Review ArticleReviewsR

Utility of Hypertension as a Surrogate Marker for Efficacy of Antiangiogenic Therapy in NSCLC

TRACEY EVANS
Anticancer Research November 2012, 32 (11) 4629-4638;

Abstract

A plateau has been reached in the efficacy of cytotoxic chemotherapy for non-small cell lung cancer (NSCLC), highlighting the need for novel treatments for this poor-prognosis malignancy. Antiangiogenic agents, including the approved vascular endothelial growth factor (VEGF)-targeted monoclonal antibody, bevacizumab, as well as a number of investigational tyrosine kinase inhibitors (TKIs) that simultaneously target multiple angiogenic pathways, have demonstrated activity in patients with NSCLC. However, unlike the epidermal growth factor receptor (EGFR) TKIs erlotinib and gefitinib, for which the presence of EGFR-activating mutations are now known to predict response, no validated markers currently exist for the efficacy of antiangiogenic agents. Hypertension has been associated with antiangiogenic therapy and has also been evaluated as a surrogate marker for efficacy with this class of agents, although analyses, to date, have yielded conflicting results. This review provides a summary of currently available, clinically relevant data on the incidence of hypertension with VEGF-targeted antibodies and multitargeted antiangiogenic TKIs in advanced NSCLC and discusses the potential predictive role of hypertension on antiangiogenic therapy in such patients.

Antiangiogenic therapies have demonstrated activity across a multitude of malignancies, including colon cancer, renal cell carcinoma, breast cancer, and non-small cell lung cancer (NSCLC) (1). This efficacy, however, comes at the expense of increased toxicity, which includes risks of poor wound healing, bleeding, thrombosis, and proteinuria (2). A biomarker to identify which patients are most likely to derive benefit from antiangiogenic strategies could allow for an improved therapeutic ratio for these agents, but to date, none have been validated. Treatment-emergent hypertension has been associated with improved outcomes for some patients treated with antiangiogenic agents. While this is not as ideal as a biomarker that can be assessed prior to treatment initiation, if validated as predictive, monitoring for the development of hypertension could allow for early stratification of patients likely to benefit from continuation of antiangiogenic treatment. Establishment of a surrogate marker for efficacy may also allow for more efficient selection of new agents in this class. This review focuses on evidence, to date, from evaluation of treatment-emergent hypertension, as a surrogate marker for the efficacy of antiangiogenic therapies for NSCLC.

Bevacizumab (Avastin; Genentech, South San Francisco, CA, USA), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) ligand, was the first antiangiogenic agent approved for malignancy treatment (3). VEGF is the most widely studied pro-angiogenic growth factor, with an established role in the development and progression of malignancy (4, 5). Binding of bevacizumab to VEGF disrupts interaction of the ligand with the VEGF receptor (VEGFR), thereby preventing downstream signaling and ultimately inhibiting angiogenesis (6). In 2004, bevacizumab was approved by the US Food and Drug Administration (FDA) for the treatment of advanced colon cancer after demonstrating a survival benefit in combination with chemotherapy (3, 7).

For more than a decade, it is known that cytotoxic chemotherapy improves overall survival (OS) in advanced NSCLC, but the prognosis for these patients remains poor (8). Modern platinum-based chemotherapy doublets had reached an efficacy plateau (9, 10), so research efforts focused on the introduction of novel, targeted agents. It was not until the addition of bevacizumab to first-line chemotherapy in the Eastern Cooperative Oncology Group (ECOG) 4599 study that a statistically significant survival benefit was demonstrated from the addition of a novel agent to standard chemotherapy (11). This randomized, phase III trial compared carboplatin and paclitaxel alone or in combination with bevacizumab at 15 mg/kg. Patients treated on the bevacizumab arm had a 21% reduction in risk of death [hazard ratio (HR)=0.79; p=0.003] and a two-month improvement in median survival versus carboplatin/paclitaxel (from 10.3 to 12.3 months) (11). Bevacizumab-treated patients also experienced improved tumor response rates (RRs) and superior progression-free survival (PFS). Currently, bevacizumab is FDA-approved for the first-line treatment of unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC in combination with carboplatin and paclitaxel (3).

Inhibitors of the epidermal growth factor receptor (EGFR) have also demonstrated an improvement in survival of patients with NSCLC, both when used alone (e.g. erlotinib)(12) and in combination with cytotoxic chemotherapy (e.g. cetuximab) (13). While there are clear biomarkers for predicting the efficacy of EGFR-targeted agents in NSCLC, including EGFR-activating mutations (14, 15) and potentially immunohistochemical staining for EGFR (13, 16), biomarkers that are predictive of the efficacy of antiangiogenic agents remain elusive. Based on the results of a phase II study in which an unacceptable rate of fatal pulmonary hemorrhage was observed with bevacizumab/chemotherapy among patients with squamous NSCLC, histology remains an important factor in terms of safety in the selection of patients who receive bevacizumab (17). This risk of fatal pulmonary hemorrhage also exists, albeit at a low rate of 1% to 2% (11), in patients with non-squamous histology; as a result, there has been increasing interest in patient selection so that those unlikely to benefit are not exposed to this risk.

There are a number of small-molecule, multitargeted tyrosine kinase inhibitors (TKIs) that inhibit the VEGF signaling pathway through inhibition of the VEGFRs 1, 2, and 3. Three such agents have been approved for use in the treatment of malignancies but are not approved for NSCLC: sorafenib (18), sunitinib (19), and pazopanib (20). These TKIs inhibit not only VEGFRs but also other angiogenic and proliferative pathways, such as platelet-derived growth factor (PDGF) (21), basic fibroblast growth factor (bFGF) (22, 23), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (24), stem cell factor receptor (KIT), and fms-like tyrosine kinase-3 (FLT-3) (25). In addition to contributing to tumor angiogenesis in their own right, the PDGF and FGF pathways have also been implicated in resistance to VEGF-targeted therapy (26, 27).

All inhibitors of the VEGF signaling pathway appear to cause hypertension as an adverse effect, and it has been suggested that the development of hypertension may be a surrogate marker of efficacy. The mechanism by which hypertension is induced by these agents is uncertain, although considering the VEGF pathway is known to regulate vasodilation (28), it logically follows that inhibition of this pathway could lead to vasoconstriction and hypertension (29). Proposed mechanisms through which VEGF inhibition may lead to hypertension include signaling related to the VEGFR-1 protein (30, 31) and the vasodilators prostaglandin I-2 (PGI2) and nitric oxide (NO) (28, 30). Blockade of the VEGF signaling pathway leads to a decrease in nitric oxide production, causing vasculature constriction and a reduction in the renal excretion of sodium, potentially leading to an increase in blood pressure (32, 33). Hypertension may also be a consequence of vascular rarefaction, which is the depletion of arterioles and capillaries caused by the inhibition of the growth factors required to form new capillaries and recruit endothelial cell progenitors (2, 34-36). The mechanism and incidence of hypertension may differ between the various TKIs and bevacizumab given the ability of the former agents to inhibit VEGFR-2 and/or VEGFR-3 (28). While hypertension may be the mechanism by which antiangiogenic therapy causes proteinuria (33), there is also evidence that this may occur independently (37).

Hypertension has been evaluated as a surrogate marker for the efficacy of antiangiogenic agents, with results from analyses, to date, yielding mixed findings (38, 39). Analyses in advanced renal cell carcinoma suggest that treatment-emergent hypertension may predict outcomes (39). However, patients with renal cell cancer are likely to be unique in their propensity for hypertension, based on their disease pathophysiology, hence extrapolation of this finding to other malignancies is not necessarily warranted (40). Hypertension has also appeared to be predictive of outcome in other treatment settings, such as bevacizumab-treated colon cancer (41-44), glioblastoma (45), and sunitinib-treated gastrointestinal stromal tumors (46). In patients with metastatic breast cancer treated with bevacizumab and paclitaxel, those patients with grade 3/4 hypertension had significantly longer OS relative to those who did not experience hypertension (47). However, a study of bevacizumab in glioblastoma failed to demonstrate a correlation between hypertension and outcome (48).

This review provides a summary of data on the association of hypertension with VEGF-targeted antibodies and the various multitargeted TKIs, with a focus on evidence for the role of hypertension as a surrogate for efficacy in advanced NSCLC. Molecular targets of agents for which phase III trials in advanced NSCLC are completed or ongoing are summarized in Table I.

Incidence of Hypertension on Antiangiogenic Therapy for NSCLC

Antibody-based therapies. There have been two published articles on phase III trials of chemotherapy alone or with bevacizumab in advanced NSCLC. The first, as previously discussed, was ECOG 4599 (11). In this study (N=878), patients with recurrent or advanced non-squamous NSCLC were randomized to receive either carboplatin/paclitaxel alone or in combination with bevacizumab at 15 mg/kg. Patients underwent a total of six cycles of chemotherapy alone or with bevacizumab, and in the absence of disease progression, those randomized to the bevacizumab arm continued to receive maintenance bevacizumab every three weeks until disease progression. The incidence of grade 3/4 hypertension in ECOG 4599 was significantly higher in the bevacizumab arm, compared with chemotherapy alone (7% versus 0.7%, respectively; p<0.001) (11). In the AVAiL trial (N=1,043), patients with recurrent or advanced non-squamous NSCLC received either cisplatin/gemcitabine-alone or with one of two dose levels of bevacizumab, either 7.5 mg/kg or 15 mg/kg (49). The incidence of grade ≥3 hypertension was 6% with bevacizumab at 7.5 mg/kg, 9% with the 15 mg/kg dose, and 2% with chemotherapy-alone (49).

View this table:
Table I.

Antiangiogenic antibody-based agents and tyrosine kinase inhibitors (TKIs) reaching phase III development for advanced non-small cell lung cancer (NSCLC).

Meta-analyses have described an increased risk of hypertension during treatment with bevacizumab. In a meta-analysis of hypertension with bevacizumab among various malignancies (N=1,850 patients across seven studies, including a phase II trial in NSCLC), the relative risk of all-grade hypertension was 3.0 [95% confidence interval (CI)=2.2-4.2; p<0.001] for bevacizumab 7.5 mg/kg and 7.5 (95% CI=4.2-13.4; p<0.001) for bevacizumab at 15 mg/kg (30). In a subsequent, larger meta-analysis of hypertension with bevacizumab among various malignancies (N=12,656 patients across 20 studies, including four phase II or III trials in NSCLC), the incidence of all-grade hypertension was 23.6% and that of grade 3/4 hypertension was 7.9% (29). The relative risk of grade 3/4 hypertension was 7.06 (95% CI=3.66-13.62) in the NSCLC subset (29).

Aflibercept, formerly known as AVE0005 (VEGF Trap; Regeneron, Tarrytown, NY, USA), is an antiangiogenic agent consisting of portions of the extracellular domains of human VEGFR-1 and VEGFR-2 fused to the Fc portion of human immunoglobulin G. In a phase I, dose-escalation trial of aflibercept in various types of advanced solid tumor (N=47), the incidence of all-grade hypertension was 38.3%, which was mostly grade 3 in severity (n=13) (50).

Multitargeted TKIs. Hypertension has also been reported with multitargeted TKIs that simultaneously inhibit multiple proangiogenic factors. Sorafenib (Nexavar®; Bayer, Leverkusen, Germany) was evaluated in combination with first-line carboplatin/paclitaxel in a phase III study in advanced NSCLC (ESCAPE; N=926) (51). This study was closed due to futility in reaching the primary end-point of improved OS. The observed incidence of grade 3/4 hypertension was 3% in the sorafenib arm compared with 1% in the chemotherapy-alone arm. The incidence of all-grade hypertension was 12% in the sorafenib arm versus 6% in chemotherapy-alone (p<0.001) (51). In a meta-analysis of hypertension with sorafenib among various malignancies (N=4,599 across nine studies, including a phase II trial in NSCLC), the incidence of all grade and grade 3/4 hypertension was 23.4% and 5.7%, respectively (52).

Sunitinib (Sutent®; Pfizer, New London, CT, USA) has been evaluated in phase II trials in NSCLC. On an intermittent dosing schedule of 4 weeks on and 2 weeks-off in patients with pre-treated advanced NSCLC (N=63), the incidence of all-grade and grade 3 hypertension was 11% and 5%, respectively (53). In a continuous-dose study of sunitinib in previously treated advanced NSCLC (N=47), the incidence of all-grade hypertension was 28% and that of grade 3 hypertension was 9% (54). Finally, in a meta-analysis of hypertension with sunitinib across various malignancies (N=4,999 patients across 13 studies, including two phase II trials in NSCLC), the incidence of all-grade and grade 3/4 hypertension was 21.6% and 6.8%, respectively (55).

In a phase II trial (N=35) of single-agent, pazopanib (Votrient; GlaxoSmithKline, London, UK), as neoadjuvant therapy for stage I/II resectable NSCLC, hypertension was the most common adverse event (43% incidence) but was limited to grade 1/2 severity (56).

Vandetanib (Zactima; AstraZeneca, Wilmington, DE, USA) is no longer being studied in advanced NSCLC due to futility, based on the results of several large phase III clinical trials (57-60). In the ZEPHYR phase III trial (N=924), the incidence of all-grade hypertension was 26% among patients receiving vandetanib versus 3% receiving placebo (57). In a phase III trial of second-line vandetanib plus pemetrexed versus pemetrexed alone (ZEAL; N=534), all-grade hypertension occurred in 12% of those receiving vandetanib versus 3% of those receiving chemotherapy-alone (58). In another phase III trial of second-line docetaxel-alone or with vandetanib (ZODIAC; N=1,391), all-grade hypertension was reported in 6% of patients in the vandetanib arm versus 2% of patients who received docetaxel-alone (60). The corresponding grade 3 incidence of hypertension was 0.9% with vandetanib and 0.1% with docetaxel-alone (60). In a phase III trial of single-agent vandetanib versus erlotinib in pre-treated advanced NSCLC (ZEST; N=1,240), the incidence of all-grade hypertension was 16% with vandetanib versus 2% with erlotinib (59).

Nintedanib (BIBF 1120; Boehringer Ingelheim, Ingelheim, Germany) may have a lower propensity for causing hypertension relative to other multitargeted TKIs. In a phase I study of nintedanib in combination with pemetrexed as second-line therapy for advanced NSCLC (N=26), there was one reported case of grade 1 hypertension (61). In a phase II trial of two doses of single-agent nintedanib in advanced, previously-treated NSCLC (N=73), no patients developed more than grade 2 hypertension (62). There was one confirmed partial response at the higher dose, although no difference in efficacy between dose groups was noted overall, and 48% of patients achieved stable disease (62).

In a phase III trial of motesanib (Amgen; Thousand Oaks, CA, USA) plus first-line carboplatin/paclitaxel in non-squamous advanced NSCLC (MONET1; N=1,090), which failed to meet the primary objective of prolonged OS, hypertension was among the grade 3 or greater toxicities that occurred more frequently with motesanib versus placebo (7% versus 1%, respectively) (63).

In a phase I/II trial (BR24; N=296), first-line cediranib (Recentin; AstraZeneca, Wilmington, DE, USA) in combination with carboplatin/paclitaxel demonstrated activity but significant toxicity despite a protocol amendment to reduce the cediranib dose from 45 mg to 30 mg (64). Hypertension of grade 3 or more was among the most common toxicities observed at the 30 mg dose (19% with cediranib versus 2% with placebo). The corresponding all-grade incidence of hypertension was 38% versus 10%, respectively (64).

Correlation of Hypertension with Response to Antiangiogenic Therapy for NSCLC

Hypertension has been evaluated as a potential marker of efficacy of antiangiogenic therapy in NSCLC and in mixed solid tumor analyses that included NSCLC. In a recent meta-analysis of the association between hypertension and clinical outcome in six phase III studies of bevacizumab for metastatic cancer (N=~5,900 patients, including NSCLC patients on the AVAiL study), hypertension did not predict clinical benefit based upon OS or PFS in five out of the six studies (the one exception being a metastatic colon cancer trial) (65). In the meta-analysis, the primary definition of early hypertension was a systolic blood pressure increase of >20 mmHg or a diastolic blood pressure increase of >10 mmHg in the first 60 days of treatment. In the AVAiL study, specifically, hypertension was not found to be predictive of benefit with bevacizumab (65). The HRs in the control group for hypertension were 0.95 for PFS (p=0.69) and 0.85 for OS (p=0.33). HRs for the correlation between the control and bevacizumab-treated groups were 1.04 for PFS (p=0.83) and 1.32 for OS (p=0.21) (65).

In the first study to model blood pressure over time in patients with NSCLC, Dahlberg et al. performed a retrospective analysis of ECOG 4599 to examine the hypothesis that the onset of hypertension during treatment denotes successful blockage of the VEGF pathway and is therefore correlated with an improved outcome (66). The primary analysis classified patients as being hypertensive if blood pressure during cycle 1 ever exceeded 150/100, or if diastolic blood pressure increased at the end of the first cycle by >20 mmHg from baseline. Of the 850 patients enrolled on ECOG 4599, eligible for inclusion, 106 patients had missing blood pressure measurements at baseline or at the end of cycle 1, and three patients had progressive disease or death prior to the end of cycle 1. Therefore, 741 patients were included in the primary analysis. There were no differences in baseline blood pressure measurements between patients in the bevacizumab arm versus those in the chemotherapy arm. No differences in survival by blood pressure status were observed within the chemotherapy arm, indicating hypertension was not a predictive factor in this study. On multivariate analysis, bevacizumab-treated patients who developed hypertension did have a significantly longer OS and PFS compared with those who did not develop hypertension (OS=15.9 versus 11.5 months, p=0.0002; PFS=7.0 versus 5.5 months, p<0.0001; Figure 1). However, in a formal test for treatment by blood pressure interaction, statistical significance was not reached, and the authors noted that this analysis was not sufficiently powered to evaluate the predictive value of hypertension. In addition, ECOG 4599 did not require reporting of grade 1/2 hypertension or blood pressure changes that were not unexpected or considered at least possibly treatment-related (66).

Figure 1.
Figure 1.

Analysis of hypertension in Eastern Cooperative Oncology Group 4599 trial. A: Overall survival (OS) and B: progression-free survival (PFS) after one cycle of therapy. Adapted from Dahlberg et al. (66). Reprinted with permission. American Society of Clinical Oncology © 2010. All rights reserved. CI, confidence interval.

In a retrospective analysis of the BR24 trial of first-line carboplatin/paclitaxel with and without cediranib in advanced NSCLC, the association between hypertension and efficacy was explored (67). The definition utilized included both new-onset hypertension and worsening hypertension (in patients with pre-existing hypertension). The development of hypertension was associated with a reduced risk of death in both the cediranib arm (HR=0.62; 95% CI=0.38-1.03; p=0.06) and the placebo arm (HR=0.49; 95% CI=0.30-0.80; p=0.0045). For both arms combined, hypertension was an independent predictive factor for better OS (HR=0.7; 95% CI=0.5-1.0; p=0.06). Landmark analyses at the end of cycles 1 and 2 demonstrated improved OS among hypertensive patients in both arms (Figure 2). However, development of hypertension in this study did not predict benefit from cediranib (67).

Additional smaller studies and retrospective analyses have evaluated the potential predictive value of hypertension with bevacizumab treatment. A recent retrospective chart review (N=454; n=104 with lung cancer) stratified patients treated with bevacizumab by hypertension status: group A developed hypertension or required an increase in antihypertensives during treatment with bevacizumab; group B did not develop hypertension or did not require increased antihypertensives during treatment with bevacizumab (68). The median OS was significantly prolonged in group A versus group B (607 versus 355 days, p<0.0001). The median PFS was also significantly prolonged in group A versus group B (197 versus 117 days, p<0.0001) (68). In addition, a recently published case series described six patients who developed hypertension and proteinuria on bevacizumab-containing treatment, all with prolonged PFS (69). One of these patients had NSCLC and experienced a PFS of >6 months with bevacizumab/pemetrexed (69).

A retrospective analysis of data from five phase II trials of axitinib (N=230; n=30 patients with NSCLC), focused on the relationship between diastolic blood pressure ≥90 mmHg and efficacy (70). In a pooled analysis, patients who developed a diastolic blood pressure ≥90 mmHg while on therapy had significantly prolonged OS compared with normotensive patients (25.8 versus 14.9 months, respectively; HR=0.55; 95% CI=0.39-0.77; p<0.001) and a significantly higher RR (43.9% versus 12.0%, respectively, p<0.001). PFS was also numerically prolonged in these patients compared with those who had diastolic blood pressure <90 mmHg (10.2 versus 7.1 months, respectively; HR=0.76; 95% CI=0.54-1.06; p=0.107). Specific analysis of patients with NSCLC showed that median OS was not reached for patients with diastolic blood pressure ≥90 mmHg versus 12.8 months for patients without diastolic blood pressure ≥90 mmHg (70).

Figure 2.
Figure 2.

Analysis of hypertension in BR24 trial. Overall survival for patients with and without hypertension, by treatment arm. A: Cediranib, end of cycle 1; B: cediranib, end of cycle 2; C: placebo, end of cycle 1; D: placebo, end of cycle 2. CI, confidence interval; HR, hazard ratio. Adapted from Goodwin et al. by permission of Oxford University Press © 2010 (67).

Discussion

Because hypertension is a treatment-emergent adverse event, its potential use as a surrogate marker for efficacy has inherent limitations (38). Currently, there are no known patient characteristics that predict for development of hypertension during antiangiogenic therapy. While genetic polymorphisms protecting against or predisposing patients to antiangiogenic therapy-induced hypertension have been described (47, 71, 72), the clinical applicability of these are as yet uncertain. Because the earliest time point for detecting antiangiogenic therapy-induced hypertension may be as early as the first day of treatment, monitoring would need to begin immediately upon treatment initiation (73, 74). Notably, the relative importance of early versus later blood pressure changes is also unknown (38).

Under real-world conditions, there are numerous shortcomings that could limit the implementation of blood pressure monitoring as a potential surrogate for antiangiogenic therapy efficacy. Repeated measurements in the clinical setting may not reflect true hypertension status, and therefore patients may require ambulatory blood pressure monitoring (40, 75). Additional confounding factors are the differing definitions of hypertension utilized and the unknown impact of patient history of antihypertensive management on its potential predictive value. Analyses to date have focused on patients who either do or do not develop hypertension, and the relevance of blood pressure elevations that remain within the normal range is uncertain (40).

Dosing to hypertension is an intriguing concept for antiangiogenic agents, but one for which validation is lacking. An analysis of blood pressure changes in a mixed solid tumor population treated with varying doses of sorafenib did not support a dose-to-hypertension approach to increasing activity (76). The dose escalation utilized in this study did not lead to a consistent elevation in diastolic blood pressure.

Conclusion

Hypertension is a common adverse event of therapy with antiangiogenic agents. However, hypertension may not be a true class effect as the incidence and severity varies across agents. Available evidence, albeit limited, suggests that hypertension does not represent a surrogate for the efficacy of antiangiogenic therapy in advanced NSCLC. Indeed, agents that caused considerable hypertension, such as vandetanib and sorafenib, did not show sufficient efficacy for continued development in NSCLC. Ongoing investigation of antiangiogenic agents and the association between efficacy and various biomarkers, including hypertension, is nevertheless in order.

Acknowledgements

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Editorial assistance was provided by Allison Michaelis, Ph.D., of MedErgy, which was contracted by BIPI for these services. The Author met criteria for authorship as recommended by the International Committee of Medical Journal Editors, was fully responsible for all content and editorial decisions, and was involved in all stages of manuscript development. The Author received no compensation related to the development of the manuscript.

Footnotes

  • Conflicts of Interest

    Dr. Evans has served as a consultant for Genentech and Lilly.

  • Received May 30, 2012.
  • Revision received September 17, 2012.
  • Accepted September 20, 2012.

References

  1. ↵
    1. Van Meter ME,
    2. Kim ES
    : Bevacizumab: current updates in treatment. Curr Opin Oncol 22(6): 586-591, 2010.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Gressett SM,
    2. Shah SR
    : Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother 43(3): 490-501, 2009.
    OpenUrlCrossRefPubMed
  3. ↵
    AVASTIN® (bevacizumab) Solution for intravenous infusion [package insert]. South San Francisco, CA: Genentech, Inc., 2011.
  4. ↵
    1. Folkman J,
    2. Shing Y
    : Angiogenesis. J Biol Chem 267(16): 10931-10934, 1992.
    OpenUrlFREE Full Text
  5. ↵
    1. Folkman J,
    2. Klagsbrun M
    : Vascular physiology. A family of angiogenic peptides. Nature 329(6141): 671-672, 1987.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Ferrara N,
    2. Hillan KJ,
    3. Novotny W
    : Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333(2): 328-335, 2005.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Hurwitz H,
    2. Fehrenbacher L,
    3. Novotny W,
    4. Cartwright T,
    5. Hainsworth J,
    6. Heim W,
    7. Berlin J,
    8. Baron A,
    9. Griffing S,
    10. Holmgren E,
    11. Ferrara N,
    12. Fyfe G,
    13. Rogers B,
    14. Ross R,
    15. Kabbinavar F
    : Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23): 2335-42, 2004.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Non-Small Cell Lung Cancer Collaborative Group
    : Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311(7010): 899-909, 1995.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Breathnach OS,
    2. Freidlin B,
    3. Conley B,
    4. Green MR,
    5. Johnson DH,
    6. Gandara DR,
    7. O'Connell M,
    8. Shepherd FA,
    9. Johnson BE
    : Twenty-two years of phase III trials for patients with advanced non-small cell lung cancer: Sobering results. J Clin Oncol 19(6): 1734-1742, 2001.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Carney DN
    : Lung cancer-time to move on from chemotherapy. N Engl J Med 346(2): 126-128, 2002.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Sandler A,
    2. Gray R,
    3. Perry MC,
    4. Brahmer J,
    5. Schiller JH,
    6. Dowlati A,
    7. Lilenbaum R,
    8. Johnson DH
    : Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355(24): 2542-2550, 2006.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Shepherd FA,
    2. Rodrigues Pereira J,
    3. Ciuleanu T,
    4. Tan EH,
    5. Hirsh V,
    6. Thongprasert S,
    7. Campos D,
    8. Maoleekoonpiroj S,
    9. Smylie M,
    10. Martins R,
    11. van Kooten M,
    12. Dediu M,
    13. Findlay B,
    14. Tu D,
    15. Johnston D,
    16. Bezjak A,
    17. Clark G,
    18. Santabarbara P,
    19. Seymour L
    : Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353(2): 123-132, 2005.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Pirker R,
    2. Pereira JR,
    3. Szczesna A,
    4. von PJ,
    5. Krzakowski M,
    6. Ramlau R,
    7. Vynnychenko I,
    8. Park K,
    9. Yu CT,
    10. Ganul V,
    11. Roh JK,
    12. Bajetta E,
    13. O'Byrne K,
    14. de MF,
    15. Eberhardt W,
    16. Goddemeier T,
    17. Emig M,
    18. Gatzemeier U
    : Cetuximab plus chemotherapy in patients with advanced non-small cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 373(9674): 1525-1531, 2009.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Lynch TJ,
    2. Bell DW,
    3. Sordella R,
    4. Gurubhagavatula S,
    5. Okimoto RA,
    6. Brannigan BW,
    7. Harris PL,
    8. Haserlat SM,
    9. Supko JG,
    10. Haluska FG,
    11. Louis DN,
    12. Christiani DC,
    13. Settleman J,
    14. Haber DA
    : Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 350(21): 2129-2139, 2004.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Paez JG,
    2. Janne PA,
    3. Lee JC,
    4. Tracy S,
    5. Greulich H,
    6. Gabriel S,
    7. Herman P,
    8. Kaye FJ,
    9. Lindeman N,
    10. Boggon TJ,
    11. Naoki K,
    12. Sasaki H,
    13. Fujii Y,
    14. Eck MJ,
    15. Sellers WR,
    16. Johnson BE,
    17. Meyerson M
    : EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304(5676): 1497-1500, 2004.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Pirker R,
    2. Pereira JR,
    3. von PJ,
    4. Krzakowski M,
    5. Ramlau R,
    6. Park K,
    7. de MF,
    8. Eberhardt WE,
    9. Paz-Ares L,
    10. Storkel S,
    11. Schumacher KM,
    12. von HA,
    13. Celik I,
    14. O'Byrne KJ
    : EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 13(1): 33-42, 2012.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Johnson DH,
    2. Fehrenbacher L,
    3. Novotny WF,
    4. Herbst RS,
    5. Nemunaitis JJ,
    6. Jablons DM,
    7. Langer CJ,
    8. DeVore RF III.,
    9. Gaudreault J,
    10. Damico LA,
    11. Holmgren E,
    12. Kabbinavar F
    : Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 22(11): 2184-2191, 2004.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    NEXAVAR (sorafenib) tablets, oral [package insert]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc., 2010.
  19. ↵
    SUTENT® (sunitinib malate) capsules, oral [package insert]. New York, NY: Pfizer Inc., 2011.
  20. ↵
    Votrient™ (pazopanib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2010; revised April 2010.
  21. ↵
    1. Levitzki A
    : PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev 15(4): 229-235, 2004.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Kano MR,
    2. Morishita Y,
    3. Iwata C,
    4. Iwasaka S,
    5. Watabe T,
    6. Ouchi Y,
    7. Miyazono K,
    8. Miyazawa K
    : VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling. J Cell Sci 118(Pt 16): 3759-3768, 2005.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Nissen LJ,
    2. Cao R,
    3. Hedlund EM,
    4. Wang Z,
    5. Zhao X,
    6. Wetterskog D,
    7. Funa K,
    8. Brakenhielm E,
    9. Cao Y
    : Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 117(10): 2766-2777, 2007.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Vakiani E,
    2. Solit DB
    : KRAS and BRAF: Drug targets and predictive biomarkers. J Pathol 223(2): 219-229, 2011.
    OpenUrlPubMed
  25. ↵
    1. Kumar R,
    2. Crouthamel MC,
    3. Rominger DH,
    4. Gontarek RR,
    5. Tummino PJ,
    6. Levin RA,
    7. King AG
    : Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 101(10): 1717-1723, 2009.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Erber R,
    2. Thurnher A,
    3. Katsen AD,
    4. Groth G,
    5. Kerger H,
    6. Hammes HP,
    7. Menger MD,
    8. Ullrich A,
    9. Vajkoczy P
    : Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18(2): 338-340, 2004.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Casanovas O,
    2. Hicklin DJ,
    3. Bergers G,
    4. Hanahan D
    : Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4): 299-309, 2005.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Roodhart JM,
    2. Langenberg MH,
    3. Witteveen E,
    4. Voest EE
    : The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol 3(2): 132-143, 2008.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Ranpura V,
    2. Pulipati B,
    3. Chu D,
    4. Zhu X,
    5. Wu S
    : Increased risk of high-grade hypertension with bevacizumab in cancer patients: A meta-analysis. Am J Hypertens 23(5): 460-468, 2010.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Zhu X,
    2. Wu S,
    3. Dahut WL,
    4. Parikh CR
    : Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 49(2): 186-193, 2007.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Launay-Vacher V,
    2. Deray G
    : Hypertension and proteinuria: A class-effect of antiangiogenic therapies. Anticancer Drugs 20(1): 81-82, 2009.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Hood JD,
    2. Meininger CJ,
    3. Ziche M,
    4. Granger HJ
    : VEGF up-regulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274(3 Pt 2): 1054-1058, 1998.
    OpenUrl
  33. ↵
    1. van Heeckeren WJ,
    2. Ortiz J,
    3. Cooney MM,
    4. Remick SC
    : Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: Clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 25(21): 2993-2995, 2007.
    OpenUrlFREE Full Text
  34. ↵
    1. Sane DC,
    2. Anton L,
    3. Brosnihan KB
    : Angiogenic growth factors and hypertension. Angiogenesis 7(3): 193-201, 2004.
    OpenUrlCrossRefPubMed
    1. Bobik A
    : The structural basis of hypertension: Vascular remodelling, rarefaction and angiogenesis/arteriogenesis. J Hypertens 23(8): 1473-1475, 2005.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Mourad JJ,
    2. des Guetz G,
    3. Debbabi H,
    4. Levy BI
    : Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 19(5): 927-34, 2008.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Eremina V,
    2. Jefferson JA,
    3. Kowalewska J,
    4. Hochster H,
    5. Haas M,
    6. Weisstuch J,
    7. Richardson C,
    8. Kopp JB,
    9. Kabir MG,
    10. Backx PH,
    11. Gerber HP,
    12. Ferrara N,
    13. Barisoni L,
    14. Alpers CE,
    15. Quaggin SE
    : VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358(11): 1129-1136, 2008.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Jubb AM,
    2. Harris AL
    : Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11(12): 1172-1183, 2010.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Rini BI
    : Hypertension as a biomarker for anti-VEGF efficacy: incidence, mechanisms, and association with clinical outcome. Kidney Cancer J 8(4): 106-117, 2011.
    OpenUrl
  40. ↵
    1. Mir O,
    2. Ropert S,
    3. Alexandre J,
    4. Goldwasser F
    : Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol 20(5): 967-970, 2009.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Ryanne Wu R,
    2. Lindenberg PA,
    3. Slack R,
    4. Noone AM,
    5. Marshall JL,
    6. He AR
    : Evaluation of hypertension as a marker of bevacizumab efficacy. J Gastrointest Cancer 40(3-4): 101-108, 2009.
    OpenUrlCrossRefPubMed
    1. Scartozzi M,
    2. Galizia E,
    3. Chiorrini S,
    4. Giampieri R,
    5. Berardi R,
    6. Pierantoni C,
    7. Cascinu S
    : Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 20(2): 227-230, 2009.
    OpenUrlCrossRefPubMed
    1. De Stefano A,
    2. Carlomagno C,
    3. Pepe S,
    4. Bianco R,
    5. De Placido S
    : Bevacizumab-related arterial hypertension as a predictive marker in metastatic colorectal cancer patients. Cancer Chemother Pharmacol 68(5): 1207-1213, 2011.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Osterlund P,
    2. Soveri LM,
    3. Isoniemi H,
    4. Poussa T,
    5. Alanko T,
    6. Bono P
    : Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer 104(4): 599-604, 2011.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Nangia CS,
    2. Wang D,
    3. Scarpace L,
    4. Schultz L,
    5. Khanshour A,
    6. Mikkelsen T
    : The role of the development of hypertension or proteinuria in predicting outcome with the use of bevacizumab for patients with glioblastoma multiforme (GBM). J Clin Oncol 29(suppl): Abstract 2021, 2011.
  46. ↵
    1. Rutkowski P,
    2. Bylina E,
    3. Switaj T,
    4. Klimczak A,
    5. Falkowski S,
    6. Kroc J,
    7. Lugowska IA,
    8. Brzeskwiniewicz M,
    9. Wozniak A,
    10. Siedlecki J,
    11. Limon J
    : An analysis of arterial hypertension and mutational status as predictive factors for results of sunitinib (SU) therapy in gastrointestinal stromal tumors (GIST). J Clin Oncol 29(suppl): Abstract 10017, 2011.
  47. ↵
    1. Schneider BP,
    2. Wang M,
    3. Radovich M,
    4. Sledge GW,
    5. Badve S,
    6. Thor A,
    7. Flockhart DA,
    8. Hancock B,
    9. Davidson N,
    10. Gralow J,
    11. Dickler M,
    12. Perez EA,
    13. Cobleigh M,
    14. Shenkier T,
    15. Edgerton S,
    16. Miller KD
    : Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26(28): 4672-4678, 2008.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Wick A,
    2. Schafer N,
    3. Dorner N,
    4. Schemmer D,
    5. Platten M,
    6. Bendszus M,
    7. Wick W
    : Arterial hypertension and bevacizumab treatment in glioblastoma: No correlation with clinical outcome. J Neurooncol 97(1): 157-158, 2010.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Reck M,
    2. von Pawel J,
    3. Zatloukal P,
    4. Ramlau R,
    5. Gorbounova V,
    6. Hirsh V,
    7. Leighl N,
    8. Mezger J,
    9. Archer V,
    10. Moore N,
    11. Manegold C
    : Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small cell lung cancer: AVAiL. J Clin Oncol 27(8): 1227-1234, 2009.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Lockhart AC,
    2. Rothenberg ML,
    3. Dupont J,
    4. Cooper W,
    5. Chevalier P,
    6. Sternas L,
    7. Buzenet G,
    8. Koehler E,
    9. Sosman JA,
    10. Schwartz LH,
    11. Gultekin DH,
    12. Koutcher JA,
    13. Donnelly EF,
    14. Andal R,
    15. Dancy I,
    16. Spriggs DR,
    17. Tew WP
    : Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 28(2): 207-214, 2010.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Scagliotti G,
    2. Novello S,
    3. von Pawel J,
    4. Reck M,
    5. Pereira JR,
    6. Thomas M,
    7. brao Miziara JE,
    8. Balint B,
    9. de Marinis F,
    10. Keller A,
    11. Aren O,
    12. Csollak M,
    13. Albert I,
    14. Barrios CH,
    15. Grossi F,
    16. Krzakowski M,
    17. Cupit L,
    18. Cihon F,
    19. DiMatteo S,
    20. Hanna N
    : Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small cell lung cancer. J Clin Oncol 28(11): 1835-1842, 2010.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Wu S,
    2. Chen JJ,
    3. Kudelka A,
    4. Lu J,
    5. Zhu X
    : Incidence and risk of hypertension with sorafenib in patients with cancer: A systematic review and meta-analysis. Lancet Oncol 9(2): 117-123, 2008.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Socinski MA,
    2. Novello S,
    3. Brahmer JR,
    4. Rosell R,
    5. Sanchez JM,
    6. Belani CP,
    7. Govindan R,
    8. Atkins JN,
    9. Gillenwater HH,
    10. Pallares C,
    11. Tye L,
    12. Selaru P,
    13. Chao RC,
    14. Scagliotti GV
    : Multicenter, phase II trial of sunitinib in previously treated, advanced non-small cell lung cancer. J Clin Oncol 26(4): 650-656, 2008.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Novello S,
    2. Scagliotti GV,
    3. Rosell R,
    4. Socinski MA,
    5. Brahmer J,
    6. Atkins J,
    7. Pallares C,
    8. Burgess R,
    9. Tye L,
    10. Selaru P,
    11. Wang E,
    12. Chao R,
    13. Govindan R
    : Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. Br J Cancer 101(9): 1543-1548, 2009.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Zhu X,
    2. Stergiopoulos K,
    3. Wu S
    : Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: Systematic review and meta-analysis. Acta Oncol 48(1): 9-17, 2009.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Altorki N,
    2. Lane ME,
    3. Bauer T,
    4. Lee PC,
    5. Guarino MJ,
    6. Pass H,
    7. Felip E,
    8. Peylan-Ramu N,
    9. Gurpide A,
    10. Grannis FW,
    11. Mitchell JD,
    12. Tachdjian S,
    13. Swann RS,
    14. Huff A,
    15. Roychowdhury DF,
    16. Reeves A,
    17. Ottesen LH,
    18. Yankelevitz DF
    : Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol 28(19): 3131-3137, 2010.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Lee J,
    2. Hirsh V,
    3. Park K,
    4. Qin S,
    5. Blajman CR,
    6. Perng R,
    7. Emerson L,
    8. Langmuir PB,
    9. Manegold C
    : Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): A randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 28(15s): Abstract 7525, 2010.
  58. ↵
    1. De Boer RH,
    2. Arrieta O,
    3. Yang CH,
    4. Gottfried M,
    5. Chan V,
    6. Raats J,
    7. de Marinis F,
    8. Abratt RP,
    9. Wolf J,
    10. Blackhall FH,
    11. Langmuir P,
    12. Milenkova T,
    13. Read J,
    14. Vansteenkiste JF
    : Vandetanib plus pemetrexed for the second-line treatment of advanced non-small cell lung cancer: A randomized, double-blind phase III trial. J Clin Oncol 29(8): 1067-1074, 2011.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Natale RB,
    2. Thongprasert S,
    3. Greco FA,
    4. Thomas M,
    5. Tsai CM,
    6. Sunpaweravong P,
    7. Ferry D,
    8. Mulatero C,
    9. Whorf R,
    10. Thompson J,
    11. Barlesi F,
    12. Langmuir P,
    13. Gogov S,
    14. Rowbottom JA,
    15. Goss GD
    : Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small cell lung cancer. J Clin Oncol 29(8): 1059-1066, 2011.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Herbst RS,
    2. Sun Y,
    3. Eberhardt WE,
    4. Germonpre P,
    5. Saijo N,
    6. Zhou C,
    7. Wang J,
    8. Li L,
    9. Kabbinavar F,
    10. Ichinose Y,
    11. Qin S,
    12. Zhang L,
    13. Biesma B,
    14. Heymach JV,
    15. Langmuir P,
    16. Kennedy SJ,
    17. Tada H,
    18. Johnson BE
    : Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (ZODIAC): A double-blind, randomised, phase 3 trial. Lancet Oncol 11(7): 619-626, 2010.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Ellis PM,
    2. Kaiser R,
    3. Zhao Y,
    4. Stopfer P,
    5. Gyorffy S,
    6. Hanna N
    : Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 16(10): 2881-2889, 2010.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Reck M,
    2. Kaiser R,
    3. Eschbach C,
    4. Stefanic M,
    5. Love J,
    6. Gatzemeier U,
    7. Stopfer P,
    8. von Pawel J
    : A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small cell lung cancer. Ann Oncol 22(6): 1374-1381, 2011.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Scagliotti G,
    2. Vynnychenko I,
    3. Ichinose Y,
    4. Park K,
    5. Kubota K,
    6. Blackhall FH,
    7. Pirker R,
    8. Galiulin R,
    9. Ciuleanu T,
    10. Sydorenko O,
    11. Dediu M,
    12. Papai-Szekely Z,
    13. Martinez Banaclocha N,
    14. McCoy S,
    15. Yao B,
    16. Hei Y,
    17. Spigel DR
    : An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol 29(suppl): Abstract LBA7512, 2011.
  64. ↵
    1. Goss GD,
    2. Arnold A,
    3. Shepherd FA,
    4. Dediu M,
    5. Ciuleanu TE,
    6. Fenton D,
    7. Zukin M,
    8. Walde D,
    9. Laberge F,
    10. Vincent MD,
    11. Ellis PM,
    12. Laurie SA,
    13. Ding K,
    14. Frymire E,
    15. Gauthier I,
    16. Leighl NB,
    17. Ho C,
    18. Noble J,
    19. Lee CW,
    20. Seymour L
    : Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small cell lung cancer: NCIC Clinical Trials Group BR24 study. J Clin Oncol 28(1): 49-55, 2010.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Hurwitz H,
    2. Douglas PS,
    3. Middleton JP,
    4. Sledge GW,
    5. Johnson DH,
    6. Reardon DA,
    7. Chen D,
    8. Rosen O
    : Analysis of early hypertension (HTN) and clinical outcome with bevacizumab (BV). J Clin Oncol 28(7S): Abstract 3039, 2010.
  66. ↵
    1. Dahlberg SE,
    2. Sandler AB,
    3. Brahmer JR,
    4. Schiller JH,
    5. Johnson DH
    : Clinical course of advanced non-small cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 28(6): 949-954, 2010.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Goodwin R,
    2. Ding K,
    3. Seymour L,
    4. Lemaitre A,
    5. Arnold A,
    6. Shepherd FA,
    7. Dediu M,
    8. Ciuleanu T,
    9. Fenton D,
    10. Zukin M,
    11. Walde D,
    12. Laberge F,
    13. Vincent M,
    14. Ellis PM,
    15. Laurie SA
    : Treatment-emergent hypertension and outcomes in patients with advanced non-small cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24. Ann Oncol 21(11): 2220-2226, 2010.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Munoz J,
    2. Sanchez BE,
    3. Sharifi M,
    4. Kostoff D,
    5. Ali HY,
    6. Hanbali AS,
    7. Kuriakose P,
    8. Wollner IS
    : Hypertension as a clinical marker of response to bevacizumab across malignancies. J Clin Oncol 29(suppl): Abstract e16601, 2011.
  69. ↵
    1. Saloustros E,
    2. Androulakis N,
    3. Vamvakas L,
    4. Mavroudis D,
    5. Georgoulias V
    : Favorable clinical course of patients experiencing bevacizumab-induced proteinuria. Case Rep Oncol 3(3): 368-371, 2010.
    OpenUrlPubMed
  70. ↵
    1. Rini BI,
    2. Schiller JH,
    3. Fruehauf JP,
    4. Cohen EE,
    5. Tarazi JC,
    6. Rosbrook B,
    7. Bair AH,
    8. Ricart AD,
    9. Olszanski AJ,
    10. Letrent KJ,
    11. Kim S,
    12. Rixe O
    : Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 17(11): 3841-3849, 2011.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    1. Jain L,
    2. Sissung TM,
    3. Danesi R,
    4. Kohn EC,
    5. Dahut WL,
    6. Kummar S,
    7. Venzon D,
    8. Liewehr D,
    9. English BC,
    10. Baum CE,
    11. Yarchoan R,
    12. Giaccone G,
    13. Venitz J,
    14. Price DK,
    15. Figg WD
    : Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. J Exp Clin Cancer Res 29: 95, 2010.
    OpenUrlCrossRefPubMed
  72. ↵
    1. van der Veldt AA,
    2. Eechoute K,
    3. Oosting S,
    4. Kappers MH,
    5. Haanen JBAG,
    6. Reyners AKL,
    7. Gelderblom H,
    8. Guchelaar H,
    9. Van Herpen C,
    10. Boven E,
    11. Mathijssen R
    : Single-nucleotide polymorphisms (SNPs) in endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension. J Clin Oncol 29(suppl): Abstract 4611, 2011.
  73. ↵
    1. Maitland ML,
    2. Kasza KE,
    3. Karrison T,
    4. Moshier K,
    5. Sit L,
    6. Black HR,
    7. Undevia SD,
    8. Stadler WM,
    9. Elliott WJ,
    10. Ratain MJ
    : Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res 15(19): 6250-6257, 2009.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Levine MR,
    2. Wroblewski K,
    3. Dharanipragada D,
    4. Sit L,
    5. Karrison T,
    6. Seiwert TY,
    7. Cohen EE,
    8. Vokes EE,
    9. Maitland ML
    : Use of typical in-patient blood pressure measurements to detect bevacizumab-induced elevation in systolic pressure after the first infusion. J Clin Oncol 28(suppl): Abstract e13622, 2010.
  75. ↵
    1. Azizi M,
    2. Chedid A,
    3. Oudard S
    : Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 358(1): 95-97, 2008.
    OpenUrlCrossRefPubMed
  76. ↵
    1. Maitland ML,
    2. Karrison T,
    3. Bakris GL,
    4. Fox K,
    5. Janisch LA,
    6. Karovic S,
    7. Levine MR,
    8. House L,
    9. Wright JJ,
    10. Cohen EE,
    11. Fleming GF,
    12. Seiwert TY,
    13. Villaflor VM,
    14. Stadler WM,
    15. Ratain MJ
    : Pharmacodynamic (PD) assessment of blood pressure (BP) in a randomized dose-ranging trial of sorafenib (S). J Clin Oncol 29(suppl): Abstract 3016, 2011.
    1. Wilhelm SM,
    2. Carter C,
    3. Tang L,
    4. Wilkie D,
    5. McNabola A,
    6. Rong H,
    7. Chen C,
    8. Zhang X,
    9. Vincent P,
    10. McHugh M,
    11. Cao Y,
    12. Shujath J,
    13. Gawlak S,
    14. Eveleigh D,
    15. Rowley B,
    16. Liu L,
    17. Adnane L,
    18. Lynch M,
    19. Auclair D,
    20. Taylor I,
    21. Gedrich R,
    22. Voznesensky A,
    23. Riedl B,
    24. Post LE,
    25. Bollag G,
    26. Trail PA
    : BAY 43-9006 exhibits broad-spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19): 7099-7109, 2004.
    OpenUrlAbstract/FREE Full Text
    1. Sun L,
    2. Liang C,
    3. Shirazian S,
    4. Zhou Y,
    5. Miller T,
    6. Cui J,
    7. Fukuda JY,
    8. Chu JY,
    9. Nematalla A,
    10. Wang X,
    11. Chen H,
    12. Sistla A,
    13. Luu TC,
    14. Tang F,
    15. Wei J,
    16. Tang C
    : Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46(7): 1116-1119, 2003.
    OpenUrlCrossRefPubMed
    1. Hilberg F,
    2. Roth GJ,
    3. Krssak M,
    4. Kautschitsch S,
    5. Sommergruber W,
    6. Tontsch-Grunt U,
    7. Garin-Chesa P,
    8. Bader G,
    9. Zoephel A,
    10. Quant J,
    11. Heckel A,
    12. Rettig WJ
    : BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12): 4774-4782, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Roth GJ,
    2. Heckel A,
    3. Colbatzky F,
    4. Handschuh S,
    5. Kley J,
    6. Lehmann-Lintz T,
    7. Lotz R,
    8. Tontsch-Grunt U,
    9. Walter R,
    10. Hilberg F
    : Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem 52(14): 4466-4480, 2009.
    OpenUrlCrossRefPubMed
    1. Nikolinakos P,
    2. Heymach JV
    : The tyrosine kinase inhibitor cediranib for non-small cell lung cancer and other thoracic malignancies. J Thorac Oncol 3(6 Suppl 2): S131-S134, 2008.
    OpenUrlPubMed
    1. Kumar R,
    2. Knick VB,
    3. Rudolph SK,
    4. Johnson JH,
    5. Crosby RM,
    6. Crouthamel MC,
    7. Hopper TM,
    8. Miller CG,
    9. Harrington LE,
    10. Onori JA,
    11. Mullin RJ,
    12. Gilmer TM,
    13. Truesdale AT,
    14. Epperly AH,
    15. Boloor A,
    16. Stafford JA,
    17. Luttrell DK,
    18. Cheung M
    : Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7): 2012-2021, 2007.
    OpenUrlAbstract/FREE Full Text
    1. Podar K,
    2. Tonon G,
    3. Sattler M,
    4. Tai YT,
    5. Legouill S,
    6. Yasui H,
    7. Ishitsuka K,
    8. Kumar S,
    9. Kumar R,
    10. Pandite LN,
    11. Hideshima T,
    12. Chauhan D,
    13. Anderson KC
    : The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci USA 103(51): 19478-19483, 2006.
    OpenUrlAbstract/FREE Full Text
    1. Fujisaka Y,
    2. Yamada Y,
    3. Yamamoto N,
    4. Shimizu T,
    5. Fujiwara Y,
    6. Yamada K,
    7. Tamura T,
    8. Watanabe H,
    9. Sun YN,
    10. Bass MB,
    11. Seki M
    : Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 66(5): 935-943, 2010.
    OpenUrlCrossRefPubMed
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