Non-small cell lung cancer is a malignant tumor with a high degree of malignancy, prone to recurrence and metastasis. More than half of the patients are relatively advanced at the time of diagnosis, and treatment must be based on a multidisciplinary approach (including surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy) that targets the whole body as well as the local area. Molecularly targeted tumor therapy refers to treatments that target cellular signaling and other biological pathways involved in the development of tumors. Targeted therapies have played an extremely important role in the treatment of advanced NSCLC, and some of them have entered the norms of standard treatment protocols recognized by the international oncology community according to the principles of evidence-based medicine. More and more research results have reasons to believe that the current drug treatment of advanced NSCLC is transforming from pure cytotoxic drugs to the era of molecular targeted therapy.
Targeted therapy for lung cancer has achieved many landmark achievements after more than a decade of research. For example, in May 2003, the US FDA approved gefitinib (Iressa) for the treatment of advanced NSCLC after paclitaxel/cisplatin therapy; although the FDA modified the indication for gefitinib due to the negative results of ISEL and the 2006 edition of NCCN guidelines withdrew the recommendation for gefitinib, given that gefitinib is still a clinical option in view of the good efficacy shown in Eastern populations; erlotinib (Tarceva) was significantly better than placebo in terms of overall survival in the BR21 study and was approved by the FDA as second- and third-line treatment for advanced NSCLC in November 2004, and the same recommendation was made by the NCCN in 2006; the ECOG4599 study showed for the first time that in The ECOG4599 study showed for the first time that combining bevacizumab (Avastin, bevacizumab) on top of the standard first-line paclitaxel/carboplatin regimen could improve the efficacy, and the NCCN recommended it as the preferred choice for patients who met the indications in 2006; in China, YH-16 (Endostar) combined with vincristine/cisplatin chemotherapy also passed the SDA approval.
I. Overview
(i) Molecular targets.
Molecular targets in lung cancer include any subcellular molecules from DNA to protein/enzyme level involved in the processes of differentiation, cell cycle, apoptosis, migration, infiltration, lymphatic metastasis and systemic metastasis of lung cancer cells. Drugs targeting molecular targets mainly include monoclonal antibodies, small molecule drugs that inhibit enzyme/protein activity, anti-angiogenic drugs, antisense RNAs that inhibit protein translation and drugs with intracellular molecular specificity.
1. Cell signaling targets: cell surface receptors (EerB receptor family, c-kit, insulin-like growth factor receptor, integrins); intracellular factors (BCR-ABL, Ras, Raf, MAP kinase, PI3 kinase, protein kinase C, STAT protein, adhesion proteins, ALK, JNK kinase); nuclear transfer protein factors (hormone-like receptors such as estrogen, Androgen receptor, C/N-myc, NF-kB, Bcl-2, p53, etc.).
2. Cell cycle targets: cell cycle-dependent kinases, cell cycle elements, cell cycle-dependent kinases, etc.
3, Apoptosis targets: Bcl-2, NF-kB, p53, TRAIL, Fas, etc.
4. Induction of differentiation targets: retinoic acid, vitamin D nuclear hormone receptor.
5.Tumor neovascularization targets: VEGFR, matrix metalloproteinase, endothelin integrator aVB3, neovascularization inhibitors (vasopressor, endothelial inhibitor), HIF-1a and HIF-2a.
6, metastatic targets: matrix metalloproteinases, chemokine receptors.
7, cell surface antigen targets: CD20, CDE22, CD33, CD52, CD56, epithelial cell adhesion molecules, C242, PSMA, MUC1, etc.
8, other potentially important targets: farnesylase, protease 20S, telomerase, DNA methylesterase, heat shock protein Hsp-90.
(B) Key pathways of targeted therapy
To date, two key target pathways for lung cancer growth and metastasis have been studied in depth and have entered clinical practice: epidermal growth factor and receptor (EGF/EGFR), and vascular endothelial growth factor and receptor (VEGF/VEGFR).
The main modes of action are also.
1, monoclonal antibodies bind to growth factors or receptors, thus competitively blocking the signaling pathway.
2. Small molecule compounds are used to block the tyrosine kinases of the above two key pathways intracellularly to achieve the purpose of inhibiting and blocking the signaling pathway.
They are small molecule epidermal growth factor receptor tyrosine kinase inhibitors: gefitinib and erlotinib, large molecule VEGF monoclonal antibody: bevacizumab and multi-target drug ZD6474.
II. Targeted therapeutic agents for the epidermal growth factor receptor pathway
(A) Iressa (Gefitinib)
Iressa is an EGFR tyrosine kinase inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-naïve advanced NSCLC, and is the first drug to be used in targeted lung cancer therapy. patients’ quality of life with no serious side effects. Two multicenter randomized phase III clinical trials evaluated the efficacy of Iressa in combination with chemotherapy, enrolling 1098 (INTACT1) and 1037 (INTACT2) cases, respectively, and showed that Iressa in combination with chemotherapy did not significantly improve outcomes or prognosis.
Previous worldwide studies (IDEAL1 and IDEAL2) affirmed the role of Gefitinib in Asian, female, non-smoking, pathologically adenocarcinoma patients, recommending it as second- and third-line treatment. 2 publications from the 2006 American Society of Clinical Oncology (ASCO) on first-line treatment with Gefitinib are of interest, one by Taiwanese investigators reporting 44 cases of first-line The other study, IFCT0401, looked at the efficacy of gefitinib in 85 patients with pneumonic lung cancer, and found that gefitinib was well tolerated as first-line therapy for primary treatment of NSCLC, with an objective efficiency rate of 13% and a disease control rate of 30%. These studies suggest that the screening of the “benefit” population for future targeted therapies is more important than the stage of the tumor and the early or late use (several lines).
(ii) Tarceva (OSI-774, erlotinib)
Tarceva can improve the survival rate of NSCLC patients who have failed first- or second-line chemotherapy, but two phase III clinical trials of Tarceva in combination with chemotherapy for advanced NSCLC have shown that the combination of Tarceva with cisplatin/gemcitabine or Tarceva with carboplatin/paclitaxel has not shown superiority in improving survival and quality of life of patients.
The main side effects of Tarceva are reversible rash and skin redness. Several clinical phase II trials have also demonstrated that Tarceva is highly effective in Asian, female, non-smoking, adenocarcinoma; one study also recruited 121 patients with stage IIIB-IV squamous carcinoma taking Tarceva with an overall effectiveness rate of 7.25% and a disease-free survival of 3.6 months and a median survival of 5.7 months in the analyzed intention-to-treat population, with substratum analysis showing that effectiveness was independent of smoking, and gender. Miller et al. analyzed the TALENT study and found median survival of 23 months and 10 months in nonsmokers treated with combination Tarceva and control chemotherapy groups, respectively (HR = 0.49). A retrospective genetic analysis of 274 patients in the Tarceva group of the TRIBUTE study (a randomized clinical trial of Tarceva in combination with chemotherapy) showed a 13% EGFR mutation rate with better survival than other patients in the TRIBUTE group (P < 0.001), a higher efficiency rate in those with EGFR mutations in the Tarceva combination chemotherapy group (P < 0.05), and the K-ras mutation rate was 21%, and their survival was significantly lower than that of other patients receiving Tarceva combination chemotherapy.
(iii) IMC-C225 (cetuximab, erbitux)
IMC-C225 is an early clinical use of anti-EGFR human/mouse chimeric monoclonal antibody, which was approved by FDA for the treatment of colon cancer in February 2004. Experimental studies found that C-225 alone significantly inhibited the survival of NSCLC cell lines with high EGFR expression, and flow cytometry assays showed that C-225 blocked NSCLC cells in the G0/G1 phase, but was ineffective in NSCLC cell lines with negative EGFR expression. 29 cases were enrolled in the phase I clinic for C-225 treatment of non-small cell lung cancer, including 2 PR cases and 5 stable cases Kim used IMC-C225+docetaxel (Tesotec) to treat 20 chemotherapy-naïve NSCLC with a 20% (4) efficacy rate. 30% (6) of patients had stable disease. DDP+NVB+C225 and NP chemotherapy alone in 43 cases each, RR: C225 group: 31.7%, chemotherapy group 20%, TTP: 4.7 vs 4.2.
In the phase II randomized clinical study (LUCAS study) by Rosell et al. comparing cetuximab combined with NP regimen (vincristine/cisplatin) vs NP regimen alone in patients with EGFR-positive expression progressive NSCLC, 43 cases each in the treatment and control groups at the time of reporting had an efficiency rate of 31.7% and 20%, respectively, with median survival times (MST) of The results suggest that cetuximab in combination with vincristine/cisplatin further improves efficacy and that skin response is predictive of efficacy, and the addition of cetuximab did not significantly increase the typical toxic side effects of NVB/DDP. cetuximab in combination with other chemotherapeutic agents such as cetuximab with docetaxel for NSCLC in the phase II The phase II randomized clinical study (SWOG0342) of cetuximab in combination with other chemotherapeutic agents such as cetuximab and docetaxel for NSCLC and cetuximab in combination with chemotherapy vs. cetuximab sequential therapy after chemotherapy for the first-line treatment of advanced NSCLC also showed efficiency and long-term survival advantages, especially for paclitaxel/carboplatin in combination with cetuximab in combination with chemotherapy up to 10 months MST, which may serve as a standard for similar studies in the future. It can be used as a standard for similar studies in the future.
The key to successful targeted therapy is the selection of specific target population
The methods available for predicting the sensitivity of targeted drugs are: matrix-assisted laser dissociation adsorption time-of-flight mass spectrometry (MALDI-TOF MS), immunohistochemistry (IHC), in situ immunofluorescence (FISH), and high-resolution melting analysis (HRMA), which can be applied to detect mutations in genes.
In 2004, Harvard Medical School found that EGFR mutant cancer cells were less sensitive to cytotoxic chemotherapeutic drugs, but these cells were 100-fold more sensitive to gefitinib than wild-type without the mutation. 2005 study by Lynch and Paez et al. suggested that deletion mutations in EGFR exons 19-21 were associated with the efficacy of Iressa, for example, in Lynch et al. The results showed that 89% (8/9) of NSCLC patients in the Iressa treatment effective group had mutations in the tyrosine structural domain of the EGFR gene, while no patients (0/7) in the treatment ineffective group had mutations (p < 0.001). The same findings were confirmed at ASCO 2006 by Prof. Yilong Wu in a Chinese population: high remission rates and long survival with gefitinib treatment in the presence of EGFR mutations. A Japanese study found that mutations in EGFR were more clinically predictive than gene copy number; further studies revealed that mutations in exon 19 correlated more with efficacy than mutations in exon 21. A Spanish study enrolled 297 stage IIIB and IV patients with tumors obtained by laser microdissection capture technique, and using TaqMan Assay in combination with Genscan, found that 100% of patients with deletion of exon 19 were effective against Tarceva, while 75% of patients with L858R mutation were effective against Tarceva.
In 2005, Dr. William Pao found that an acquired mutation in the EGFR gene resulted in loss of sensitivity to Gefitinib and Tarceva in lung adenocarcinoma, thus suggesting that a second mutation in the EGFR gene was responsible for the loss of sensitivity to these drugs. It appears that the second mutation in the EGFR gene is responsible for the development of acquired resistance to long-term use of these drugs. The second mutation, now thought to be T790M, is located in the kinase region of EGFR and includes a substitution of methionine for threonine. 14 patients were studied by Mitsudomi: those who were sensitive to Gefitinib at the beginning of treatment developed acquired resistance to Gefitinib later. Mutations in EGFR (9 with exon 19 deletions and 5 with mutations in L858) were detected in all 14 patients using a real-time quantitative PCR method combined with fluorescently labeled mutation-specific probes. In addition, 7 of these 14 patients were found to have T790M mutations, which occurred predominantly in non-smoking women. none of the 14 patients had K-ras mutations. As a control, the presence of T790M mutations was not found in specimens not treated with EGFR-TKI. This is a good indication that mutations in EGFR are a pointer to the effectiveness of TK inhibitors and also that mutations in T790 are a second target in patients who are first sensitive and then resistant to such TK inhibitors, and therefore, studying drugs targeting mutations in T790 has the potential to benefit this group of patients again.
IV. Anti-tumor neovascular drugs
Anti-tumor neovascularization drugs mainly use monoclonal antibodies to VEGF or VEGFR or VEGFR tyrosine kinase inhibitors.
(i) Bevacizumab (Avastin, rhuMAb-VEGF)
Bevacizumab, a recombinant human anti-vascular endothelial growth factor monoclonal antibody, binds to VEGFR, blocks cellular signaling in tumor blood vessels, inhibits tumor blood vessel growth, and suppresses tumor cells. combined with Bevacizumab regimen, including 99 patients with NSCLC, were 31.5% and 18.8% effective in the Bevacizumab and control groups, respectively, with median survival times of 17.7 and 14.9 months, suggesting that chemotherapy combined with Bevacizumab was efficacious.
The ECOG-E4599 study, a randomized clinical trial of Avastin in combination with chemotherapy, was initiated in July 2004 and enrolled 878 patients with advanced lung cancer (NSCLC). The study compared the effect of the standard chemotherapy regimen for NSCLC, polytenatase + carboplatin, with or without Bevacizumab on the efficacy of stage IIIB or IV NSCLC. With a median follow-up of 9.4 months, the results showed that the chemotherapy plus Bevacizumab group (434 cases) had a median survival of 12.5 months and 10.2 months, respectively, compared with the standard combination chemotherapy group (444 cases), with clinical remission rates of 27% and 10%, respectively, and tumor progression-free survival of 6.4 months and 4.5 months, respectively, with 1- and 2-year survival rates:51.9% in the bevacizumab group and 22.1 51.9% and 22.1%, compared with 43.7% and 16.9% in the control group. The most common serious adverse effect in the clinical study was pulmonary hemorrhage, with hemoptysis in 6 patients and death in 4. All 6 patients had tumors located next to large blood vessels and 5 had cavity formation or necrosis in the tumor, 4 of which were squamous carcinomas, and overall Bevacizumab increased chemotherapy toxicity.
This study demonstrates for the first time that Bevacizumab in combination with chemotherapy (paclitaxel + carboplatin) can significantly improve time to disease progression (TTP) and prolong survival in NSCLC with recurrent or distant metastases, demonstrating the importance of Bevacizumab in the treatment of lung cancer. This study is also one of the few positive studies of standard chemotherapy (polytocopherol + carboplatin) in combination with targeted agents to improve survival in advanced primary NSCLC in 10 years, and the first study with positive results for monoclonal antibody-targeted agents in combination with chemotherapy in advanced NSCLC, suggesting that the standard of care paradigm has changed for some specific patients. Therefore, the ECOG-E4599 study recommended paclitaxel/carboplatin in combination with bevacizumab as a reference regimen for first-line treatment of advanced non-squamous NSCLC patients without contraindications (history of bleeding, brain metastases), and the US NCCN revised its NSCLC treatment guidelines last year to include bevacizumab in combination with chemotherapy as one of the recommended regimens for first-line treatment of advanced NSCLC.
(II) ZD6474
ZD6474 is a novel oral tyrosine kinase inhibitor that acts on VEGF, EGF and RET receptors. It is also the first dual pathway inhibitor that acts on both VEGFR and EGFR, and is designed to block a key signaling pathway that causes tumor angiogenesis (new blood vessel generation to supply tumor growth with nutrients), which means that the drug can stop both tumor neovascularization and tumor cell expansion. This means that the drug can stop both the growth of new blood vessels and the expansion of tumor cells, and is extremely convenient for oral administration.
According to a phase I clinical study conducted in Japan, ZD6474 (300 mg/d) was well tolerated and had good anti-tumor effects (4 PRs out of 9 NSCLC patients), and the main adverse effects were rash, diarrhea, and prolonged QT interval. According to a phase II clinical study of ZD6474 300 mg/d alone versus gefitinib 250 mg/d alone, ZD6474 had a higher tumor remission rate and longer progression-free survival (PFS), with a more pronounced increase in PFS in patients with poorer prognosis lung cancer. Another phase II clinical trial of ZD6474 combined with doxorubicin in the second line treatment of 127 cases of NSCLC showed that there was a trend of prolonged PFS with doxorubicin combined with ZD6474 compared with doxorubicin alone.
V. Chemotherapy combined with targeted therapy
Does the combination of targeted therapy and conventional chemotherapy have additive or synergistic effects? Attempts have been made to obtain an answer to this question. Although preclinical studies have shown synergistic effects of targeted therapy in combination with chemotherapy, the results of several large-scale clinical studies have shown that small molecules acting intracellularly such as gefitinib, erlotinib, affinitak, lonafarnib, bexarotene, etc. did not increase the efficacy of chemotherapy in combination with chemotherapy and failed to show a benefit in terms of survival, but Some large molecule drugs (monoclonal antibodies) such as cetuximab, bevacizumab, and endostar showed synergy with chemotherapy, from efficacy to survival time, although standard first-line chemotherapy combined with targeted therapy in these positive outcome studies also benefited only some patients.
These findings have prompted clinical scholars to think more rationally about targeted therapies, how to master the appropriate timing and dosing sequence of targeted drugs in combination with chemotherapy? How to make targeted therapies really effective in “targeting” the most likely beneficiaries?
One of the new trends of future research will be the organic combination of chemotherapy and biologic targeted therapy to develop highly effective and low-toxic individualized treatment plans for patients, in this regard, foreign scholars have been a step ahead, which is worthy of our careful study and reference. In the near future, chemotherapy and targeted therapy for advanced NSCLC will achieve a major breakthrough.