Angiogenesis Inhibitors

Angiogenesis results in the formation of new blood vessels, and in tumors, this process promotes tumor growth and metastasis. The VEGF family, composed of VEGFs and VEGF receptors (VEGFRs), regulates the process of angiogenesis, and various strategies have evolved to inhibit this signaling pathway. Bevacizumab is a humanized monoclonal antibody that binds to VEGF-A, thereby preventing the binding of this growth factor to its associated VEGFRs. Besides inhibiting angiogenesis, it has been postulated that anti-VEGF therapy can transiently normalize tumor vasculature and improve drug and oxygen delivery to tumor cells, making them more chemosensitive and radiosensitive. The potential role for bevacizumab in the treatment of CRC was initially shown in a phase 2 trial that compared 2 doses of bevacizumab in combination with 5-FU/FA with 5-FU/FA alone in patients with metastatic CRC. This study showed that the bevacizumab combinations produced improved response rates and extended median time to disease progression and median survival rates and favored the lower bevacizumab dose of 5 mg/kg. This study led to the pivotal randomized phase 3 trial that gained the approval of bevacizumab in the United States in 2004 as the first-line agent in the treatment of metastatic CRC ( Table 1 ). When compared with the irinotecan and 5-FU/FA combination (coined IFL), the addition of bevacizumab to IFL showed improved median survival (20.3 vs 15.6 months, hazard ratio [HR] 0.66, P <.001), response rates (44.8% vs 34.8%, P = .004), and median duration of response (10.4 vs 7.1 months, HR 0.62, P = .001). Grade 3 hypertension was more common in the bevacizumab group but was easily treated with antihypertensives. Bevacizumab has also shown improved clinical efficacy with a comparable safety profile, when combined with the current standard oxaliplatin- and irinotecan-based regimens for advanced CRC.

Bevacizumab is at present approved by the FDA for use in the first and second-line treatment of metastatic CRC. At present, in the United States, first-line therapy for patients with advanced CRC is combination chemotherapy of FOLFOX, XELOX or FOLFIRI, all given in combination with bevacizumab. The role of bevacizumab beyond the first progression was analyzed in the Bevacizumab Regimens: Investigation of Treatment Effects (BRiTE) study, which showed an improved overall survival with continued VEGF inhibition with bevacizumab beyond the initial progression of disease. This study supports the hypothesis that continued suppression of the VEGF pathway may be important to maximize the clinical benefit of bevacizumab in metastatic CRC. Further data supporting this hypothesis include observations of a rebound increase in VEGF concentration in human tumors and rapid tumor growth in mouse xenograft models after stopping the administration of a VEGF inhibitor. Bevacizumab was approved as a second-line agent in metastatic CRC treatment after the Eastern Cooperative Oncology Group (ECOG) 3200 trial demonstrated that the combination of FOLFOX with bevacizumab significantly improved PFS (7.3 vs 4.7 months) and median survival (12.9 vs 10.8 months) compared with FOLFOX alone. The role of bevacizumab in addition to chemotherapy to increase the resectability of liver metastasis has been explored by several small studies. One study showed that the use of bevacizumab with chemotherapy in a preoperative setting can achieve a high objective tumor response rate of 73% and the treatment was also safe, whereby the incidence of wound and bleeding complications and liver dysfunction was not increased. Confirmation of the ability of bevacizumab to enable more patients to undergo resection of hepatic metastases requires larger studies.

The most common side effects from bevacizumab are hypertension, which is seen in 11% to 24% of cases, and the potential for bleeding, gastrointestinal perforations (1.5%–2% of patients), arterial thrombotic events (approximately 4%–5%), and proteinuria. In clinical practice, bevacizumab can be given to patients with advanced CRC with intact primary tumors, and in circumstances in which surgery is planned, the drug administration is generally stopped 4 weeks before surgery so as not to increase bleeding or interfere with wound healing. At present, there are no predictive biomarkers available to predict which patient cohorts may benefit most from bevacizumab therapy. Expression of VEGF protein in human CRC tissues has not correlated with the clinical outcome of bevacizumab therapy.

A variety of novel molecules, which target the VEGF signaling pathway, are currently under investigation. Vatalanib and axitinib are tyrosine kinase inhibitors that block VEGFR-1, VEGFR-2, and VEGFR-3. Vatalanib was studied in the first and second-line setting in the Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases (CONFIRM) 1 and 2 trials, respectively, and no significant benefit was observed in the treatment of metastatic CRC when vatalanib was combined with FOLFOX. Targeted agents, which are currently being tested in the first-line setting for metastatic CRC, include a phase 1 or 2 trial of axitinib and bevacizumab, a phase 3 trial of cediranib (tyrosine kinase inhibitor to VEGFR-1, VEGFR-2, VEGFR-3, and c-kit) with FOLFOX, a phase 2 trial of aflibercept (VEGF Trap) and FOLFOX, and a phase 3 trial of sunitinib (oral multitarget tyrosine kinase inhibitor) with FOLFIRI. In the second-line setting, ongoing clinical trials include a phase 3 trial of aflibercept and FOLFIRI, a phase 3 trial of brivanib (dual kinase inhibitor of VEGFR-2 and fibroblast growth factor) with cetuximab, a phase 2 trial of axitinib with FOLFOX or FOLFIRI, and a phase 1b study of AMG 706 (tyrosine kinase inhibitor to VEGF, platelet-derived growth factor, and c-kit) with panitumumab in addition to FOLFOX or FOLFIRI.

EGFR Inhibitors

EGFR expression in tumor cell membranes is detected in approximately two-thirds of human CRC and is an adverse prognostic marker in this malignancy. Cetuximab is a chimeric IgG1 monoclonal antibody against EGFR. By binding to the extracellular domain of the human EGFR, cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and other ligands to EGFR, blocking receptor phosphorylation and activation of receptor-associated kinases, thereby inhibiting downstream signal transduction and resulting in the inhibition of cell proliferation, induction of apoptosis, and reduction in angiogenesis. EGFR is upregulated in 60% to 80% of CRC cases. Initial in vivo studies on human colon cancer cells xenografted into nude mice indicated that cetuximab enhanced antitumor activity when combined with irinotecan. Subsequent clinical trials validated these findings. In a phase 2 clinical trial, single-agent cetuximab was used to treat patients with advanced and treatment-refractory CRC with prior exposure to irinotecan either alone or in a combination regimen. Partial response was achieved in 10.5% of 57 evaluable patients, and the median survival time was 6.4 months. The activity of cetuximab in combination with irinotecan in refractory metastatic CRC was confirmed in the Bowel Oncology with Cetuximab Antibody (BOND) trial that showed a significantly higher response rate and median time to progression (TTP) in the combination arm compared with cetuximab alone (22.9% versus 10.8%, P = .007 and 4.1 versus 1.5 months, P <.001, respectively) (see Table 1 ). In contrast to bevacizumab, cetuximab shows activity as monotherapy with an approximate 10% response rate in patients with advanced CRC. Cetuximab monotherapy was shown to be superior to BSC in patients who had been either previously treated with a fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimen or had contraindications to treatment with these drugs. In this study, cetuximab improved overall survival (HR 0.77; 95% confidence interval [CI], 0.64–0.92; P = .005) with a median survival of 6.1 months in the cetuximab group compared with 4.6 months in the BSC group and it also preserved quality-of-life measures. The administration of anti-EGFR monoclonal antibodies can cause an acneiform rash in more than 80% of patients, with the incidence of grade 3 or 4 skin rash in less than 10% of patients. Other side effects include hypomagnesemia, diarrhea, and hypersensitivity reactions, particularly with the chimeric antibody cetuximab. Cetuximab is FDA approved as a single agent in metastatic CRC treatment after the failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based regimens. Cetuximab is also approved in combination with irinotecan in patients with metastatic CRC who are refractory to irinotecan-based chemotherapy.

Panitumumab is a high-affinity fully human IgG2 monoclonal antibody that also targets EGFR. In a phase 2 trial of heavily pretreated patients with metastatic CRC, single-agent panitumumab had a median PFS of 14 weeks and median overall survival of 9 months. The overall response rate of 9% was similar to single-agent cetuximab. Skin toxicities occurred in 95% of patients but were rarely severe, and there was a very low incidence of hypersensitivity reactions (1 of 148 patients) when compared with cetuximab. This led to a pivotal phase 3 trial that led to the approval of panitumumab as a single-agent salvage therapy for patients with metastatic CRC in the United States (see Table 1 ). In this study, patients previously exposed to fluoropyrimidine-, irinotecan-, or oxaliplatin-based treatment were randomized to panitumumab and BSC versus BSC alone. Results demonstrated that panitumumab, in a third-line setting, was superior to BSC alone with a response rate of 10% and PFS of 8 weeks versus 7.3 weeks (HR 0.54; 95% CI, 0.44–0.66; P <.0001). Overall survival was not significantly different because 76% of the patients crossed over from the BSC arm to the panitumumab arm. Panitumumab monotherapy was approved in patients with metastatic CRC with progression on or after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

Predictive Biomarkers for Anti-EGFR Therapy

The use of biomarkers to predict the clinical outcomes of EGFR-targeted therapy in metastatic CRC has been highlighted recently. Several trials with cetuximab and panitumumab have noted an intriguing correlation between rash intensity and survival outcomes, whereby the higher the grade of skin rash, the better the clinical outcome. This finding suggests that the intensity of the skin rash induced by anti-EGFR antibodies can serve as a predictive marker of therapeutic efficacy.

The most important recent development is the finding that the mutational status of KRAS oncogene is a predictive biomarker for the efficacy of anti-EGFR therapies. KRAS encodes for the RAS protein, which functions as a GTPase that is involved in signal transduction events, and loss of RAS is associated with hyperproliferation. Mutation in the codons 12 and 13 of KRAS gene is present in approximately 40% of human CRCs and is an early event in tumorigenesis such that the frequency of mutation is not affected by the tumor stage. When KRAS status was determined on archived tissue from completed anti-EGFR clinical trials in CRC, improved clinical outcomes were observed in patients with wild-type KRAS tumors but not in those with mutant KRAS tumors. When cetuximab was compared with BSC, overall survival was nearly doubled in tumors with wild-type KRAS compared with CRCs with mutated KRAS (9.5 vs 4.8 months; HR 0.55; 95% CI, 0.41–0.74; P <.001). Importantly, patients whose tumors had mutated KRAS showed no significant difference in outcomes between cetuximab therapy and BSC. Similar observations have been noted with panitumumab. Using archived tissue from a phase 3 trial comparing panitumumab monotherapy with BSC, patients with wild-type KRAS tumors who were treated with panitumumab had a response rate of 17% and a median PFS of 12.3 weeks versus 7.3 weeks in patients with wild-type KRAS tumors who were in the BSC group (HR 0.45; 95% CI, 0.34–0.59; P <.0001). In the patients with mutated KRAS tumors, the response rate was 0% and PFS was identical, that is, 7.4 weeks versus 7.3 weeks (HR 0.99; 95% CI, 0.73–1.36) in the panitumumab versus BSC study arms.

The RAS/RAF/MAPK signaling pathway occurs downstream from EGFR pathway. Once RAS is activated, it recruits the oncogene RAF that phosphorylates MAP2K-1 and MAP2K-2, thus initiating MAPK signaling that ultimately leads to expression of proteins involved in cell proliferation, differentiation, and survival. More recently, mutations in the BRAF oncogene have been shown to be another potential predictive marker for response to anti-EGFR therapy. Mutations in BRAF oncogene are detected in approximately 10% of sporadic CRCs. Tumors with mutations in the BRAF gene do not respond to EGFR inhibitors, and patients with mutant BRAF tumors have been shown to have significantly shorter PFS and overall survival rates compared with patients whose tumors carry wild-type BRAF . Although mutations in BRAF and loss of PTEN expression seem to be associated with resistance to EGFR-targeted monoclonal-antibody treatment, these markers require validation before they can be used in clinical practice. At present, all patients with a new diagnosis of metastatic CRC should be tested for KRAS mutation in the tumor sample, and the use of cetuximab or panitumumab should be restricted to patients with CRCs containing wild-type KRAS .

Based on the results outlined earlier, the idea of combining the agents targeting both VEGF and EGFR pathways has been tested. The use of combined targeted therapy in refractory CRC was an attractive concept, with the potential to eliminate the use of conventional cytotoxic drugs. This concept was first highlighted in the BOND-2 study, in which the combination of bevacizumab and cetuximab was used as a salvage therapy in heavily pretreated patients with metastatic CRC. This study showed a modest response rate of 20% for combined targeted therapy with a 4.9-month median TTP when compared with an approximate 10% response rate and 1.5-month median TTP reported in previous studies. Two prospective randomized phase 3 trials, Capecitabine, Irinotecan, and Oxaliplatin in advanced colorectal cancer (CAIRO)-2 and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE), were subsequently performed in an attempt to validate these findings but showed inferior outcomes and increased toxicities with the combination of anti-VEGF and anti-EGFR treatment and chemotherapy. Based on these results, anti-VEGF and anti-EGFR antibodies should not be used concurrently in patients with CRC in clinical practice outside a clinical trial. Other strategies under investigation include combining an anti-EGFR antibody with a small molecule such as a tyrosine kinase inhibitor against EGFR, such as erlotinib (Tarceva). In preclinical studies, this combination has shown synergistic effects compared with either drug alone, and phase 2 trials are currently ongoing to evaluate this strategy.

Angiogenesis Inhibitors

Angiogenesis results in the formation of new blood vessels, and in tumors, this process promotes tumor growth and metastasis. The VEGF family, composed of VEGFs and VEGF receptors (VEGFRs), regulates the process of angiogenesis, and various strategies have evolved to inhibit this signaling pathway. Bevacizumab is a humanized monoclonal antibody that binds to VEGF-A, thereby preventing the binding of this growth factor to its associated VEGFRs. Besides inhibiting angiogenesis, it has been postulated that anti-VEGF therapy can transiently normalize tumor vasculature and improve drug and oxygen delivery to tumor cells, making them more chemosensitive and radiosensitive. The potential role for bevacizumab in the treatment of CRC was initially shown in a phase 2 trial that compared 2 doses of bevacizumab in combination with 5-FU/FA with 5-FU/FA alone in patients with metastatic CRC. This study showed that the bevacizumab combinations produced improved response rates and extended median time to disease progression and median survival rates and favored the lower bevacizumab dose of 5 mg/kg. This study led to the pivotal randomized phase 3 trial that gained the approval of bevacizumab in the United States in 2004 as the first-line agent in the treatment of metastatic CRC ( Table 1 ). When compared with the irinotecan and 5-FU/FA combination (coined IFL), the addition of bevacizumab to IFL showed improved median survival (20.3 vs 15.6 months, hazard ratio [HR] 0.66, P <.001), response rates (44.8% vs 34.8%, P = .004), and median duration of response (10.4 vs 7.1 months, HR 0.62, P = .001). Grade 3 hypertension was more common in the bevacizumab group but was easily treated with antihypertensives. Bevacizumab has also shown improved clinical efficacy with a comparable safety profile, when combined with the current standard oxaliplatin- and irinotecan-based regimens for advanced CRC.

Table 1

Targeted therapy in metastatic colorectal cancer

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Nonsteroidal Antiinflammatory Drug-Related Injury to the Gastrointestinal Tract: Clinical Picture, Pathogenesis, and Prevention New Pharmacologic Therapies for Gastroenteropancreatic Neuroendocrine Tumors Pharmabiotic Manipulation of the Microbiota in Gastrointestinal Disorders, from Rationale to Reality Current Medical Treatments of Dyspepsia and Irritable Bowel Syndrome Clinical Pharmacology of 5-ASA Compounds in Inflammatory Bowel Disease New Pharmacologic Therapies in Gastrointestinal Disease

Stay updated, free articles. Join our Telegram channel

Join