The most important growth factor for angiogenesis, vascular endothelial growth factor (VEGF), was discovered by Dvorak [1] in 1983 and its receptor (vascular endothelial growth factor receptor, VEGFR) was subsequently discovered by Ferrara [2]. The first antibody against VEGF, bevacizumab (Avastin, Chinese trade name: 安维汀), was synthesized in 1997.) In 2004, bevacizumab was approved by the FDA as the first anti-angiogenic agent for the treatment of metastatic colon cancer; it was subsequently approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC), progressive or metastatic renal cell carcinoma, and Her-2 negative advanced breast cancer. The domestic launch of recombinant human vascular endothelial inhibitor (Endostar, trade name: Endo) has also been successful in the treatment of advanced NSCLC. Because of this, anti-angiogenic therapy is increasingly becoming an important component of molecularly targeted tumor therapy.
I. Bevacizumab encountered a “bottleneck”
The U.S. Food and Drug Administration (FDA) announced on December 16, 2010 that it was recommending the removal of breast cancer as an indication from the drug’s specification because there was no evidence of safety and efficacy of bevacizumab for the treatment of breast cancer.
The E2100 study, published in the New England Journal of Medicine in 2007, laid an important foundation for the first-line treatment of metastatic breast cancer (MBC) with bevacizumab in combination with chemotherapy. This study showed that paclitaxel in combination with bevacizumab prolonged progression-free survival (PFS) by nearly a factor of 1 in patients with MBC cancer (5.8 months vs. 11.4 months, P < 0.0001) with no significant increase in toxic effects and a favorable safety profile [3]. In February 2008, the FDA approved bevacizumab + paclitaxel through the fast track approval for chemotherapy-naïve The evidence for bevacizumab in combination with paclitaxel was reinforced by the AVADO study published in 2008, which not only looked at the efficacy and safety of bevacizumab in combination with docetaxel, but also explored the effects of different doses of bevacizumab. The results of this study showed that for Her-2 negative MBC patients, PFS was significantly prolonged with both low and high doses of bevacizumab in combination with docetaxel compared to the control group, and the PFS benefit was largely consistent across subgroups [4]. Subsequently, the RIBBON-1 study reported the latest results of its subgroup analysis. A total of 1,237 patients with Her-2 negative MBC were enrolled and randomized into bevacizumab combined with chemotherapy and chemotherapy alone groups. The results showed that the addition of bevacizumab significantly improved the efficacy of chemotherapy, with statistically significant differences in both PFS (capecitabine combination group: 8.6 months vs. 5.7 months, P=0.0002; paclitaxel/anthracycline combination group: 8.0 months vs. 9.2 months, P=0.0001) [5]. 2009 San Antonio Breast Cancer Conference (SABCS) the RIBBON-2 study, also for bevacizumab, was reported. This study was in patients who had failed first-line therapy and also showed that bevacizumab in combination with chemotherapy prolonged PFS (7.2 months vs. 5.1 months, P= 0.0072) [6].
However, although PFS was significantly prolonged in the bevacizumab combination chemotherapy group compared to the chemotherapy alone group in all four studies, there was no significant advantage in overall survival (OS) in the former. In the three subsequent studies, bevacizumab was less effective and resulted in an increase in serious grade 3 to 5 adverse events. According to FDA statistics, the mortality rate due to bevacizumab treatment in the studies was 0.8 to 1.2 percent. Therefore, after a detailed review of data from four clinical studies of bevacizumab for MBC, the FDA made the decision to recommend that Genentech withdraw bevacizumab for the indication of breast cancer.
The “encounter” with bevacizumab in breast cancer treatment reflects the fact that not all breast cancer patients benefit from bevacizumab treatment, with only some having improved outcomes and others only having an increased risk of complications. Unfortunately, there are still no molecular markers that can predict the efficacy of bevacizumab therapy to screen for the right population. Therefore, bevacizumab still has a long way to go from improving PFS, to improving OS.
Second, the emergence of new anti-vascular target drugs
The oral multi-targeted small molecule tyrosine kinase inhibitor sunitinib acts on VEGFR, platelet-derived growth factor receptor (PDGFR) and other tyrosine kinases such as FLT3 and CSF-1R.
A phase II study analyzed the efficacy and safety of sunitinib combined with Herceptin in the treatment of Her-2-positive MBC. 54 patients received sunitinib 37.5 mg/d + Herceptin/3 weeks or + Herceptin/week therapy. Due to intolerable toxicities, the sunitinib dose was adjusted to 25 mg/d in 39% of patients. 52 patients with evaluable efficacy had an ORR of 35% and a median PFS of 26 weeks. The majority of toxic reactions were grade 1 to 2, with three grade 4 toxic reactions of decreased left ventricular ejection fraction, pulmonary embolism, and pancreatitis, and one grade 5 toxic reaction of cardiogenic shock. Studies have shown that sunitinib combined with Herceptin has antitumor activity and that patients tolerate the toxic side effects [7]. Another exploratory study analyzed the role of sunitinib in the neoadjuvant treatment of breast cancer. Eighteen patients with Her-2 negative stage Ic to III breast cancer were included in the study and were given sunitinib monotherapy 100 mg/d1, 37.5 mg/d2 to 13 followed by paclitaxel 80 mg/m2 + sunitinib 25 mg/d. The results showed that the patients were well tolerated by sunitinib monotherapy. The mean tumor interstitial pressure (IFP) was significantly reduced from 18.87 mmHg before treatment to 6.38 mmHg after treatment (P=0.002) after patients received sunitinib, showing that sunitinib can significantly reduce tumor IFP by regulating vascular infiltration through vascular endothelial growth factor (VEGF) [8]. However, the way forward will not be easy. a multicenter phase II clinical trial conducted by Wildiers et al. investigated whether sunitinib could prolong PFS after chemotherapy by enrolling 55 MBC patients who received paclitaxel-based chemotherapy and achieved PR or CR, divided into two groups, one receiving oral sunitinib and one receiving no treatment, with the primary endpoint of PFS. the results showed that the two groups of PFS were 2.8 and 3.1 months, respectively, which did not differ, and patients in the trial group experienced varying degrees of toxic side effects [9]. In the results of a phase III clinical trial published in 2010, sunitinib combined with paclitaxel for first-line treatment of Her-2 negative MBC did not show a significant prolongation of PFS [10], while similar results were obtained in another phase III study of sunitinib combined with capecitabine in patients with treated MBC [11].
Sorafenib (sorafenib) is also a multitargeted agent that acts on VEGFR, PDGFR, and a multicenter phase II open study of sorafenib for MBC, enrolling 56 patients who had at least one chemotherapy and failed, sorafenib 400 mg, bid. 54 evaluable, resulting in 1 PR and 20 SD (37%) [12]. A phase IIB randomized double-blind controlled study demonstrated that sorafenib combined with paclitaxel was superior to paclitaxel combined with placebo in first-line treatment of MBC, with a PFS of 8.1 months versus 5.6 months, respectively (p=0.017) [13]. Another study evaluated the efficacy of capecitabine in combination with sorafenib or capecitabine in combination with placebo for MBC, with a PFS of 6.4 months versus 4.1 months, respectively (P=0.0006) [14]. A phase III trial of expanded cases will confirm the efficacy of sorafenib in combination with chemotherapy.
Thalidomide (thalidomide) has well established anti-angiogenic and immunomodulatory effects. A phase II trial enrolled 24 patients with treated MBC and found a significantly increased incidence of grade 3-4 toxicities in the thalidomide combined with capecitabine group and no prolongation of PFS and OS compared to patients in the capecitabine alone group [15].
Preclinical trials have demonstrated the anti-angiogenic and tumor cell growth inhibitory effects of the COX-2 inhibitor celecoxib. In a phase II study enrolling 220 Her-2 negative stage II-III breast cancer patients, the trial group was treated with EC (epirubicin + cyclophosphamide) → D (docetaxel) + C (celecoxib) regimen, while the control group was treated without celecoxib, and it was found that celecoxib did not improve the pathological complete remission rate in the trial group (pCR: 13% vs. 11.5%) [14].
Endo, a recombinant human vascular endothelial inhibitor developed independently in China, was first applied to non-small cell lung cancer (NSCLC) and achieved good efficacy. Yuan Xia et al. were the first to report Endo combined with chemotherapy (including paclitaxel, anthracycline and gemcitabine) for five cases of Her-2 negative MBC, of which one case achieved CR and two cases achieved PR with an objective effective rate of 60% (3/5) [16]. Song Shijun et al. also reported 6 cases of MBC (unspecified Her-2 status) treated with Endo combined with capecitabine, of which 1 case had CR, 2 cases had PR, and 2 cases had SD, with an objective effective rate of 50% [17]. However, the number of cases is too small to make a comprehensive evaluation of Endo, and larger clinical trials are needed to provide more robust evidence.
Endostar has a short half-life in humans (8-10 h) and requires daily intravenous infusion, which is inconvenient for patients and not conducive to long-term maintenance therapy. Recombinant protein polyethylene glycol (PEG) modification is currently an important development in the protein drug market, and PEG is a good material for protein modification that is non-toxic, non-antigenic and strongly biocompatible. Modified proteins have less chance to be enzymatically cleaved, longer drug half-life, improved stability, reduced immunogenicity, longer retention time in human body, and increased proteolysis, which can reduce the number of drug injections and turn recombinant protein-based drugs into long-acting formulations.
M2ES is a polyethylene glycol (PEG) single site modification product of recombinant human endothelial inhibitor (Endostatin) expressed in E. coli. Preclinical studies have shown that the half-life of M2ES is approximately 7-fold longer than before modification, and weekly dosing has shown good inhibition rates in a variety of human-derived tumors. Two phase I clinical studies that have been conducted have shown that the half-life of M2ES is about 7 to 10 times longer compared to the same dose of Endo in healthy subjects and tumor patients. It is promising to be a long-acting vasopressor-like antitumor drug. In a phase I clinical study of multiple dosing of M2ES in tumor patients, the inhibitory effect of M2ES on blood flow at the tumor site was observed, while the effect on normal tissue blood flow was less, indicating that M2ES may specifically target the blood vessels at the tumor site. In a phase I dose creep trial of M2ES in combination with paclitaxel/carboplatin (PC), it was shown that the dose below 15 mg/m2 was well tolerated by tumor patients; in the 10 mg/m2 dose group of 6 NSCLC patients who completed 2 cycles of chemotherapy, 3 achieved PR and 3 SD, showing a good short-term efficacy. Recently, it is preparing to enter a phase II clinical trial in advanced NSCLC, and the results are expected. It may be a new hope for anti-angiogenic therapy for advanced breast cancer.
The search for molecular markers to predict efficacy is urgent
Finding a molecular marker that can predict the efficacy of anti-angiogenic therapy is a critical, complex and lengthy process. Unlike KRAS and Her-2, which have become clear predictors of efficacy in cetuximab and trastuzumab therapy, there are still no recognized predictors of efficacy for anti-angiogenic therapies (especially anti-VEGF monoclonal antibodies).
Throughout the course of anti-angiogenic therapy, any target or event related to its mechanism of action may be a candidate efficacy predictor, including the molecular biology of tumor cells, the response of tumor angiogenesis to therapy, and alternative markers secreted by tumors into the peripheral blood. Anti-angiogenesis-related markers being explored include vascular endothelial cell adhesion molecules (VCAM) and E-Selectin in the plasma of breast cancer patients, angiogenin-2 (ANG-2) in colorectal cancer tissue specimens and VEGF and endothelial cell adhesion molecule-1 (ICAM-1) in the plasma of NSCLC patients [18- 20]. In addition, the observation of changes in the blood supply to the tumor by imaging means may also provide some information on the efficacy of the treatment. However, so far, no valuable marker has been found that can predict the efficacy of anti-angiogenic therapy, so the search for clear predictors of efficacy will be one of the priorities of oncologists’ research.
IV. Conclusion
Anti-angiogenic targeted therapy has failed to achieve the expected results in the treatment of MBC, and how to apply such drugs in the best way to the most suitable patients is still being explored. It is undeniable that some patients can achieve good outcomes from anti-angiogenic therapies, but no effective molecular markers have been identified as predictors to select sensitive patients, so the overall efficacy varies. Even so, as molecular biology and evidence-based medical research continue to progress, we expect that this new therapy will bring surprises to oncology clinics.