Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions (original) (raw)
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Correspondence: Francesco Perrone, M.D., Ph.D., Clinical Trials Unit, National Cancer Institute, Via Mariano Semola, 80131 Naples, Italy. Telephone: 390815903571; Fax: 390817702938; e-mail: francesco.perrone@uosc.fondazionepascale.it
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27 December 2005
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Alessandro Morabito, Ermelinda De Maio, Massimo Di Maio, Nicola Normanno, Francesco Perrone, Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions, The Oncologist, Volume 11, Issue 7, July 2006, Pages 753–764, https://doi.org/10.1634/theoncologist.11-7-753
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Abstract
Learning Objectives
After completing this course, the reader will be able to:
- Discuss the mechanism of action of tyrosine kinase inhibitors of VEGFRs that are in clinical trials.
- Describe the current status of clinical development and the early clinical results observed with these small molecule inhibitors of VEGFRs.
- Discuss the optimal study design for evaluation of these compounds, the criteria for patient selection, and the optimal modalities of combination with other drugs.
- Discuss the differences in the design of clinical trials between chemotherapeutics and target-based agents.
Access and take the CME test online and receive 1 _AMA PRA Category 1 Credit_™ at CME.TheOncologist.com
Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For other agents, such as vatalanib, contrasting outcomes in metastatic colorectal cancer patients have been reported: the final results of these trials are expected in 2006. However, several key questions remain to be addressed, regarding the choice of an adequate dose or schedule, the presence of “off-target” effects, the safety of long-term administration, and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents.
Introduction
The vascular endothelial growth factor (VEGF) family of angiogenic growth factors includes six secreted glycoproteins referred to as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placenta growth factor (PlGF)-1, and PlGF-2 [1–3]. VEGF-A, first identified as a vascular permeability-inducing factor secreted by tumor cells [4], is the most critical regulator of the development of the vascular system and is commonly overexpressed in a variety of human solid tumors [5]. VEGF ligands act through specific binding to three different cell membrane receptors: VEGFR-1 (Flt-1) and VEGFR-2 (Flk/KDR), originally identified on endothelial cells but also expressed on various hematopoietic cell lineages in the adult [6–8], and VEGFR-3 (Flt-4) [9]. These receptors consist of an extracellular domain that binds specific VEGF ligands, a transmembrane domain, and an intracellular region that contains a tyrosine kinase domain. In addition, neuropilin 1 (NRP-1) and NRP-2 are coreceptors for specific isoforms of VEGF family members and increase the binding affinity of these ligands to their respective receptors [10]. Ligand–receptor interaction induces the activation of the tyrosine kinase domain of the VEGFRs, which finally leads to the activation of intracellular signaling transduction pathways that are involved in regulating cellular proliferation and survival, such as the Raf/mitogen-activated protein kinase–extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3′ kinase (PI3K)/protein kinase B (Akt) pathways (Fig. 1). VEGFR-1 is a potent, positive regulator of physiologic and developmental angiogenesis and is thought to be important for endothelial cell migration and differentiation [11, 12]. Recently, it has been demonstrated that VEGFR-1 is also present and functional on human colorectal cancer cells and that activation by VEGF family ligands can activate processes involved in tumor progression and metastasis [13]. VEGFR-2 mediates the majority of the downstream effects of VEGF-A, including vascular permeability, endothelial cell proliferation, invasion, migration, and survival [14–16]. VEGFR-3 is involved in lymphangiogenesis, and its expression has been associated with the dissemination of tumor cells to regional lymph nodes [9, 17–19]. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. There are many agents that target VEGF function, including those targeting VEGF (e.g., VEGF antibodies such as bevacizumab and soluble VEGFRs) and those targeting VEGFRs (e.g., VEGFR antibodies, small-molecule kinase inhibitors, and ribozyme).
Figure 1
Mechanism of action of vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors. Sorafenib (BAY 43-9006) additionally inhibits the Raf kinase enzyme involved in one of the intracellular pathways activated after VEGF binding. ZD6474 and AEE788 are dual inhibitors of both the epidermal growth factor receptor (EGFR) and VEGFR tyrosine kinases. Abbreviations: ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; PI3K, phosphatidylinositol 3′ kinase; PKB, protein kinase B.
This review focuses on the tyrosine kinase inhibitors of VEGFRs in clinical trials. These inhibitors are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEGFRs, resulting in a blockade of intracellular signaling. Table 1 summarizes the most important VEGFR small-molecule inhibitors, the specific molecular targets, the enzyme 50% inhibitory concentration (IC50) measurements, and the current phase of clinical development.
Table 1
VEGFR inhibitors, molecular targets, IC50, and phase of clinical development
Table 1
VEGFR inhibitors, molecular targets, IC50, and phase of clinical development
Vatalanib (PTK787/ZK 222584)
Vatalanib is a synthetic, low-molecular-weight, orally bio-available agent belonging to the chemical class of aminophthalazines. It is a potent inhibitor of all known VEGFR tyrosine kinases and is active in the submicromolar range. It also inhibits other kinases, such as platelet-derived growth factor receptor beta (PDGFR-β) and c-Kit tyrosine kinase, but at higher concentrations [20]. Preclinical studies have demonstrated that vatalanib inhibits growth and reduces microvasculature in s.c. implanted human xenografts in nude mice [20, 21]. Phase I clinical studies evaluated the safety, pharmacokinetics, pharmacodynamic effects, and biologic activity of vatalanib as a single agent in several advanced cancers known to overexpress VEGF and VEGFRs, including colorectal cancer, breast cancer, glioblastoma multiforme, prostate cancer, and renal cancer (Table 2) [22–24]. Pharmacokinetic results for doses up to 1,000 mg/day showed that vatalanib once a day is rapidly adsorbed, with a time to maximum concentration of 1.5 hours and a terminal half-life of about 3–6 hours [25]. In view of the short half-life of the drug, a phase I study with vatalanib given twice daily has been conducted to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF signaling [26]. Pharmacokinetic data and dynamic contrast-enhanced magnetic resonance imaging indicated that vatalanib ≥ 1,000 mg total daily dose is the biologically active dose and showed that, at equivalent daily doses, drug exposure is comparable with the previous once-daily-dosing study. However, the trough levels are significantly higher with the twice-daily administration. Whether this could improve the activity of the drug over once-daily administration is unknown at this time because there are no comparative studies. Although activity was not the primary end point of these phase I studies, promising antitumor activity was observed in patients with metastatic colorectal cancer (MCRC). Vatalanib has been subsequently evaluated in two phase I/II studies as a single daily dose in combination with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX-4) or irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI), as first-line treatment for patients with MCRC. In the first study, the pharmacokinetics and toxicity profiles of both vatalanib and FOLFOX-4 were unaffected by coadministration [27]. Dizziness and neurologic toxicities were seen at higher doses of vatalanib. The response rate in 28 evaluable patients was 54%, with a median progression-free survival (PFS) duration of 11 months (95% confidence interval [CI], 6.8–12.0 months) and an estimated median overall survival (OS) time of 16.6 months (95% CI, 12.9–21.0 months). In the second study [28], coadministration of vatalanib at 1,250 mg/day with FOLFIRI had minor effects on irinotecan exposure but lowered by 40% the area under the concentration–time curve (AUC) of the active metabolite of irinotecan, SN-38, in patients’ serum: the clinical relevance of this effect is under investigation. The response rate in 17 evaluable patients was 41%, with a median PFS duration of 7.1 months (95% CI, 6.2–11.7 months) and a median OS time of 24.3 months (95% CI, 18 months– unknown). Two large, randomized, double-blinded, placebo-controlled, phase III trials compared the efficacy of oral vatalanib at 1,250 mg once a day in combination with FOLFOX-4 with FOLFOX-4 alone, in both the first-line Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases (CONFIRM)-1 trial and second-line CONFIRM-2 trial of the treatment of MCRC (Table 3). The primary end point of CONFIRM-1 was not met [29]: PFS, based on central review, showed only a modest benefit of adding vatalanib to FOLFOX-4, which did not reach statistical significance. A possible explanation of such a result could be the short half-life of vatalanib (about 6 hours), suggesting that the once-daily administration of the drug might not be the optimal schedule to maintain constant blood levels of vatalanib. However, in contradiction with these data, pharmacokinetic results suggest that an active dose of vatalanib is maintained in the blood circulation for 24 hours after a single administration and that it has substantial antivascular effects [30]. An exploratory analysis in patients with pretreatment high serum levels of lactate dehydrogenase (LDH) showed a statistically significant longer PFS time in the group treated with vatalanib, confirmed by central assessment (hazard ration [HR], 0.68; 95% CI, 0.50–0.92; p = .012). Coregulation of VEGF and LDH via hypoxia-inducible factor 1 alpha (HIF-1α) may provide the biologic link for favorable results in this group of patients because patients with high LDH levels have tumors in which the VEGF pathway is most activated [31]. Therefore, high serum levels of LDH may predict for the optimal benefit from vatalanib inhibition of VEGFR. The most frequently reported grade 3–4 adverse events in the two treatment arms (vatalanib with FOLFOX-4 vs. placebo with FOLFOX-4) were hypertension (21% vs. 6%), neutropenia (31% vs. 32%), diarrhea (15% vs. 10%), nausea (9% vs. 5%), peripheral neuropathy (9% vs. 7%), venous thrombosis (7% vs. 4%), dizziness (7% vs. 2%), and pulmonary embolism (6% vs. 1%). Final results of the CONFIRM-1 and CONFIRM-2 trials, with survival data, are expected in 2006. The role of vatalanib is also being evaluated in patients with lung cancer, in a phase II study in France and Germany (the Growth Arrest with Oral Anti-angiogenesis in Lung Cancer [GOAL] study). Moreover, the Hoosier Oncology Group has recently activated a phase I/II study of vatalanib in combination with trastuzumab in patients with newly diagnosed HER-2-overexpressing metastatic breast cancer.
Table 2
Main phase I clinical trials with vascular endothelial growth factor receptor tyrosine kinase inhibitors
Table 2
Main phase I clinical trials with vascular endothelial growth factor receptor tyrosine kinase inhibitors
Table 3
Main phase II–III clinical trials with vascular endothelial growth factor receptor tyrosine kinase inhibitors
Table 3
Main phase II–III clinical trials with vascular endothelial growth factor receptor tyrosine kinase inhibitors
Semaxanib (SU5416)
Semaxanib is a small, lipophilic, synthetic molecule that inhibits VEGFR-1, and -2 tyrosine kinases [32]. Semaxanib inhibits VEGF-dependent endothelial cell proliferation in vitro and in vivo [32] and increases the sensitivity of murine B16 melanoma and murine GL261 glioma to radiation therapy [33]. In phase I clinical studies, two schedules of semaxanib have been tested, one consisting of a 5-day loading dose followed by a weekly i.v. infusion and the other consisting of biweekly i.v. infusions without a loading dose (Table 2). In both schedules, a dose of 145 mg/m2 was recommended for additional testing [34, 35]. Several phase II studies did not demonstrate significant antitumor activity of semaxanib as a single agent against advanced soft tissue sarcoma [36], metastatic renal cell carcinoma [37], melanoma [38], hormone-refractory prostate cancer [39], and multiple myeloma [40]. A promising response of 31.6% was observed with semaxanib in combination with fluorouracil plus leucovorin as first-line therapy for 28 patients with MCRC [41]. However, a randomized, multicenter, phase III trial failed to show any improvement in clinical outcome with semaxanib in combination with fluorouracil and leucovorin (Roswell Park regimen) versus fluorouracil and leucovorin alone as first-line therapy for 737 MCRC patients; moreover, worse toxicity in the semaxanib arm (in terms of diarrhea, cardiovascular events, vomiting, dehydration, and sepsis) was observed (Table 3) [42]. Finally, a surprisingly high incidence of severe thromboembolic events was reported in a phase I study with the combination of semaxanib with cisplatin and gemcitabine in patients with solid tumors, discouraging further investigation of this regimen [43]. Overall, the disadvantage of i.v. administration for long-term treatment, the negative results of the phase II/III studies, and the severe toxicity of the drug resulted in the cessation of further clinical development of semaxanib.
Sunitinib (SU11248)
Sunitinib is a novel, oral, multitargeted receptor tyrosine kinase inhibitor, with both direct antiproliferative effects and antiangiogenic properties, targeting the VEGFRs, PDGFR-β, and c-Kit [44]. In mouse xenograft models, sunitinib exhibited potent antitumor activity causing regression, growth arrest, or reduced growth of various established xenografts derived from human or rat tumor cell lines [45]. In phase I clinical studies, the recommended dose of sunitinib was found to be 50 mg orally, once daily for 4 weeks, followed by 2 weeks off, in a repeated 6-week cycle (Table 2) [46, 47]. Pharmacokinetic data indicated good oral absorption and a long half-life of the drug (~40 hours). Promising activity in patients with renal cancers was observed. Using this schedule, a multicenter, phase II clinical trial was conducted to assess the clinical activity and safety of sunitinib as second-line therapy for patients with metastatic renal cancer who progressed after one prior cytokine therapy (Table 3) [48]. Twenty-five (40%) of 63 patients treated with sunitinib achieved a partial response and 17 additional patients (27%) demonstrated stable disease. The median time to progression (TTP) was 8.7 months (95% CI, 5.5–10.7), while the median survival time was 16.4 months (95% CI, 10.8– not yet attained). The most common adverse event was fatigue, which was categorized as grade 3 severity in seven patients (11%). These results are particularly noteworthy when compared with those of prior studies of second-line therapy in metastatic renal cancer and sustain the rationale of an ongoing phase III trial of sunitinib versus interferon-α as first-line treatment of metastatic renal cancer.
In addition to targeting VEGFRs, sunitinib targets c-Kit, often expressed in gastrointestinal stromal tumors (GISTs), and it is thus a good candidate for the treatment of this disease. In a phase I–II study conducted in 97 patients with progressive, metastatic GISTs refractory to imatinib mesylate, sunitinib induced clinical benefit in 65% of patients, with an 8% partial response rate and 58% stable disease rate [49]. A phase III, multicenter, randomized, double-blind, placebo-controlled trial definitively demonstrated the efficacy of sunitinib in the treatment of imatinib-resistant patients with GIST (Table 3) [50]. In that trial, treatment was unblinded after progression, and patients who had received placebo were crossed over to sunitinib therapy. Sunitinib treatment resulted in a more than fourfold longer median TTP (6.3 vs. 1.5 months with placebo; p < .00001; HR, 0.335) and a statistically significant longer OS time (p = .00674; HR, 0.491). The survival benefit for sunitinib could be underestimated as a result of the crossover of patients from placebo to active treatment. Sunitinib was generally tolerated with manageable toxicities: fatigue, diarrhea, sore mouth, skin discoloration, and hypertension. In consideration of these positive results, in January 2006, the U.S. Food and Drug Administration (FDA) announced the approval of sunitinib for patients with advanced renal cancer and GIST after disease progression on or intolerance to imatinib mesylate.
Currently, sunitinib is being evaluated in metastatic breast cancer patients resistant to anthracyclines and taxanes. Preliminary data show a good safety profile. Four partial responses and five cases of stable disease have been observed in 23 patients [51].
Sorafenib (BAY 43-9006)
Sorafenib is a novel bi-aryl urea, initially developed as a specific inhibitor of Raf kinase. Subsequent studies have shown this compound to also inhibit several other tyrosine kinases involved in tumor progression, including VEGFRs [52]. Xenograft models of colon, breast, and non-small cell lung cancer (NSCLC) treated with sorafenib demonstrated significant inhibition of tumor angiogenesis, as measured by anti-CD31 immunostaining [53]. Phase I studies of sorafenib, involving 163 patients treated with different continuous oral dosage schedules, identified 400 mg twice daily as the recommended phase II dose (Table 2) [54, 55]. Preliminary activity data from these studies suggest that sorafenib is associated with clinically durable stabilization of progressive disease in patients affected by refractory solid tumors (mostly renal carcinoma). A large phase II randomized discontinuation trial was conducted with sorafenib, 400 mg orally twice daily, in patients with different types of tumors (Table 3). Results have been reported for 202 patients with advanced renal cell carcinoma [56]. After a 12-week induction phase, 65 patients had stable disease and were randomized to remain on sorafenib (n = 32) or to take placebo (n = 33). The median PFS time after randomization was longer with sorafenib than with placebo (24 vs. 6 weeks; p = .0087; HR, 0.29). The toxicity profile was acceptable, with rash, hand-foot skin reaction, fatigue, and hypertension responsive to standard medications. A subsequent randomized, placebo-controlled, phase III trial confirmed the efficacy of sorafenib in cytokine-refractory advanced renal carcinoma patients [57]. The median PFS times were 24 weeks for sorafenib versus 12 weeks for placebo (HR, 0.44; p < .00001). The 12-week progression-free rate was 79% for sorafenib versus 50% for placebo. Sorafenib was well tolerated, with manageable side effects: rash (34%), diarrhea (33%), hand-foot skin reactions (27%), fatigue (26%), and hypertension (11%). Based on these results, the FDA announced in December 2005 the approval of sorafenib for patients with advanced renal cancer. Moreover, the European Commission recently granted orphan medicinal product status to sorafenib for the treatment of hepatocellular carcinoma [58]. This approval is based on a recommendation from the European Medicines Agency (EMEA) and data from a phase II, single-agent study, presented at the 16th American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer meeting in 2004. In that trial, 43% of patients treated with sorafenib experienced stable disease for at least 4 months and an additional 9% of patients experienced tumor shrinkage.
Currently, phase III clinical trials are evaluating the efficacy of sorafenib in hepatocellular carcinoma, metastatic melanoma, and NSCLC; moreover, several other phase I/II studies are ongoing with sorafenib combined with several chemotherapeutic (irinotecan, dacarbazine) or molecular targeted (gefitinib) agents in advanced solid tumors, to maximize the therapeutic potential of the drug [59–61].
ZD6474
ZD6474 is an orally bioavailable, anilquinazoline derivative, multitargeted tyrosine kinase inhibitor that targets VEGFR-2, EGFR, and RET tyrosine kinases [62, 63]. Therefore, this compound inhibits two key pathways in tumor growth, VEGFR-dependent tumor angiogenesis and EGFR-dependent tumor cell proliferation and survival. ZD6474 has shown antitumor activity in a broad range of preclinical models [64]. Phase I studies of ZD6474 in patients with advanced solid tumors have demonstrated that the once-daily oral administration of ZD6474 at 100–300 mg/day is well tolerated and recommended for phase II studies (Table 2) [65, 66]. Four partial responses were observed in nine patients with refractory NSCLC in the Japanese study [66]. Two randomized, phase II studies evaluated the combination of ZD6474 and chemotherapy in advanced NSCLC patients. In the first study, 127 patients with pretreated NSCLC were randomized to receive ZD6474 (100 or 300 mg once a day) or placebo, in combination with docetaxel (75 mg/m2, every 21 days) (Table 3) [67]. The study met its efficacy end point, TTP. The estimated HR for TTP was 0.635 for the comparison of ZD6474 (100 mg) plus docetaxel with docetaxel alone and 0.829 for the comparison of the 300-mg dose of ZD6474 plus docetaxel with docetaxel alone. The estimated median TTP were 18.7 weeks for docetaxel plus ZD6474 at 100 mg, 17 weeks for docetaxel plus ZD6474 at 300 mg, and 12 weeks for docetaxel alone. In the second ongoing study, ZD6474 (at 200 or 300 mg) is being investigated in combination with carboplatin (AUC 6 mg/ml × minute) and paclitaxel (200 mg/m2) as first-line therapy for NSCLC patients [68]. Objective responses were observed in 7/18 patients at both the dose levels. The randomized component of the study has been initiated and continues to recruit. The side effects reported with ZD6474 in these studies were manageable and included diarrhea, rash, fatigue, and asymptomatic grade I prolongation of the QTc (generally observed with doses >500 mg/day). Recently, a phase II randomized trial also compared ZD6474 (300 mg) with gefitinib (250 mg) in advanced previously treated NSCLC patients [69]. Preliminary data showed a statistically significant longer PFS duration with ZD6474 than with gefitinib (11.9 vs. 8.1 weeks, respectively; p = .011). These positive results were not confirmed in breast cancer, for which limited activity (no objective responses and only one stable disease) was observed with ZD6474 as monotherapy in 46 women with heavily pretreated disease [70]. Other phase II studies with ZD6474 as a single agent in small-cell lung cancer and thyroid cancer are ongoing.
Other Agents
SU6668 is a second-generation synthetic derivative of SU5416, orally available, that displays activity against VEGFR-2 but also inhibits the receptors for basic fibroblast growth factor and PDGFR [71]. Oral administration of SU6668 has been shown in vivo to result in regression, stasis, or growth inhibition of large, established, s.c. tumor xenografts in mice [72]. In a phase I trial including patients with solid malignancies who failed to respond to conventional treatment, the maximum-tolerated dose (MTD) of SU6668 given orally, thrice daily, was defined at 100 mg/m2 (Table 2) [73]. The most relevant side effects of the drug were fatigue, nausea, abdominal pain, and chest pain. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected. Another phase I study was stopped before the goal was reached because of toxicity, with subsequent termination of further clinical development of the drug [74, 75].
AG-013736 is a substituted indazole derivative, potent inhibitor of all known VEGFRs, PDGFR-β, and c-Kit [76]. AG-013736 selectively blocks in vitro VEGFR autophosphorylation, leading to inhibition of endothelial cell proliferation and survival, and inhibits, in mice, tumor vascular angiogenesis and the growth of human colorectal and murine lung tumors. Given strong preclinical evidence for antitumor activity, a phase I study was conducted to test AG-013736 in patients with advanced solid malignancies (Table 2) [77]. The recommended dose of AG-013736 was found to be 5 mg twice daily. The observed dose-limiting toxicities included hypertension, hemoptysis, and stomatitis, mainly at the higher dose levels. There were three confirmed partial responses (two in patients with renal cell carcinoma) and another three minor responses. Based on the encouraging clinical results from that trial, current phase II trials are evaluating the efficacy of AG-013736 as a single agent or in combination with chemotherapy in a variety of malignancies.
AZD2171 is a highly potent and orally available inhibitor of VEGFR tyrosine kinase activity, also showing selectivity to a range of additional kinases (PDGFR-β, c-Kit) [78]. AZD2171 prevents VEGF-induced angiogenesis in vivo and showed dose-dependent activity in a range of human tumor xenografts in mice [78]. This compound has pharmacokinetic properties that make it suitable for chronic once-daily oral dosing. In a phase I study, AZD2171 was generally well tolerated at doses ≤45 mg/day; the most common adverse events were fatigue, nausea, diarrhea, and vomiting (Table 2) [79]. Early clinical response data were encouraging, with two partial responses in the ongoing 60-mg cohort and three minor responses at lower doses. Another phase I trial is evaluating the combination of ascending once-daily oral doses of AZD2171 (20, 30, and 45 mg) with the EGFR tyrosine kinase inhibitor gefitinib (250 or 500 mg) [80].
AEE788 is a novel, synthesized, oral small-molecule inhibitor of both EGFR and VEGFR tyrosine kinases [81]. The dual inhibition of EGFR and VEGFR phosphorylation by AEE788 reduced growth and metastases of human colon carcinoma in an orthotopic nude mouse model [82]. The drug is currently being evaluated in phase I studies in patients with advanced solid tumors and with recurrent glioblastoma (Table 2) [83–85].
Open Questions and Future Directions
The increased understanding of the VEGF ligand-receptor network and the favorable clinical results observed with several tyrosine kinase inhibitors of VEGFR are likely to make this new therapeutic approach an important treatment modality in the field of oncology. However, there are several clinical and methodological questions that need to be addressed. Why are there contrasting clinical results among the different tyrosine kinase inhibitors as single agents or combined with chemotherapy? What is the safety of long-term administration of VEGFR tyrosine kinase inhibitors? Are new clinical end points and methodological approaches needed to conduct studies with molecular-targeted agents? The different antitumoral activity of these agents could be explained by their different molecular targets, potency, or just by the choice of ineffective doses in clinical trials. Identifying optimal dosing and scheduling of molecular-targeted agents is a significant challenge. Moreover, high expression of target may not necessarily correlate with response to targeted agents, as reported for EGFR in lung cancer. The combination of chemotherapy plus anti-VEGF therapy with bevacizumab has yielded superior OS or PFS in several phase III trials [86–89], confirming the potential benefit of targeting both neoplastic and endothelial cells. The discrepancy between these results and those observed with VEGFR tyrosine kinase inhibitors (vatalanib, semaxanib) has yet to be explained. In the case of semaxanib, the severe toxicity and the disadvantage of the chronic i.v. administration of the drug strongly discouraged further development of this agent. Several reasons could be given for vatalanib: the administration of a single daily dose as inadequate for the short half-life of the agent, the result of unknown negative drug interactions, or the presence of “off-target” effects, such as targeting PDGFR-β on perivascular cells. Blocking PDGFR-β may interfere with vascular normalization by blocking perivascular cell recruitment and thus prevent the synergistic effects of combined therapy [90]. A recently raised hypothesis is that multitargeted tyrosine kinase inhibitors as single agents could mimic the synergistic effect induced by bevacizumab plus chemotherapy more effectively than combinations of multitargeted tyrosine kinase inhibitors and chemotherapy [91]. This concept is supported by the positive results recently observed with multitargeted tyrosine kinase inhibitors as single agents, such as sunitinib in renal cell carcinoma and in imatinib-resistant GIST and sorafenib in renal cell carcinoma. The early positive results obtained with the combination of another multitargeted agent, ZD6474, with chemotherapy in advanced NSCLC seem in contrast with this hypothesis. However, enhancement of the activity of chemotherapy has been observed mostly at low doses of ZD6474 (100 mg), but not at high doses (300 mg). Intriguingly, this kinase inhibitor has a higher affinity for VEGFR-2 than for EGFR. Therefore, we might assume that, at low doses, the drug efficiently inhibits only VEGFR-2 and in this way enhances the efficacy of cytotoxic agents, as observed with bevacizumab and chemotherapy. At higher doses, which are likely to block both VEGFRs and EGFRs, the synergism with docetaxel is no longer seen, and this observation is in agreement with the negative results reported with the combination of EGFR inhibitors and chemotherapy [92]. For all these reasons, a further understanding of the VEGF/VEGFR family, their role in angiogenesis, and mechanisms of action of VEGF tyrosine kinase inhibitors is necessary.
Another major issue is the long-term toxicity of these agents, taking into account the lack of adequate knowledge in this matter and the possibility of prolonged periods of therapy in nonprogressing patients. Hypertension is emerging as one of the most common adverse effects of therapy with VEGFR tyrosine kinase inhibitors. The mechanisms underlying the development of essential hypertension are not well known and it can be a result of vascular rarefaction, endothelial dysfunction, and/or altered nitrous oxide metabolism [93]. However, hypertension is usually manageable with medical treatment. Fatigue is another common side effect, but it rarely affects the duration of treatment. Other toxicities are observed more commonly with specific agents: light-headedness/dizziness and ataxia with vatalanib; diarrhea, mucositis, and skin toxicity with sunitinib; anorexia, diarrhea, and skin toxicity with sorafenib; an asymptomatic QTc prolongation with ZD6474. However, with an increasing number of patients receiving these drugs for prolonged periods, it is reasonable to expect more toxicities in the future.
Several unanswered questions also remain regarding the optimal methodological approaches in the clinical development of these agents. For phase I studies, a major problem is the identification of appropriate, biologically active dosages of these compounds; the minimum target-inhibiting dose (MTID), which could be different from the MTD, should be determined using a validated assay with biological surrogate biomarkers identified during the preclinical phase of development of the drugs. Part of the difficulty in translating preclinical efficacy to the clinical setting is the lack of valid, predictive, preclinical models: the dose and schedule tested may be suboptimal and plasma levels above an IC obtained from in vitro studies may not be a good end point. For phase II studies, innovative end points of activity should be considered in trial design, such as the rate of nonprogression, the TTP, or the Growth Modulation Index [94]. The randomized discontinuation design, chosen to demonstrated the activity of sorafenib in metastatic renal cancer patients, allowed assessment of the disease-stabilizing effect of the drug and can be particularly suitable in the early development of targeted agents, where a reliable assay to identify sensitive patients is not available [95, 96]. For phase III trials, biologically driven patient selection criteria and predictive biological markers of activity should be included in study design. Patient selection should be target oriented and no longer, or much less, disease oriented. An intriguing issue is the optimal clinical setting of evaluation for these compounds, which is preferably comprised of patients with a small tumor burden, as suggested by preclinical studies. Patients with a large tumor burden, pretreated with several lines of chemotherapy, and resistant to conventional therapies may receive minimal benefit from therapy with target-based agents, which are thought to produce cytostatic effects without shrinkage of existing tumors. A major challenge is also the choice of the proper modalities of combination of VEGFR tyrosine kinase inhibitors with cytotoxic agents, hormone therapy, radiotherapy, or other biological compounds, attacking different targets, with the aim to produce a synergistic antitumoral effect.
In conclusion, a large number of small molecule inhibitors of VEGFR tyrosine kinase are currently in clinical development and they represent a new opportunity for the treatment of patients with different metastatic tumors resistant to conventional therapies. Ongoing and new, well-designed trials will better define the optimal clinical application of these drugs.
Acknowledgments
We thank Jane Bryce for language revision. N.N. and F.P. receive support from AIRC (Associazione Italiana per la Ricerca sul Cancro) for their research.
Disclosure of Potential Conflicts of Interest
The authors indicate no potential conflicts of interest.
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© 2006 AlphaMed Press
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