Cetuximab

Cetuximab is a chimeric monoclonal antibody directed against the external cell surface of the epidermal growth factor receptor (EGFR). It has been shown that the EGFR is over-expressed in up to 8% of colorectal tumors, and its expression has been correlated with metastatic disease and poor prognosis.Activation of the EGFR signaling pathway results in activation of cellular processes involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. Moreover, this pathway inhibits the cytotoxic activity of various anticancer agents and radiation therapy, thereby leading to the development of cellular drug resistance.

The initial clinical studies with cetuximab were performed in the US. Saltz et al reported a 17% response rate in patients with irinotecan-refractory, metastatic colorectal cancer,who were treated with the combination of cetuximab and irinotecan.⁴³ An additional 31% of patients had stable disease giving a disease control rate of 48%.A subsequent study evaluated the clinical activity of cetuximab monotherapy in patients with refractory CRC whose tumors expressed EGFR.⁴⁴ Cetuximab was administered intravenously on a weekly schedule.A total of 57 patients were evaluated,and the overall response rate was 9% with a median survival of 6.4 months. In general, this treatment was well tolerated, and the most common side-effects were acne-like skin rash presenting mainly on the face and upper torso and a composite of asthenia, fatigue, malaise, and/or lethargy. At the ASCO 2004 meeting, Lenz and colleagues reported the results of a large (n=346) Phase II study of single-agent cetuximab in heavily pretreated patients who had previously failed both irinotecan and oxaliplatin.45 The response rate in this trial was 12%,and the median overall survival was 6.7 months, which exactly paralleled the results previously reported by Saltz et al in irinotecan-refractory patients. Cunningham et al presented the results of the Bowel Oncology with Cetuximab Antibody (BOND) randomized Phase II study in heavily pretreated patients with advanced CRC.

This study enrolled 329 patients with EGFR-positive metastatic CRC who had failed to respond to irinotecan (progressing on or within 30 days).46 Patients were randomized in a 2:1 ratio to cetuximab 400mg/m² infusion, followed by weekly cetuximab 250mg/m², plus irinotecan at the same dose and schedule on which they had been progressing, or cetuximab monotherapy. The objective response rate (22.9% versus 10.8; P=0.0074), TTP (4.1 versus 1.5 months; P<0.0001), and disease control rate (55.5% versus 32.4%; P=0.0001) were significantly higher in the combination therapy group.

There was a trend towards improvement in median survival in patients treated with the combination of cetuximab and irinotecan when compared with cetuximab monotherapy (8.6 versus 6.9 months;P=0.48), although this difference did not reach statistical significance. Of note, cetuximab treatment did not worsen the toxicities normally associated with irinotecan chemotherapy. The most frequent grade 3/4 events in patients receiving combination therapy were diarrhea (21.2%), asthenia (13.7%), neutropenia (9.5%), acne-like rash (9.4%), and vomiting (6.1%). Patients receiving cetuximab alone had fewer adverse effects, including asthenia (10.4%), acne-like rash (5.2%), and abdominal pain (5.2%).Based on the results of this randomized study as well as Phase II clinical studies conducted in the US, cetuximab was approved for use in combination with irinotecan for the treatment of EGR-expressing, metastatic colorectal cancer in patients who are refractory to irinotecan-based chemotherapy. This agent was also granted approval for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal cancer in patients who are intolerant to irinotecan-based chemotherapy.

Bevacizumab

The vascular endothelial growth factor (VEGF) is established to be one of the most important angiogenic growth factors known to regulate angiogenesis. Since the growth of primary tumors, as well as metastatic disease, requires an intact vasculature,VEGF and the VEGF-signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEG signaling, and they include inhibition of VEGF/VEGF receptor interactions by targeting either the VEGF ligand with antibodies or soluble chimeric receptors, or by direct inhibition of the VEGF receptor-associated tyrosine kinase activity by small molecule inhibitors.

Bevacizumab is a recombinant humanized monoclonal antibody targeted against all splice variants and post- translationally modified forms of VEGF-A. It binds to and prevents VEGF-A from interacting with their target VEGF receptors. A randomized Phase II trial (AVF0780) investigated the safety and efficacy of two dose levels of BV in combination with 5-FU/LV in patients with metastatic CRC.47 The two treatment arms that included BV (at doses of 5mg/kg or 10mg/kg, respectively) resulted in higher response rates (40% and 24%) and a longer median time to disease progression (nine and 7.2 months) and median survival (21.5 and 16.1 months) compared with the control arm consisting of 5-FU/LV alone (17%; 5.2 months; 13.6 months). Because higher clinical efficacy was observed in the 5mg/kg arm compared with the 10mg/kg arm, the 5mg/kg dose of BV was chosen for further clinical study. Although BV was generally well-tolerated, this trial identified a number of important safety signals associated with BV therapy, including an increased incidence of thromboembolic complications, hypertension, proteinuria, bleeding complications in the form of epistaxis, headache, fever, and rash. In general, however, these adverse events were either clinically insignificant or easily manageable.

In the pivotal randomized Phase III study, previously untreated patients with metastatic CRC who received BV plus standard chemotherapy with the bolus weekly IFL regimen had longer progression-free survival (10.6 months versus 6.2 months, P<0.00001) and survived significantly longer (20.3 months versus 15.6 months; P=0.00003) than those receiving IFL chemotherapy plus placebo.⁴⁸ The only adverse event that occurred with greater frequency in the anti-VEGF regimen was grade 3 hypertension, which was managed effectively with oral medications. In contrast to the randomized Phase II study described above, no increases in thromboembolic events, bleeding complications, and proteinuria were observed. Based on the positive clinical results of this Phase III pivotal trial, BV received approval in February of 2004 from the US Food and Drug Administration (FDA) as a first-line treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidine-containing regimen.

Trial AVF2192g was a randomized, double-blind, placebo-controlled, multicenter study in patients in the first-line setting, who were deemed to not be optimal candidates for irinotecan-based chemotherapy.⁴⁹ The primary objective of the trial was duration of survival.

Secondary end-points included response rate (RR), progression-free survival (PFS), response duration, quality of life assessment, and safety. Patients were randomized to one of two treatment arms. In arm one, patients received the Roswell Park regimen of 5-FU/LV and BV 5mg/kg, while in the second arm, patients received the Roswell Park regimen of 5-FU/LV plus placebo.The preliminary results of this trial were presented by Kabbinavar et al at the recent 2004 ASCO meeting. The overall median survival was 12.9 months on the placebo arm compared with 16.6 months on the BV arm (P=0.159).

Progression-free survival in the placebo arm was 5.5 months compared with 9.2 months in the BV arm (P=0.0002). The overall response rate was 15% in the placebo arm and 26% in the BV arm (P=0.0552),with all responses being partial responses in both arms. The toxicities most commonly associated with BV included bleeding, thromboembolic events, hypertension, and proteinuria. Hypertension (4.8% versus 32%) and proteinuria (19.2% versus 38%) were observed more frequently in patients treated with BV,and two patients in the BV arm experienced gastrointestinal perforations.