In recent years, with the improvement of molecular biology technology and the further understanding of tumor pathogenesis at the molecular level of cell receptors and proliferation regulation, people have started to target cell receptors, key genes and regulatory molecules, and call it “molecular targeted therapy”. Compared with conventional chemotherapy, which does not selectively kill cells, molecularly targeted therapy works on tumor cells and improves the precision of tumor treatment. Instead of targeting tumor cells, molecularly targeted drugs target molecules specifically or highly expressed on tumor cell membranes or within cells, which can not only act more specifically on tumor cells to block their growth, metastasis or induce apoptosis, but also reduce the killing effect on normal cells. In recent years, novel molecular targeted drugs targeting signal transduction, growth factors and their receptors in lung cancer treatment have shown promising efficacy. Wei Min, Department of Respiratory Medicine, Shandong Provincial Chest Hospital
I. Targeted lung cancer therapy with EGFR as the target
Epidermal growth factor receptor (EGFR) is the expression product of the proto-oncogene C-erbB-1 (HER-1). 40%-80% of non-small cell lung cancer (NSCLC) overexpress EGFR. EGFR forms dimer with ligand to activate tyrosine kinase (TK), which causes tumor cells to proliferate and divide and immortalize, therefore, EGFR-targeted therapy is now widely used in lung cancer treatment. Therefore, EGFR-targeted therapy is now widely used in the field of lung cancer treatment.
Gefitinib (gefitinib)
Gefitinib is an orally available small molecule inhibitor of EGFR TK that primarily blocks cancer cells in the G1 phase. Two multicenter double-blind randomized controlled phase II clinical trials, IDEAL 1 and IDEAL 2, were completed in 2003. It was the results of these two Phase II trials that prompted the U.S. Food and Drug Administration (FDA) to quickly approve gefitinib as a third-line treatment for NSCLC before Phase III clinical trials were even completed.
However, two multicenter, randomized, double-blind, controlled phase III trials of gefitinib in combination with standard first-line chemotherapy regimens, INTACT 1 and INTACT 2, yielded disappointing results, both of which showed that gefitinib in combination with chemotherapy was not superior to chemotherapy alone. It has been suggested that this may be due to the fact that the drug acts on cells in the same cycle as the chemotherapeutic drugs and its effects are masked by the chemotherapeutic drugs.
Thatcher et al. published the results of the ISEL study showing that gefitinib failed to prolong survival in chemotherapy-naïve NSCLC patients compared with placebo. Although the study showed an advantage of gefitinib in terms of tumor shrinkage and remission rates, this did not translate into a statistically significant difference in survival prolongation.
The SWOG0023 study of advanced inoperable stage III NSCLC patients treated with cisplatin plus pegylated glycosides (VP16) chemotherapy + chest radiotherapy followed by docetaxel consolidation chemotherapy and then gefitinib maintenance therapy suggested that maintenance gefitinib failed to prolong patient survival.
The study showed that EGFR mutations, an activating mutation that makes TK more sensitive to gefitinib, correlated with the efficacy of TK inhibitors; and the frequency of mutations was consistent with the population that was relatively sensitive to gefitinib treatment: women > men, adenocarcinoma > non-adenocarcinoma, non-smokers > smokers, and Japanese patients > Caucasian patients; mutations were associated with objective remission rather than with stabilization or symptom improvement. This result could help clinicians select those patients suitable for gefitinib treatment and is consistent with the concept of individualized tumor treatment.
Also of interest is the rash. Many clinical studies have found a correlation between the incidence and severity of rash and the remission rate and survival of patients treated with gefitinib. Therefore, the feasibility of using rash as a monitoring prognostic indicator needs to be further investigated.
The most common adverse reactions in gefitinib treatment were seizure-like rash and diarrhea, with a higher incidence of rash and diarrhea in patients of Japanese descent than in non-Asian patients (71%, 59% versus 46%, 39%), but a similar incidence of severe rash and diarrhea (≥3 degrees) (3%, 5% versus 4%, 3%). The most serious of the complications was interstitial lung disease (ILD).
In summary, gefitinib has a rapid onset of action for the treatment of NSCLC (77% of patients with EGFR mutations in a Japanese study had an effect within 1 month) and an objective effect (80% of patients had visible tumor shrinkage). However, clinical studies of gefitinib also bring us many questions: why is it effective and particularly effective in only some patients? Why does the efficacy last only for a short period of time? What patients are suitable for gefitinib? What biological indicators can predict the efficacy and usefulness? It is worthwhile to continue to study this in depth in the future.
Erlotinib (troche, erlotinib)
Erlotinib is an effective, reversible, selective HER1/EGFR TK inhibitor. A large phase III clinical trial (BR.21) showed that patients with advanced NSCLC treated with erlotinib monotherapy had significantly longer median survival, disease-free progression (PFS), and disease remission compared to the placebo group; 1-year survival and remission rates (CR+PR) were significantly higher. This phase III trial brought to light the value of erlotinib as a single oral agent in the treatment of refractory advanced NSCLC.
Is erlotinib combined with chemotherapy for first-line treatment equally effective? Two phase III clinical studies (TALENT and TRIBUTE), the former with carboplatin and paclitaxel and the latter with cisplatin and gemcitabine based in combination with erlotinib compared to the placebo group, suggest that the combination regimen did not show superiority in terms of remission rates and survival. The combination regimen is not currently recommended as first-line therapy.
Perez-Soler et al. suggest that this is similar to gefitinib in that non-smoking, female, adenocarcinoma (especially alveolar cell carcinoma) patients are more sensitive to erlotinib treatment and that the degree of rash appearance after erlotinib treatment is positively correlated with remission rates and survival, which has not been confirmed in the gefitinib study.
The most common adverse reactions after erlotinib treatment are rash (75%), diarrhea (56%), and most severely, life-threatening ILD. If ILD is diagnosed, erlotinib treatment should be interrupted and treated accordingly.
Imatinib (Gleevec, imatinib)
Imatinib is a TKc-kit inhibitor. A recent phase II randomized clinical trial containing 68 patients investigated the role of imatinib in combination with chemotherapy in the first-line treatment of progressive small cell lung cancer. Carboplatin + irinotecan + imatinib was used in the tested patients, resulting in a remission rate of 66%, PFS of 5.7 months, median survival of 6.3 months, and granulocyte deficiency of 10% and 6% in 3rd and 4th degree, respectively, suggesting that imatinib in combination with chemotherapy is safe and effective for extensive-stage small cell lung cancer.
Cetuximab (epirubicin, cetuximab)
Cetuximab is an EGFR monoclonal antibody. In a randomized phase II clinical trial, Rosell et al. divided 62 patients with stage IIIB and IV EGFR+ NSCLC who had not received prior chemotherapy into two groups and gave NP regimen (cisplatin + vincristine) chemotherapy and NP regimen combined with cetuximab, respectively, and the results showed that the efficiency of the chemotherapy and combination groups were 32% and The results showed that the efficiency of chemotherapy and combination groups were 32% and 59%, respectively, and the phase III clinical study is currently underway.
Targeted therapy targeting angiogenesis of lung cancer
Vascular endothelial growth factor (VEGF) plays an important role in the growth of primary tumors, the formation of metastatic tumors and blood vessel growth. In most human tumor tissues (including lung cancer), VEGF expression is substantially higher than in other normal tissues.
Bevacizumab (Avastin, bevacizumab)
In a phase III randomized clinical trial (ECOG-E4599) reported by the American Society of Clinical Oncology (ASCO) in 2005, patients with NSCLC were randomized to receive first-line chemotherapy (carboplatin AUC of 6, paclitaxel 200 mg/m2 every 3 weeks for 6 cycles) in combination with or without bevacizumab (15 mg/kg every 3 weeks for 1 year). The results found that the group receiving bevacizumab had significantly better efficiency (27% vs. 10%), PFS and stability than the control group, with overall survival improving from 10.2 months to 12.5 months. As a result, the US FDA approved a new two-drug regimen of bevacizumab combined with platinum-containing agents as the standard first-line treatment option. The results of this study changed the standard first-line treatment regimen for NSCLC, which is far-reaching and has attracted widespread attention.
In a phase II clinical study of 40 patients with relapsed NSCLC after treatment who received erlotinib 150 mg/d in combination with bevacizumab 15 mg/kg, the results showed that 8 cases (20%) achieved partial remission (PR) and 26 cases (65%) had stable disease (SD), with a median survival of 12.6 months and PFS of 6.2 months. This study suggests that the combination of bevacizumab and erlotinib, two targeted agents with different mechanisms of action, is safe and effective for refractory advanced NSCLC, but further confirmation is needed in clinical studies with larger samples. This study is also the first successful report on the use of targeted drug combinations in lung cancer treatment.
Zactima (ZD6474)
ZD6474 is a synthetic anilinoquinazoline compound with high solubility and bioactive effects that selectively inhibits VEGFR-1, VEGFR-2, VEGFR-3, and to some extent EGFR as well. The recommended oral dose of this drug in clinical phase II trials is 100-300 mg/d.
Natale et al. reported a randomized, double-blind phase II trial in which 168 patients with NSCLC who had failed first-line platinum-containing chemotherapy were divided into two groups: group A received ZD6474 300 mg/d orally or gefitinib 250 mg/d; group B was patients who crossed over to receive ZD6474 300 mg/d or gefitinib 250 mg/d when disease progression occurred in group A cases after a 4-week washout period. The results suggest that although there was no significant difference in overall survival between the two drug treatments, PFS was significantly better in the group taking ZD6474 than in the group taking gefitinib.
Sunitinib (Sunitinib)
Sunitinib is a small molecule TK inhibitor (TKI) that binds to VEGFR tyrosine residues after phosphorylation and inhibits signaling. It is mainly metabolized by the liver and has a long half-life (40 hours), yet has no cumulative effect. Currently, the recommended oral dose in clinical phase II trials is 50 mg/d for 4 weeks with a 2-week off period.
Scoinski et al. reported the results of a phase II clinical trial at the 2006 ASCO Annual Meeting in which 63 NSCLC patients who failed first-line chemotherapy were treated with oral sunitinib 50 mg/d for 4 weeks, resulting in partial remission in 6 cases (9.5%) and stable disease in 12 cases (19%). The most common grade 3 to 4 toxic reaction was malaise (21%).
Sorafenib (doxorubicin, sorafenib)
Sorafenib inhibits both Raf kinase and VEGFRs, including VEGFR-2, VEGFR-3, PDGFR, and c-Kit. At the 2006 ASCO Annual Meeting, Gatzemeier reported the results of a phase II clinical trial in which 52 patients with stage IV NSCLC received sorafenib 400 mg twice daily, resulting in 30 cases (59% The PFS was 11.9 weeks, with 23.7 weeks in patients with stable disease. The most common adverse reactions were diarrhea (40%), skin reactions in the hands and feet (37%) and malaise (27%).
Vascular endothelial inhibitor (Endo, endostatin)
Angiostatin and endostatin are newly discovered potent and specific vasopressor factors. To verify the role of recombinant human vascular endothelial inhibitor in combination with chemotherapy in advanced NSCLC, a randomized, double-blind, placebo-parallel-controlled, multicenter phase III clinical trial was conducted by Sun Yan and other Chinese scholars from April 2003 to June 2004 to evaluate the efficacy and safety of NP regimen combined with vascular endothelial inhibitor versus NP combined with placebo in the treatment of advanced NSCLC. The results suggest that the combination of vascular endothelial inhibitor and NP regimen can improve the response rate and median time to tumor progression in advanced NSCLC with better safety, and has better clinical application prospects.
Currently, most anti-angiogenic therapeutic measures are still in experimental studies or clinical trials, and there are still many problems. For example, after anti-angiogenic treatment, tumor cells can become tolerant, and after stopping the drug, tumor will start to grow again, and the comprehensive evaluation of its efficacy also needs to be confirmed by long-term clinical observation. Although anti-angiogenic therapy is still in the early stage of trial, with the in-depth research on the mechanism of angiogenesis and tumor development, we can optimistically expect that anti-angiogenic therapy will receive more and more attention in the treatment of lung cancer and become one of the important measures in the comprehensive treatment of lung cancer.
III. Summary
Reviewing the progress of targeted therapy for lung cancer, many questions need to be addressed: ①How can targeted therapeutic drugs act only on tumor cell targets, but not on the same targets in normal cells? ②How to understand the effect of “targeted drugs” on lung cancer through some indicators in clinical practice? ③How to select the combination of “targeted drugs” and other therapies to produce additive or synergistic effects? ④How to determine the optimal biological dose of “targeted drugs”?
Due to the slow progress of chemotherapy and radiotherapy for advanced lung cancer, people are paying more and more attention to targeted therapy for lung cancer, which is a new field of lung cancer treatment.