Among the various molecular markers, only EGFR mutation status was predictive of efficacy for erlotinib maintenance therapy, while KRAS mutation and EGFR amplification largely did not affect the efficacy of erlotinib maintenance therapy, with a trend toward greater benefit in nonsmokers and those who developed skin rash. Erlotinib maintenance therapy can securely prolong the survival of EGFR wild-type patients while enabling very excellent remission and survival in patients with EGFR mutations, providing an important new option for the optimization of the therapeutic framework in advanced NSCLC.
I. The place of EGFR-TKI in the treatment of advanced non-small cell lung cancer
Lung cancer is one of the most common cancers worldwide, with 1.2 million new cases each year, of which non-small cell lung cancer (NSCLC) accounts for about 80%. Lung cancer is the most prevalent cancer in China, with an annual incidence rate of 35/100,000 (i.e., 35 per 100,000 people). from 2000 to 2005, the number of lung cancer cases in China increased by 30.5%. Epidemiological review studies have shown that lung cancer has become the number one lethal cancer in China, with 600,000 patients dying of cancer each year.
For the treatment of advanced non-small cell carcinoma, a shift from the absolute dominance of traditional chemotherapeutic drugs to the current new phase of combining traditional chemotherapy with novel targeted drugs has begun. Erlotinib inhibits the growth and proliferation of tumor cells by inhibiting the epidermal and long factor receptor tyrosine kinase (EGFR-TK), thereby stopping the growth of tumor cells. Compared to conventional chemotherapy, erlotinib avoids the strong side effects of conventional chemotherapy, such as white blood cell decline, nausea and vomiting, and only requires once daily oral dosing, significantly improving patients’ quality of life. A large randomized controlled phase III trial (BR21 trial) compared erlotinib with placebo in patients with NSCLC who had failed prior first- or second-line therapy. 731 patients were assigned in a 2:1 ratio to the erlotinib treatment group and the placebo group. The results showed increased efficiency in the erlotinib treatment group compared to the placebo group (8.9% vs <1%, P < 0.001), prolonged progression-free survival (2.2 months vs 1.8 months, P < 0.001) and prolonged median survival (6.7 vs 4.7 months, HR=0.70,P < 0.001). Patients had a 27% lower risk of death.
As the only targeted anti-cancer drug in the world that has been shown to significantly extend the survival of patients with advanced NSCLC, erlotinib has been marketed in more than 80 countries, and more than 200,000 patients worldwide have been treated with erlotinib, with sufficient safety data confirming that it is a lung cancer treatment with low toxicity and good tolerability, with clear efficacy in advanced NSCLC, and is a good choice for second- and third-line use. In 2005, the Chinese version of the NCNN guidelines for non-small cell lung cancer was published in China, the content of which was aligned with international standards and combined with empirical evidence of Chinese characteristics to include the targeted drug surface growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in the guidelines for non-small cell lung cancer treatment for the first time.
In 2004, to further understand the clinical use experience of erlotinib in treating more patients, a large phase IV open clinical study (Trarceva Lung Cancer Suivival Treatment, TRUST study) was conducted worldwide, enrolling 11,500 patients in 57 countries. Survival in the Chinese subgroup of TRUST patients was also reported at this Congress, with results showing higher disease control rates (68% vs. 44%) and longer progression-free survival (13 weeks vs. 9.7 weeks) compared to the BR21 study treatment arm, with global data on median survival not yet available. Erlotinib has benefited more than 6,000 Chinese lung cancer patients since its one-year launch in China in March 2007.
II. EGFR-TKI in locally advanced and metastatic non-small cell lung cancer second/third line treatment benefit population
Scholars from Canada and Hong Kong presented at the meeting relevant studies by foreign scholars in recent years exploring the predictors of EGFR-TKI treatment and selecting the most beneficiary population into. In terms of clinical characteristics, the BR21 study found that all subgroups, including those of different genders, histological types, and smoking status, gained survival benefit from erlotinib second/third-line treatment compared to placebo. In addition, the BR21 study found that patients with varying degrees of rash after erlotinib treatment had longer survival than those without rash, with a median survival time of 11.1 months for those with 2nd degree or greater rash, 7.1 months for those with 1st degree rash, and 3.3 months for those without rash, with a statistically significant difference between the three groups in a two-way comparison. data from the TRUST study in China showed that Erlotinib prolonged the median tumor progression-free survival of Chinese patients by an average of 5.65 months, with an even better disease control rate of 79%, a result far better than the global results. These results suggest that Asian patients benefit more from EGFR-TKI therapy.
In terms of molecular biological markers, many retrospective studies have confirmed that EGFR exon 19 and 20 mutations are important predictors of EGFR-TKI efficacy. Further studies have found that EGFR mutations are mostly seen in non-smoking, female, Asian and adenocarcinoma patients, and that remission rates are higher in these patients given EGFR-TKI therapy in clinical practice. It was also found that there are ethnic differences in mutations in this gene, with the incidence of mutations in Asian patients being 25% 50%, significantly higher than in North American and Western European countries (10%), which may be related to the different genetic backgrounds of different populations. In addition, current research evidence shows that tumor cells with K-rax mutations, ERBB2 mutations, EGFR exon 20 mutations and C-met overexpression (de novo or acquired) also do not benefit from EGFR-TKI therapy. However, there is insufficient evidence from evidence-based medicine to recommend the application of biological markers to decide whether to apply EGFR-TKI.
III. Attempts of EGFR-TKI alone or in combination with chemotherapy as first-line treatment
The conference also invited clinical experts engaged in lung cancer research in China, Professor Tension from the Cancer Hospital of Sun Yat-sen University and Professor Cai-Cun Zhou from Shanghai Pulmonary Hospital, to give a presentation on whether targeted therapy can be used for first-line treatment. At this stage, the indications for EGFR-TKI targeted therapy approved in several countries can only be used for patients with intermediate or advanced non-small cell lung cancer who have failed first-line chemotherapy, and in fact, patients with intermediate or advanced non-small cell lung cancer may not be able to tolerate conventional first-line chemotherapy with platinum-containing regimens due to various reasons such as physical condition and age after diagnosis, and in recent years, EGFR-TKI alone or in combination with chemotherapy has been treatment has been attempted in recent years.
How to explain the effectiveness of the two-sided triple-blade species alone but not synergistically when combined is a hot topic of research in recent years. Among the possible reasons are the following.
1, whether the chemotherapeutic drugs interfere with the pharmacokinetics of EGRF-TKI?
2. Is there a certain population of benefit from the combination of EGFR-TKI and chemotherapeutic drugs?
3, Is there an antagonistic effect of EGRF-TKI and chemotherapeutic drugs?
Firstly, the TALENT study showed that chemotherapeutic drugs did not interfere with the pharmacokinetics of EGRF-TKI. Therefore, there is insufficient evidence that chemotherapeutic drugs interfere with the pharmacokinetics of EGRF-TKI. Secondly, EGFR mutation status was associated with efficacy in the TRIBUTE study, with overall efficacy of erlotinib in combination with chemotherapy at 53%, disease stabilization at 33%, and disease progression at 13% in the EGFR mutated population, and overall efficacy at 18%, disease stabilization at 30%, and disease progression at 52% in the unmutated population. It appears that the mutated population benefited more from the combination therapy, but this objective efficiency advantage in the mutated population did not translate into a survival advantage when looking at the survival time of patients in both groups. There was no difference in survival between the combination group and the chemotherapy-only group in the mutant population. Therefore, EGFR mutations may be only a prognostic indicator rather than a predictor.
In addition, the subgroup analyses shown in these two studies indicate that nonsmokers benefit from EGFR-TKI combination chemotherapy, and whether nonsmoking can be used as a clinical indicator to screen for benefit is to be confirmed from time to time in further clinical studies. Based on the evidence from current clinical studies, the question of whether there is a population with some benefit from the combination of EGFR-TKI and chemotherapeutic agents is unanswered.
Finally, the question of whether there is an antagonistic effect of EGFR-TKI and chemotherapeutic agents is one of the more recently studied questions. It is well known that EGFR signaling increases cell cycle protein D intercalation, which is a key test point protein in the G1 phase. Erlotinib induces cell arrest in G1 phase, while many chemotherapeutic drugs act in other cell cycles e.g. docetaxel induces cell arrest in M phase and apoptosis, so there may be antagonistic effects when these two classes of drugs are combined (e.g. erlotinib-induced G1 phase arrest allows fewer cells to enter other cell cycle phases, thus blocking the activity of docetaxel on M phase cells), a result that could explain the lack of synergy when these two classes of drugs are combined. The next step in clinical research is to move towards the sequential application of chemotherapy and EGFR-TKI (SARTUN study) or the sequential application of chemotherapy in combination with EGFR-TKI (e.g. FASTACT study)
The most common toxic reaction of EGFR-TKI: rash and its management
About 75% of patients taking erlotinib can develop rash, and the incidence of rash in Chinese patients in the TRUSR study can reach 87%, but clinically most patients have mild to moderate rash, which is fully tolerated, and fewer patients have reduced their dose due to severe rash. In order to improve patient compliance and reduce the discomfort caused by rash, Chinese experts in the lung cancer research community jointly developed the Chinese Clinical Guidelines for the Treatment of Cutaneous Adverse Reactions Caused by Epidermal Growth Factor Receptor Inhibitors in 2008. In this conference, Professor Wang Jie from Peking University Cancer Hospital reported this consensus with Chinese characteristics on behalf of the expert group. It is believed that the promotion of this consensus provides a better supporting role for the future application of EGFR-TKI in Chinese NSCLC patients.
V. Outlook of EGFR-TKI therapy
At present, there has been great progress in the study of EGFR biological markers, including EGFR expression, EGFR gene copy number and EGFR mutation, but it is not yet clear whether these biological markers can be the molecular indicators to predict the clinical benefit (prolongation of survival) of EGFR-TKI therapy. Initial results have been obtained with first-line therapy and in combination with chemotherapy, and studies with other targeted therapies (e.g., bevacizumab) depending on the mechanism of action are currently underway. This research will help to understand the role of EGFR-TKI in the different phases of NSCLC treatment and in different treatment strategies. It has also been suggested that after fully understanding the status of EGFR-TKI in combination therapy, it may be possible to reduce the proportion of chemotherapy in NSCLC treatment in the future to achieve greater clinical benefit with reduced toxicity. EGFR-TKI is a novel targeted therapy drug for the effective treatment of advanced lung cancer, and erlotinib has already accumulated experience with thousands of patients in China in the first year of marketing. Overall, erlotinib has better efficacy in Asians than in Westerners (disease control rate of 77% in the TRUST study), and this class of drugs is well tolerated, providing a new option for lung cancer treatment.
VI. Bevacizumab combined with chemotherapy in first-line treatment of patients with non-squamous non-small cell carcinoma has achieved a breakthrough in efficacy
Two phase III clinical studies evaluated the efficacy of bevacizumab in combination with standard first-line chemotherapy regimens for the treatment of non-squamous non-small cell lung cancer, and both achieved significant improvements in objective remission rates and PFS, with survival breaking the bottleneck of standard first-line chemotherapy regimens and overall survival exceeding one year. The bottom dose of bevacizumab was found to have similar efficacy and better safety than the high dose of bevacizumab. The efficacy of bevacizumab was further confirmed by the results of two large phase IV clinical studies, each with a caseload of 2000 patients. Overall survival in the SAIL study was 15.3 months, and the efficacy of cisplatin in combination with carboplatin was similar to that of carboplatin. A large body of data suggests that bevacizumab in combination with chemotherapy is safe, tolerable, and has a low incidence of adverse events, and can be safely used in the treatment of patients with brain metastases and advanced non-small cell carcinoma treated with coagulation.
Maintenance treatment with erteolonib brings extensive and significant benefits
Maintenance therapy refers to the mode of continuous treatment with effective drugs after the end of first-line therapy and before disease progression. As the efficacy of first-line chemotherapy no longer improves beyond 4-6 cycles, highly effective drugs without cumulative toxicity are needed for single-agent maintenance, and erlotinib presents a new opportunity for this model.
The first prospective randomized controlled phase III study in the SATURN Study Unit to explore the correlation between multiple biomarker status and the efficacy of EGFR-TK maintenance therapy, nearly 900 patients with advanced NSCLC whose disease had not progressed after 4 cycles of first-line chemotherapy were randomized to erlotinib maintenance therapy or placebo until disease progression. Patients were predominantly Caucasian, male, and smokers, and were not part of the superior population for targeted agents. Erlotinib maintenance therapy reduced the risk of disease progression by 29% in whole-tissue patients and 31% in EGFR IHC-positive patients; overall survival was significantly improved, with a 19% reduction in the risk of death. In addition, erlotinib maintenance therapy also significantly improved disease control rates (60.6% vs. 50.8%). Subgroup analysis showed that erlotinib maintenance therapy provided benefit regardless of gender, race, pathology type, and smoking history, with greater benefit in women, Asian, adenocarcinoma, and nonsmoking patients.
Biomarker stratification analysis showed that patients with different EGFR IHC/FISH and KRAS status benefited from erlotinib maintenance therapy, with significant PFS benefit in EGFR IHC-positive, EGFR FISH-positive, and KRAS wild-type. EGFR FISH-positive, KRAS wild-type had significant PFS benefit. EGFR PFS was also significantly prolonged after maintenance treatment with erlotinib in wild-type patients compared with the placebo group, with a significant 22% reduction in the risk of disease progression. In patients with EGFR mutations, the PFS in the placebo group was prolonged by nearly 2-fold in the erlotinib maintenance group, with a significant 90% risk of disease progression, a very rare magnitude of benefit, so patients with EGFR mutations who have received chemotherapy should not forego the opportunity of erlotinib maintenance therapy.
The efficacy of first-line treatment with erlotinib in patients with EGFR mutations is encouraging.
The Spanish SLCG Collaborative Group study, which was updated this year, showed that erlotinib achieved an excellent outcome of 89.8% DCR, 64% ORR, and 13.3 months TTP in 217 patients with EGFR mutations treated in first or second line, with a three-year survival rate of 58.7% and 38.5% for those with CR and PR, respectively. This means that for patients with EGFR mutations, erlotinib treatment has the potential to turn advanced NSCLC into a long-term manageable chronic disease. Drug options for first-line therapy. In a recent pooled analysis presented at the World Conference on Lung Cancer (WCLC), first- or second-line erlotinib in patients with EGFR mutations had a PFS of up to 13.8 months, significantly better than other EGFR-RKI and chemotherapy. Therefore, erlotinib is a superior efficacy option when choosing first-line targeted therapy for patients with EGFR mutations, which may be related to the higher blood concentration and adequate inhibition of wild-type EGFR when erlotinib is administered at standard doses.
IX. Efficacy predictors of erlotinib maintenance therapy
SATURN data on molecular marker analysis were also discussed at this meeting. Brugger et al. published an analysis of the risk ratio (HR) for disease progression in patients receiving maintenance treatment with erlotinib in the DATURN study with different molecular marker status, showing that IHC, FISH and CA repeat sequence length of EGFR, and KRAS mutation status had no clear predictive value for the benefit of receiving maintenance treatment with erlotinib, and only EGFR mutation status had a predictive effect. It should be noted that EGFR mutation and wild-type patients had a 90% and 22% reduction in the risk of disease progression with erlotinib maintenance therapy, respectively, with significant differences in the rate of reduction, but both had a significant benefit over the placebo group; the HR for PFS was less than 1 for patients with all other molecular marker statuses, suggesting that erlotinib maintenance therapy may benefit a broadly characterized patient population.
Spanish scholars presented a phase I study at this year’s ESMO annual meeting that applied erlotinib to 47 patients whose disease had not progressed after first-line chemotherapy and who had a time to disease progression (TTP) of 9.4 months and 19.2 months, respectively. The investigators found that age, gender, PS score, pathology type and remission status during the first-line treatment phase had an impact on the efficacy of erlotinib maintenance therapy, but patients who achieved sub-remission and non-smokers during the maintenance phase had a TTP of 31.5 months and 21.67 months, respectively, and those who developed a grade 2 or higher rash after receiving erlotinib had a significantly better TTP and OS than those without a rash. This study confirms the findings of the SATURN study that erlotinib maintenance therapy resulted in excellent remission and survival in patients with advanced NSCLC, with a greater tendency for nonsmokers, those in further remission or those with rash during maintenance therapy to benefit.
X. Erlotinib maintenance therapy optimizes the treatment framework for advanced NSCLC
Following the breakthrough of erlotinib in first- and second-line treatment, respectively, the SATURN study bridges the gap between first- and second-line treatment, which also raises new questions: at which stage is it reasonable to apply erlotinib for patients with different characteristics? The Spanish SLCG study confirmed that first-line treatment with erlotinib in patients with EGFR mutations resulted in PFS and OS of up to 14 months and 27 months, respectively, far exceeding the levels of previous studies of chemotherapy in advanced NSCLC. However, the IPASS study suggests that EGFR mutation status has a significant impact on first-line treatment with gefitinib, and that wild-type patients have a significantly increased risk of disease progression with first-line gefitinib compared to chemotherapy, making the decision to use RGFR-TKI megasurge in patients treated with chemotherapy based on clinical characteristics alone difficult until the EGFR mutation status of the patient is determined.
In the SATURN study, despite the fact that patients with EGFR wild type accounted for 89% of the total sample, maintenance treatment with erlotinib achieved a disease control rate of more than 60% and significantly reduced the risk of disease progression and death by 21% and 19%, respectively, and molecular marker analysis confirmed that patients with EGFR wild type also benefited significantly from erlotinib maintenance treatment. On the other hand, EGFR mutant patients treated with maintenance erlotinib had a 90% reduction in the risk of disease progression and a PFS of more than 40 weeks.
Thus, erlotinib maintenance therapy offers a robust option for patients with advanced NSCLC that can significantly benefit both EGFR wild-type patients and EGFR mutation-painted patients to a similar extent as erlotinib first-line therapy, which is important for a wide range of patients with unknown clinical EGFR mutation status. In addition, up to 71% of patients in the SATURN study received follow-up therapy, in contrast to previous studies in which approximately 50% of patients were lost to follow-up due to rapid deterioration in physical status after disease progression. In addition, maintenance therapy with erlotinib had no negative impact on patients’ quality of life and improved pain management indicators, allowing patients to stay in a better quality of life and physical status before disease progression for as long as possible compared to second-line therapy after disease progression, achieving the goal of “living longer and better”. The goal of keeping patients “alive and well” has been achieved.
In conclusion, after HorizonIV 2009, the characteristics of erlotinib maintenance therapy became clearer to us.