Introduction to the important target for tumor therapy—VEGF (Part Two)

Typical anti-VEGF drug-bevacizumab


Bevacizumab is a humanized IgG1 monoclonal antibody that specifically binds to VEGF, thereby blocking its receptors on the surface of endothelial cells, Flt-1 and KDR, to inhibit tumor angiogenesis. Its core patent expired in 2017 and 2019, and the biosimilar Mvasi, jointly developed by Amgen and Allergan, was approved by the FDA in September 2017.

Bevacizumab's characteristics of its suitability for many types of tumors and its high safety make its sales dominate. In 2015, the total global drug sales ranking ranked fifth, and the bioactive drug ranking ranked fourth. Its sales reached US $ 7,053 million in 2016, and it is expected to achieve a new round of growth in combination with PD-L1 monoclonal antibodies in the future.

Applications of Bevacizumab (subject to FDA approval)

1. Colorectal cancer: Avastin + 5-fluorouracil combination for first-line and second-line treatment of metastatic colorectal cancer; Avastin + fluorouracil + irinotecan / oxaliplatin for second-line treatment for metastases that have progressed after receiving Avastin first-line treatment Colorectal cancer.

2. Lung cancer: Avastin + carboplatin + paclitaxel, for first-line treatment of unresectable, locally advanced, relapsed or metastatic non-squamous non-small cell lung cancer.

3. Glioblastoma: Avastin is used to treat recognising recurrent glioblastoma.

4. Kidney cancer: Avastin + interferon alpha for the treatment of metastatic renal cell carcinoma.

5. Cervical cancer: Avastin + paclitaxel + cisplatin / topotecan, for the treatment of refractory, relapsed or metastatic cervical cancer.

6. Gynecologic tumors: Avastin + paclitaxel / PEG-modified doxorubicin liposomes / topotecan, for the treatment of platinum-resistant, recurrent, epithelial ovarian cancer, tubal cancer, and primary peritoneum that have received no more than 2 chemotherapy Tumors; Avastin + Carboplatin + Paclitaxel / Gemcitabine, for the treatment of platinum-sensitive, recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal tumors.

Safety of Bevacizumab

Gastrointestinal perforation, surgical wound healing complications, bleeding and other adverse reactions were warned by the FDA. The incidence of serious adverse reactions such as fistula, hypertension, brain syndrome, proteinuria, and heart failure is higher than that of chemotherapy.

Effectiveness of Bevacizumab

1. First- and second-line drug for metastatic colorectal cancer

Avastin is the only macromolecule that has proven effective in both mCRC's first- and second-line treatment options, with a 20-30% improvement in OS and PFS, thus establishing an important position in this indication.

Study AVF2107g: a double-blind activity control test, 402 patients in the test group used Avastin (5mg / kg every two weeks) + IFL (Irinotecan 125mg / ㎡ four times every six weeks, 5-fluorouracil 500mg / ㎡, and folinic acid 20mg / ㎡ ), 411 patients in the control group received placebo + IFL. OS vs. 20.3 vs. 15.6 months, PFS vs. 10.6 vs. 6.2 months, ORR vs. 45% vs. 35%, DR vs. 10.4 vs. 7.1 months.

Study ML18147: A prospective, randomized, multinational trial in which patients have progressed after receiving first-line treatment with Avastin. Avastin (5 mg / kg every two weeks or 7.5 mg / kg every three weeks) in the test group + fluorouracil + irinote Kang / oxaliplatin (depending on the first-line treatment regimen), the control group of 411 patients only used fluorouracil + irinotecan / oxaliplatin. OS vs. 11.2 vs. 9.8 months, PFS vs. 5.7 vs. 4.0 months.

NCCN recommended FOLFOX / FOLFIRI + Avastin for the initial resectable mCRC in the second year (2005) after approval, but since Avastin has no good prospective evidence-based medical evidence in this field, plus previous Xitu Prospective studies of cilizumab have found no significant benefit compared to FOLFOX. Therefore, in the 2017 version of the NCCN guidelines, the recommendation of targeted drugs for initially resectable mCRC was deleted and changed to pure FOLFOX, which caused a stir in the industry. The European ESMO and Chinese CSCO guidelines have not been updated.

In the hottest "right and left half battle" in colorectal cancer since 2015, Avastin proved to have no effect on the primary tumor site, that is, it benefits both left and right colon cancers, while other EGFR monoclonal antibodies such as cetuximab have significant benefits only in left colon cancer.

lung cancer

Avastin is the only drug that has improved survival to more than 1 year in amNSCLC's first-line treatment options, and is the first drug in more than a decade to have a clear advantage over standard chemotherapy regimens, increasing OS by more than 20%. NCCN recommends Avastin in combination with chemotherapy for first-line treatment of non-squamous NSCLC.

Study E4599: A randomized, open-control, multicenter trial in which no patient received chemotherapy. The 434 patients in the test group used a total of 6 three-week cycles of Avastin (15mg / kg) + paclitaxel (200mg / ㎡) + carboplatin (AUC6). Control Group 444 patients only used paclitaxel + carboplatin. OS comparison 12.3 vs 10.3 months.

Based on a clinical trial of 154 patients, the trial group using Avastin + Erlotinib was compared with the control group using only Erlotinib, with a PFS comparison of 16.0 vs. 9.7 months. The EU has approved Avastin and Erlotinib as unavailable. Resection, advanced, recurrent, non-squamous non-small cell lung cancer as a first-line treatment option, which will allow Avastin to gain greater market space in the field of lung cancer.

To be continued in Part Three…

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