Published OnlineFirst April 30, 2012; DOI: 10.1158/1078-0432.CCR-11-1275 Clinical Cancer Review Research Combining Antiangiogenics to Overcome Resistance: Rationale and Clinical Experience Victor Moreno Garcia, Bristi Basu, L. Rhoda Molife, and Stan B. Kaye Abstract Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disap- pointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early- phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies. Clin Cancer Res; 18(14); 3750–61. Ó2012 AACR. Introduction mab was also shown to prolong the time to progression as The importance of tumor angiogenesis has been recog- monotherapy (10) and in combination with interferon (13). nized for almost 80 years (1), and 4 decades ago, Folkman Tyrosine kinase inhibitors (TKI) targeting VEGFR, such as (2) proposed it as a therapeutic target, recognizing its critical sunitinib (8) and sorafenib (5), as monotherapies have also role in the growth and survival of tumors larger than 1 mm3. produced an OS benefit for patients with mRCC. Similarly, However, it is only in the last 10 years that this knowledge has sorafenib has now become the standard of care for advanced successfully translated to inhibitory strategies in clinical hepatocellular carcinoma because it was shown to increase practice. Endothelial cells (EC) have been assumed to show OS compared with placebo (14). However, in other tumors, genomic stability in comparison with the multiple somatic despite the initial benefit seen in some patients treated with mutations acquired within tumors during their growth, VEGF pathway inhibitors, complete responses have not leading to the belief that ECs would avoid resistance to generally been documented, and most patients will experi- therapy (3, 4). Targeting of angiogenesis has been validated ence tumor progression and succumb to their disease. More- by evidence of efficacy from several agents directed against over, attempts to use these drugs in the adjuvant setting (e.g., components of the main proangiogenic VEGF signaling in colorectal cancer) have thus far been disappointing, pathway at the level of the ligand (VEGF) and its receptors yielding the same results as chemotherapy alone (15). [VEGFR (5–10)]. Bevacizumab, a monoclonal antibody Lessons could be learned from the paradigm of mRCC (mAb) targeting VEGF, was shown to result in improved management, in which antiangiogenic strategies have been overall survival (OS) in metastatic colorectal and lung cancer most successfully adopted in routine clinical practice. when combined with chemotherapy (6, 9), and progression- Acquired resistance to anti-VEGF therapy may mean that free survival (PFS) in metastatic breast and ovarian cancer the order in which targeted agents are introduced to patients (11, 12). In metastatic renal cell cancer (mRCC), bevacizu- is important, such that a survival benefit may be derived from sequential monotherapy with multitargeted TKIs (16). An analysis of a prospective trial (17), numerous retrospec- Authors' Affiliation: Division of Clinical Sciences, Institute of Cancer tive studies, and a subgroup analysis of expanded-access Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom programs for sorafenib suggested that there is an increase in Note: Victor Moreno Garcia and Bristi Basu contributed equally to this PFS for a TKI switch in mRCC (18). These data support a lack article. of cross-resistance between multitargeted TKIs; however, Corresponding Author: Victor Moreno, Drug Development Unit, Division ongoing sorafenib/sunitinib crossover trials, such as of Clinical Sciences, Institute of Cancer Research/The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Phone: SWITCH (www.ClinicalTrials.gov; NCT00732914), may 44-020-8642-3539; Fax: 44-020-8642-6011; E-mail: address these issues more definitively. [email protected] An alternative to using VEGF-targeting agents sequent- doi: 10.1158/1078-0432.CCR-11-1275 ially is to focus on combining agents that affect different Ó2012 American Association for Cancer Research. aspects of angiogenesis. Our knowledge about the 3750 Clin Cancer Res; 18(14) July 15, 2012 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst April 30, 2012; DOI: 10.1158/1078-0432.CCR-11-1275 Combining Antiangiogenic Therapies complexity of angiogenesis is growing rapidly, and it is Translational Relevance recognized that VEGF-independent drivers include multiple Targeting angiogenesis in cancer has been shown to interactions among diverse growth factors and receptors increase overall and/or progression-free survival for sev- involving ECs, NOTCH/d-like ligand 4 (DLL4), angiopoie- eral tumor types, including renal, ovarian, colon, lung, tin (Ang)-Tie, placental growth factor (PlGF), tumoral cells and breast cancers. However, many tumors are intrinsi- (SDF1/CXCR4), pericytes [platelet-derived growth factor cally resistant to antiangiogenic therapies. Other tumors, (PDGF) and transforming growth factor (TGF-b)], extracel- after an initial response, acquire secondary resistance lular matrix (ECM) components (integrins and cadherins), leading to further tumor growth. There is an urgent need inflammatory cells (tumor-associated macrophages and to identify mechanisms to overcome this resistance, and Tie-2–expressing monocytes), and bone-marrow–derived preclinical studies suggest that combining different anti- cells (Fig. 1; reviewed in refs. 19 and 20). A new paradigm angiogenics could be a suitable strategy. However, over- for the development of malignant angiogenesis was recently lapping toxicities are an issue of major concern. Early proposed based on the finding in glioblastoma multiforme clinical experience shows that trials combining different (GBM) that tumor ECs can arise directly through differen- þ þ antiangiogenics are complex, and schedules cannot be tiation of CD133 /CD144 tumor cells (21). In addition, easily extrapolated from single-agent studies. Careful preclinical work is providing insights into mechanisms clinical development of these combinations will be of resistance to antiangiogenic therapy. These mechanisms crucial to assess the relevance of positive data coming are described as being intrinsic (preexisting) or adaptive from preclinical models. (acquired), and they may explain why some tumors do not respond from the outset and why others progress after initial Indirect inhibition Vertical Horizontal VEGF VEGF ANG VEGFR NRP TIE2 Proliferation NOTCH Survival DLL4 Endothelial cell PDGFR Integrin ECM MMP Invasion Direct inhibition VDA © 2012 American Association for Cancer Research Figure 1. Schematic diagram showing theoretical combinations targeting angiogenesis. MMP, matrix metalloproteinase; NRP, neuropilin. www.aacrjournals.org Clin Cancer Res; 18(14) July 15, 2012 3751 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst April 30, 2012; DOI: 10.1158/1078-0432.CCR-11-1275 Moreno Garcia et al. Table 1. Angiogenesis inhibitors Group Name Action MTD/phase II dose as single agent VEGFR and PDGFR AEE788 VEGFR-2, EGFR 550 mg qd TKIs Axitinib (AG-013736) VEGFR-1,2,3; PDGFR-b; c-KIT 5 mg b.i.d. Intedanib (BIBF 1120) VEGFR-1,2,3; PDGFR-a,b 250 mg b.i.d. Brivanib (BMS-540215) VEGFR-2,3; FGFR1,2 800 mg qd Cediranib (AZD2171) VEGFR-1,2,3 45 mg qd CP 547,632 VEGFR-2 200 mg qd Dovitinib (TKI258) VEGFR-1,2,3; PDGFR-b; c-KIT; 125 mg qd FLT3; FGFR1,2,3 Motesanib (AMG706) VEGFR-1,2,3; PDGFR-b; c-KIT 125 mg qd OSI 930 VEGFR-2; c-KIT 500 mg b.i.d. Pazopanib (GW786034) VEGFR-1,2,3; PDGFR; c-KIT 800 mg qd Semaxinib (SU5416) VEGFR-2, RET 145 mg/m2 q1w Sorafenib (BAY 43-9006) VEGFR-2,3; PDGFR-b, RET, c-KIT, 400 mg b.i.d. RAF SU6668 VEGFR-2; FGFR1, c-KIT, PDGFR-b 100 mg/m2 Sunitinib (SU11248) VEGFR-1,2; PDGFR-b; c-KIT; FLT3; 50 mg qd 4w/6w PDGFR-a,b Telatinib (BAY 57-9352) VEGFR-2,3; PDGFR-b 900 mg b.i.d. Vandetanib (AZD6474) VEGFR-2, EGFR 300 mg qd Vatalanib (PTK/ZK) VEGFR-1,2,3; PDGFR; c-KIT 1200 mg qd Anti-VEGFR Ramucirumab (IMC-1121B) mAb against VEGFR-2 13 mg/kg q1w Anti-VEGF Aflibercept (VEGF-trap) Soluble VEGFR-1,2 4 mg/kg q2w i.v. 1600 mg/kg q1w s.c. Bevacizumab mAb against VEGF-A 5–15 mg/kg q2w VEGF-AS (Veglin) VEGF antisense oligonucleotide 85 mg/m2 days 1–5 q2w VDA ABT-751 Tubulin binding 250 mg qd; 150 mg b.i.d. ASA404 (DMXAA) Flavonoid 1000–2000 mg/m2 q1w CYT 997 Tubulin binding 202 mg/m2 q3w EPC2407 Tubulin binding 13 mg/m2 days 1–3 q3w Fosbretabulin (CA4P) Tubulin binding 52 mg/m2 days q3w MN-029 Tubulin binding 180 mg/m2 q1w (3w/4w) MPC-6827 Tubulin binding 3.3 mg/m2 q1w NPI-2358 Tubulin binding 30 mg/m2 q1w (3w/4w) Ombrabulin (AVE8062) Tubulin binding 22 mg/m2 q3w OXi4503 (CA1P) Tubulin binding ND TZT 1027 Tubulin binding 2.7 mg/m2 q3w ZD 6126 Tubulin binding 80 mg/m2 q2w Integrin inhibitors ATN-161 Anti-a5b1 16 mg/kg 3x/q1w Cilengitide Anti-avb3 and anti-avb5 600 mg/m2 2x/q1w (EMD 121974) CNTO95 Anti-av 10 mg/kg days 0, 28, 35, and 42, and q3w thereafter Etaracizumab Anti-avb3 6 mg/kg 2x/q1w Volociximab Anti-a5b1 15 mg/kg q1w MMP inhibitors BMS-275291 MMP-1, -2, -7, -9, -14 1200 mg qd Marimastat (BB-2516) Pan-MMP inhibitor 50 mg b.i.d.