In recent years, with the in-depth research related to the efficacy of targeted therapy and genotyping, targeted drugs have become a new choice for individualized and comprehensive treatment of colorectal cancer, and the strategy of targeted therapy has advanced from third- or second-line treatment to first-line treatment for colorectal cancer. The advent of targeted drugs has improved the treatment expectations of colorectal cancer patients, and their combination with chemotherapy drugs has further prolonged the survival of patients.
Commonly used targeted drugs for colorectal cancer
Currently, the commonly used targeted drugs in colorectal cancer include two classes of drugs targeting epidermal growth factor receptor (EGFR) (see figure) and vascular endothelial growth factor (VEGF), specifically bevacizumab, cetuximab and panitumumab.
Bevacizumab
Bevacizumab is a humanized monoclonal antibody against VEGF.
A 2004 phase III clinical study showed that first-line treatment of metastatic colorectal cancer (mCRC) with IFL in combination with bevacizumab significantly prolonged patient survival compared with 5-fluorouracil (5-FU)/calcium folinate (LV) + irinotecan (IFL) chemotherapy (20.3 months vs. 15.6 months, P=0.00003). Based on the results of this study, the US FDA approved bevacizumab in combination with IFL as the first-line chemotherapy regimen for mCRC in 2004.
The 2006 TREE study showed that bevacizumab combined with oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer resulted in a significantly longer survival of 23.7 months compared to 18.2 months in the control group. 2007 Phase III E 3200 study showed that bevacizumab combined with 5-FU/LV + oxaliplatin (FOLFOX) in second-line treatment of colorectal cancer significantly improved overall survival (OS, 12.9 months versus 10.8 months, P=0.0011). These studies suggest that bevacizumab in combination with either oxaliplatin- or irinotecan-based regimens significantly prolonged patient survival.
Common adverse effects of combination bevacizumab therapy include bleeding, hypertension, proteinuria, and unique adverse effects include gastrointestinal perforation (incidence of approximately 2%) and poor wound healing. Therefore, caution must be exercised when combining bevacizumab therapy in patients in the perioperative period, and the drug must generally be discontinued for more than 4 weeks before and after surgery.
Cetuximab
Cetuximab is a human-mouse chimeric IgG1 monoclonal antibody that acts on the EGFR signaling pathway and has a much higher affinity for EGFR than its natural ligand (see figure).
A 2007 phase III study showed that cetuximab alone significantly prolonged patient survival (6.1 months versus 4.9 months) and improved quality of life (P<0.05) compared with best supportive care in patients with colorectal cancer who had failed treatment with both irinotecan and oxaliplatin or who had contraindications to chemotherapy. Interim results from the phase II OPUS study showed that cetuximab combined with FOLFOX in first-line treatment of mCRC may further improve efficiency. The interim results of the phase III CRYSTAL study showed that cetuximab combined with 5-FU/LV + irinotecan (FOLFIRI) in first-line treatment of mCRC significantly prolonged the progression-free survival (PFS) period of patients. This shows that cetuximab in combination with chemotherapeutic agents in first-line treatment of colorectal cancer also has significant benefits.
Data from cetuximab in third-, second- and first-line treatment have demonstrated its efficacy in colorectal cancer, and the ACORBAT study showed that cetuximab in combination with FOLFOX extended the median OS of colorectal cancer patients to 30 months. In addition, adverse reactions to cetuximab treatment were mild, and allergic reactions could be prevented by anti-allergic management. The characteristic reaction acne-like rash, although occurring at a high rate, is tolerated by patients. More importantly, the extent to which patients develop rash is positively correlated with the efficacy of cetuximab.
Panitumumab
Panitumumab is a fully humanized IgG2 monoclonal antibody with a high affinity for EGFR similar to that of cetuximab. Phase III studies have demonstrated that second-line treatment of advanced colon cancer with panitumumab alone significantly improves PFS compared to best supportive care, and phase III studies have demonstrated that first-line treatment with panitumumab in combination with FOLFOX prolongs PFS in advanced colorectal cancer.
Targeted drug efficacy prediction and individualized treatment
Patients with KRAS mutations do not benefit from anti-EGFR antibody therapy, and research on the treatment of this group of patients is bound to become a new research hotspot. At the same time, even KRAS wild-type patients do not benefit from anti-EGFR antibody therapy 100% of the time, and this will certainly be a problem for continued research.
KRAS Gene
The correlation between KRAS genes and the efficacy of anti-EGFR antibodies has truly brought the treatment of colorectal cancer into the era of individualized therapy.
Mutations in the KRAS gene, a small G protein in the downstream region of the EGFR signaling pathway, can lead to abnormal activation of the pathway, thereby affecting the efficacy of EGFR inhibitors. Currently, mutations in KRAS gene are detected mainly in codons 12 and 13, and KRAS mutant phenotypes account for about 40% of colorectal cancer patients in the West and about 35%-40% in China.
In a 2008 study, cetuximab monotherapy significantly prolonged OS compared with best supportive care in KRAS wild-type patients (9.5 months versus 4.8 months, P<0.001), but not in KRAS mutant patients. In the OPUS study, cetuximab in combination with FOLFOX significantly prolonged PFS in the KRAS wild-type group compared with the FOLFOX-only group (7.7 months versus 7.2 months), but PFS in the KRAS mutant group was even worse than in the chemotherapy-only group (5.5 months versus 8.6 months). wild-type patients, PFS was prolonged in the FOLFIRI combined with cetuximab treatment group compared with the FOLFIRI-only group, but not in the KRAS-mutant patients. In addition, studies on KRAS mutation status and the efficacy of panitumumab have confirmed that combination panitumumab treatment is more effective in KRAS wild-type patients than in KRAS mutant patients.
The mechanism of the effect of KRAS mutation status on the efficacy of anti-EGFR monoclonal antibodies is unclear, but it is certain that the efficacy of anti-EGFR monoclonal antibodies is limited to KRAS wild-type patients.
Other biomarkers
There are two major EGFR intracellular signaling pathways: the RAS-RAF-MEK-MAPK pathway, which is associated with cell proliferation, and the PI3K-PTEN-AKT pathway, which is associated with cell survival and activity (see figure). However, this can only explain the ineffectiveness of anti-EGFR antibody therapy in about 40% of patients with KRAS mutations and the ineffectiveness of therapy in another 30%-40% of patients despite being KRAS wild-type. Therefore, studies of KRAS genes are being conducted in parallel with studies of BRAF, PI3K and PTEN genes and the efficacy of anti-EGFR antibodies.
In a retrospective study, 79 patients with KRAS wild-type colorectal cancer were treated with anti-EGFR antibodies, among which 11 patients with BRAF mutant type and none of them were effective with anti-EGFR treatment, while 22/68 of BRAF wild-type were effective with longer PFS and OS than mutant type patients.
Questions to be addressed
Is the combination of targeted drugs against different targets better than monotherapy in advanced colorectal cancer? What is the role of targeted therapy in the adjuvant treatment of early stage colon cancer?
Multi-targeted drug combinations
Both EGFR and VEGF targeted drugs have shown good efficacy in colorectal cancer treatment, is it possible to combine the two types of targeted drugs? Is the efficacy of the combination better than that of the single agent? Initially, some phase II clinical studies showed good efficacy of combination therapy, but the results of subsequent phase III clinical trials changed this expectation. Both cetuximab and panitumumab, in combination with chemotherapy + bevacizumab regimens for first-line treatment of mCRC, showed no significant improvement in efficacy and an increase in toxicity.
Adjuvant therapy
The good efficacy of targeted drugs in first-line treatment of mCRC has made it possible to try them in adjuvant chemotherapy for colorectal cancer. However, the 2009 NSABP-C08 study yielded disappointing results. The study included 2672 patients with stage II or III colon cancer after surgery and randomized them to the mFOLFOX6 group or the mFOLFOX6 combined with bevacizumab group. The results showed that the 3-year disease-free survival (DFS, HR=0.89, P=0.15) of patients with early-stage colon cancer in the combination group did not improve, and the incidence of adverse effects of hypertension, pain, proteinuria and surgical wound complications was significantly higher than that in the chemotherapy-only group (P<0.001). Therefore, the use of targeted drugs for adjuvant therapy is not recommended at this time.
Similar adjuvant studies AVANT (comparing the efficacy of FOLFOX4, FOLFOX+bevacizumab and XELOX+bevacizumab) and PETACC 8 (FOLFOX±cetuximab) are underway and the results are expected to provide answers to the role of targeted agents in the adjuvant treatment of colon cancer.