Neha Vapiwala, MD The Abramson Cancer Center of the University of Pennsylvania <
Review of Pivotal Bevacizumab Studies – Colorectal Cancer
Phase I clinical trials (Gordon et al., Margolin et al.) established a half-life of 21 days, lack of dose-limiting toxicity, and safety/tolerability when bevacizumab is given with chemotherapy.
Phase II clinical trial (Kabbinavar et al.) established an overall response rate (RR) of 32% with the addition of bevacizumab to standard chemotherapy (5-FU/Leucovorin) in previously untreated metastatic colorectal cancer (CRC) patients, compared to a 17% RR with chemotherapy alone. Specifically, the "low-dose" bevacizumab arm (5 mg/kg) demonstrated a 40% RR, compared to 24% with the "high-dose" arm (10 mg/kg). Median time-to-disease-progression (TTP, 9 vs. 5.2 months, p=0.005) and median progression-free survival (PFS, 9.2 vs. 5.5 mos, p=0.0002) were also statistically significantly better with the combination of low-dose bevacizumab and chemotherapy vs. chemotherapy alone.
Phase III clinical trial (Hurwitz et al.) established a statistically significant median overall survival (OS) benefit with low-dose bevacizumab and IFL (Irinotecan, 5-FU, Leucovorin) chemotherapy, compared to placebo and IFL chemotherapy (20.3 vs. 15.6 mos, p<0.001), in previously untreated CRC patients.
Review of Additional Bevacizumab Studies – Colorectal Cancer
Second-line therapy in previously treated metastatic CRC patients: The E3200 trial (Giantonio et al.) looked at high-dose bevacizumab in combination with FOLFOX-4 chemotherapy a combination of oxaliplatin, fluorouracil (5-FU), and leucovorin), compared to either treatment alone. RR (21.8% vs. 9.2%, p<0.0001), PFS (7.2 vs. 4.8 mos, p<0.0001), and OS (12.9 vs. 10.8 mos, p=0.0018) were all statistically significantly better with the combination compared to FOLFOX-4 alone.
Refractory disease in heavily treated metastatic CRC patients: RR of 1-4%, TTP of 3-4 months.
Irinotecan-refractory disease in metastatic CRC patients: The BOND trials found greater RR and TTP with the combination of irinotecan, bevacizumab, and cetuximab in patients no longer responding to irinotecan-based chemotherapy.
CALGB/SWOG Phase III study of patients with metastatic CRC treated with FOLFOX or FOLFIRI chemotherapy, then randomized to either cetuximab, bevacizumab, or both.
NSABP C-08 Phase III study of stage II/III CRC patients after surgical resection treated with adjuvant FOLFOX with or without bevacizumab.
Review of Bevacizumab Studies – Gastric/ Gastroesophageal Junction Cancer
Phase I/II trial (Shah et al.) of 23 metastatic gastric and gastroesophageal cancer patients treated with irinotecan/cisplatin chemotherapy + bevacizumab 15 mg/kg found RR of 61%, with 95% of patients free of disease progression at 3 months.
MAGIC 2 trial (Cunningham et al.) underway in UK: preoperative chemotherapy x 3 cycles à surgery à postoperative chemotherapy x 3 cycles. Patients then randomized to bevacizumab or placebo. Chemotherapy regimen is ECX: epirubicin, cisplatin, capecitabine. RESULTS PENDING
second-line therapy for GE junction cancer with bevacizumab and docetaxel (Dana Farber Cancer Institute)
first-line therapy for GE junction cancer with bevacizumab and preoperative irinotecan/cisplatin/radiation therapy (Dana Farber Cancer Institute)
first-line therapy for esophageal cancer with bevacizumab and preoperative irinotecan/cisplatin/radiation therapy (Memorial Sloan-Kettering Cancer)
Review of Bevacizumab Studies – Pancreatic Cancer
Phase II trial (Kindler et al.) of bevacizumab and gemcitabine chemotherapy showed RR of 19%, median OS of 8.7 mos, and 6-month survival rate of 75%
CALGB: Phase III – gemcitabine with or without bevacizumab
RTOG: Unresectable disease – capecitabine + radiation therapy à bevacizumab à gemcitabine + bevacizumab
ECOG: Unresectable disease – gemcitabine + radiation therapy with either bevacizumab or cetuximab
Review of Bevacizumab Studies –Hepatocellular Cancer
Phase II study (Zhu et al.) of bevacizumab with gemcitabine and oxaliplatin produced 2 partial responses out of 27 patients treated.
Review of Bevacizumab Studies – Breast Cancer
Phase III study of 646 patients with metastatic breast cancer found prolonged PFS using first-line treatment regimen of bevacizumab (10 mg/kg) and paclitaxel: PFS of 10.7 months compared to 6.1 months with paclitaxel alone. (Clin Breast Cancer 2005 Jun;6:105-107)
Review of Bevacizumab Studies – Non-Small Cell Lung Cancer
Preliminary results of ECOG 4599 phase III study of over 700 patients with advanced non-small-cell lung cancer show prolonged OS using first-line treatment regimen of bevacizumab (15 mg/kg), paclitaxel, and carboplatin: OS of 12.5 months vs. 10.2 months with chemotherapy doublet alone (Clin Lung Cancer 2005 Mar;6(5):276-8)