54.5% (95% CI: +17.5%, +91.5%), which further increased by +96.6% (95% CI: +36.4%, +156.8%) after 7 days of axitinib holiday. Conclusions: Continuous axitinib therapy for 7 days markedly inhibited fluorothymidine uptake. Since inhibition of cancer cell proliferation can protect against the cytotoxic effects of chemotherapeutics, this could explain the failure of VEGFR inhibitor + chemotherapy regimens to improve chemotherapy. Inclusion of a short drug holiday in axitinib dosing schedule may allow resensitization of cancer cells.

A meta-analysis of potential contribution of genetic polymorphisms in drug-metabolizing enzymes/transporters to axitinib pharmacokinetic (PK) variability in healthy volunteers.

e13033 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, and 3 with clinical efficacy in various human solid tumors, including advanced renal cell...

Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): Results of phase III AXIS trial.

4503 Background: Axitinib is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, and 3. This randomized, open-label, phase III trial compared the efficacy and safety of axitinib versus (vs) sorafenib as second-line therapy for mRCC. Methods: Eligible patients had clear-cell mRCC; measurable, RECIST-defined progressive disease after 1 prior first-line systemic therapy with a sunitinib-, bevacizumab-, temsirolimus-, or cytokine-based regimen; and Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Patients were stratified by PS and prior therapy, then randomized 1:1 to axitinib, administered at a starting dose of 5 mg BID, titrated to 7 mg BID and then to 10 mg BID as tolerated, or sorafenib 400 mg BID. The primary endpoint was progression-free survival (PFS) per blinded, independent radiographic review. The study had 90% power to detect a PFS of 7 months vs 5 months, corresponding to a hazard ratio (HR) of ≤0.714 (overall 1-sided α=0.025). Results: Seven-hundred twenty-three patients were randomized to either axitinib (n=361) or sorafenib (n=362). Baseline patient characteristics included median age of 61; 72% male; 76% Caucasian; and 55% PS 0. Prior therapy included 54% sunitinib-, 35% cytokine-, 8% bevacizumab-, and 3% temsirolimus-based regimens. Median PFS was 6.7 months (95% confidence interval, 6.3-8.6) for axitinib vs 4.7 months (4.6-5.6) for sorafenib, with a HR of 0.665 (P<0.0001). PFS favored axitinib in both the prior cytokine subgroup (12.1 vs 6.5 months; P<0.0001) and the prior sunitinib subgroup (4.8 vs 3.4 months; P=0.0107). Objective response rates were 19.4% for axitinib vs 9.4% for sorafenib (P=0.0001). Common AEs more frequent with axitinib vs sorafenib were hypertension (40% vs 29%, all grades), fatigue (39% vs 32%), dysphonia (31% vs 14%), and hypothyroidism (19% vs 8%). AEs more frequent with sorafenib were hand-foot syndrome (27% vs 51%), rash (13% vs 32%), alopecia (4% vs 32%), and anemia (4% vs 12%). Conclusions: Axitinib demonstrated a significantly longer PFS and higher objective response rate vs sorafenib with an acceptable safety profile as second-line therapy for mRCC.

Novel Ultrasound and DCE-MRI Analyses After Antiangiogenic Treatment With a Selective VEGF Receptor Inhibitor

We report a comparison between tumor perfusion estimates acquired using contrast-enhanced MRI and motion-corrected contrast-enhanced ultrasound before and after treatment with AG-028262, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor. Antiangiogenic activity was determined by assessing weekly ultrasound and MRI images of rats with bilateral hind flank mammary adenocarcinomas before and after treatment with AG-028262. Images were acquired with a spoiled gradient, 1.5 T magnetic resonance sequence and a destruction-replenishment ultrasound protocol. For ultrasound, a time to 80% contrast replenishment was calculated for each tumor voxel; for MR imaging, a measure of local flow rate was estimated from a linear fit of minimum to maximum intensities. AG-028262 significantly decreased tumor growth and increased the time required to replenish tumor voxels with an ultrasound contrast agent from 2.66 to 4.54 s and to fill with an MR contrast agent from 29.5 to 50.8 s. Measures of flow rate derived from MRI and ultrasound demonstrated a positive linear correlation of r 2 = 0.86.

Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC)

5045 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, 3. An association between dBP elevation and clinical outcome has been previously reported (Rini, ASCO. 2008). The objective of this pooled analysis of two phase II mRCC studies was to explore the relationship between PK, dBP, and clinical efficacy. Methods: PK data from two phase II studies in cytokine-refractory mRCC patients (pts) and 8 single-dose healthy volunteer (HV) studies were included (n = 109 mRCC pts and 240 HV) in the population PK analysis; the efficacy analysis included mRCC pts only. PK data was analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability). Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and the dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier analyses. Results: The median overall survival (mOS) for mRCC pts with at least 1 dBP measurement ≥90 mmHg (n = 59) during axitinib therapy was 130 weeks vs. 42 weeks (p &lt; 0.01) for pts without any dBP ≥90 mmHg (n = 50). The mOS of pts with an AUC below the median (605 ng.hr/ml; n = 54) was 69 weeks vs. 88 weeks (p &gt; 0.05) for pts with an AUC above the median (n = 55). Among pts with dBP ≥90 mmHg, mOS was 120 weeks and 131 weeks (p &gt; 0.05) for pts with AUC below and above the median (n = 23 and 36), respectively. Among pts without dBP ≥90 mmHg, mOS was 42 weeks and 43 weeks (p &gt; 0.05) for pts with AUC below and above the median (n = 31 and 19), respectively. An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy. There was no apparent correlation between the AUC and maximum dBP during axitinib therapy. Conclusions: dBP ≥90 mmHg during axitinib therapy is a strong predictor of clinical efficacy in patients with mRCC, and is not merely a reflection of higher axitinib drug levels. These data support an ongoing pivotal phase III trial in previously treated mRCC that incorporates a dose-titration scheme based on patient tolerance and BP. [Table: see text]

Axitinib (AG-013736) in combination with FOLFOX and bevacizumab (Bev) in patients (pts) with metastatic solid tumors: A phase I study

4112 Background: Axitinib is an oral, potent and selective inhibitor of VEGF receptors 1, 2, and 3 that is being assessed in a broad range of tumors. This phase I portion of the study evaluated the safety and pharmacokinetics (PK) of axitinib in combination with BV and FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin) in pts with previously treated gastrointestinal and solid tumors. Methods: Pts in cohort 1 received BV 1 mg/kg, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 bolus then 2,400 mg/m2 by 46–48 h infusion, and axitinib at a starting dose of 5 mg PO BID. BV and FOLFOX were administered once every 2 weeks. Following demonstration of tolerability to BV 1 mg/kg in cohort 1, BV was escalated to doses of 2 mg/kg and 5 mg/kg in cohorts 2 and 3 respectively. Patients were evaluated for potential PK interactions between BV, FOLFOX, and axitinib. Safety and tumor response were also assessed. Results: Among pts enrolled in cohorts 1, 2, and 3 (n=15), 2 patients (13%) showed a partial response and 9 patients (60%) exhibited stable disease. The most frequently reported, treatment-emergent grade 3–5 adverse events were neutropenia (n=3), hypertension (n=3), and dyspnea (n=2). PK parameters and plasma profiles of BV, oxaliplatin, and 5-FU were similar in the presence or absence of axitinib, with mean (%CV) AUCinf for platinum clearance from ultrafiltrate of 7,155 ng.h/mL (74%) and 7,702 ng.h/mL (72%), respectively (n=14). Axitinib PK profiles were similar in the presence or absence of BV/FOLFOX. Conclusions: PK data indicate no evidence of an interaction between axitinib and BV/FOLFOX. Axitinib 5 mg BID in combination with BV 1 mg/kg or 2 mg/kg and FOLFOX was well tolerated. Tolerability data for combination treatment with the 5 mg BV dose await completion of patient enrollment into cohort 3. A 3-arm, randomized phase II study of axitinib/FOLFOX vs BV/FOLFOX vs axitinib/BV/FOLFOX in pts with metastatic colorectal cancer has been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer

Association of diastolic blood pressure (dBP) ≥ 90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736)

3543 Background: Axitinib is an oral, potent and selective inhibitor of VEGF receptors 1, 2 and 3 in clinical development in multiple tumor types. BP elevation has been proposed as a potential efficacy marker of VEGF receptor inhibitors. The relationship between dBP ≥ 90 mmHg and OS was explored retrospectively across 6 separate phase II axitinib studies. Methods: Pts with non-small cell lung cancer (NSCLC), cytokine-refractory renal cell cancer (RCC), sorafenib-refractory RCC, thyroid cancer or melanoma received 5 mg BID single- agent axitinib; advanced pancreatic cancer (APC) pts received gemcitabine (GEM) 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles plus 5 mg BID axitinib. All 6 studies required BP ≤140/90 mmHg at baseline. BP was measured in clinic at every visit (days 1, 8, and 15 for APC, every 2 weeks for sorafenib-refractory RCC and every 4 weeks for all other studies) and daily at home by patients. Only in-clinic BP measurements were used in this analysis. Antihypertensive medications and/or ...