I. Individualized treatment with targeted drugs
(I) EGFR-TKI
EGFR gene sensitive mutant lung cancer is the most significant discovery in clinical research of lung cancer in the 21st century. EGFR gene is the most studied, well-documented and well understood molecular target among many driver genes of lung cancer, and EGFR-targeted therapy has been applied to all stages of advanced NSCLC.
1. Second- and third-line therapy: In the original non-selective population, the placebo-controlled ISEL study showed that the overall survival of patients with advanced NSCLC who failed first-line chemotherapy with the EGFR-TKI gefitinib was not better than the placebo group.
A registered clinical study of gefitinib for locally advanced or metastatic NSCLC in China was initiated in 2003 and showed that gefitinib was more effective in Chinese NSCLC patients than in Western populations and was close to that of the Japanese.
Subsequent studies identified EGFR gene exon 19 deletion and L858 mutation in exon 21 as the reason for the effectiveness of gefitinib treatment, thus ushering in the era of targeted therapy for NSCLC guided by EGFR gene sensitive mutations. the results of BR21 and INTEREST further established the status of EGFR-TKI in second and third line treatment for advanced NSCLC.
In 2011, an important development in the treatment of advanced NSCLC was the launch of the new domestic drug Ectinib Hydrochloride (trade name: Kemena) developed by Zhejiang Baida Pharmaceutical Co. This drug is a new class I drug with fully independent intellectual property rights and is the third EGFR-TKI to be marketed worldwide.
The LANCET Oncology (The Lancet Oncology) also published a review of the ICOGEN trial, which is the world’s first head-to-head clinical trial with the classic EGFR-TKI gefitinib, to evaluate the efficacy and safety of ectatinib and gefitinib in advanced NSCLC that has failed first-line chemotherapy.
The results of the ICOGEN trial showed that patients in the erlotinib and gefitinib groups had comparable progression-free survival (PFS) of 4.6 months and 3.4 months, respectively (P=0.130); erlotinib had a better safety profile, with drug-related adverse events of 61% and 70% (P=0.046) and rash of 19% and 28% (P=0.033), respectively, making it more suitable for Chinese patients.
In addition, the investigators also performed EGFR gene mutation testing on tumor tissue specimens obtained from 134 patients enrolled in the study, and the results showed that EGFR gene sensitivity mutations occurred in 68 cases, with a mutation rate of 51% and a median PFS of 6.3 and 2.3 months for EGFR mutant and wild-type patients, respectively, with statistically significant differences (P<0.001). < span="">
In 2013, the TAILOR and DELTA studies showed that docetaxel had a better median PFS than erlotinib in both second- and third-line treatment of EGFR wild-type advanced NSCLC, and the CTONG0806 study confirmed that pemetrexed was more effective than gefitinib in the second-line treatment of advanced NSCLC. These findings suggest that the detection of EGFR gene mutation status is important for guiding the second-line treatment of NSCLC, which is also the future direction of EGFR gene mutation status detection.
2. First-line treatment: Japanese researchers first applied gefitinib in 16 patients with EGFR gene sensitive mutations and achieved an efficiency of 75%, thus opening the era of phase III clinical studies of targeted drug therapy for patients with EGFR gene sensitive mutations.
The results of IPASS, NEJGSG, WJTOG3405, First-SIGNAL, OPTIMAL, EURTAC and LUX-Lung3 all showed that TKI therapy in first-line treatment of patients with EGFR-sensitive mutations was significantly more effective than conventional two-drug platinum-containing chemotherapy.
The significant advantages of EGFR-TKI in terms of PFS, quality of life and tolerability in patients with EGFR-sensitive mutations in NSCLC have established EGFR-TKI as the first-line treatment for patients with advanced NSCLC with EGFR-sensitive mutations.
The ongoing COVINCE trial is a multicenter prospective phase III clinical trial (clinical trial number: NCT01719536) in patients with advanced lung adenocarcinoma with EGFR-sensitive mutations, comparing the efficacy and safety of pemetrexed maintenance therapy after first-line treatment with exatinib and pemetrexed in combination with cisplatin.
This study is the world’s first clinical study of an EGFR-TKI versus the best current chemotherapy regimen for lung adenocarcinoma in terms of efficacy and safety followed by maintenance therapy, to answer the question of whether the efficacy of erlotinib is superior to chemotherapy in the context of maintenance therapy. Patient enrollment in this study is now complete, and we look forward to seeing the results of the study soon.
3. Maintenance therapy: While the place of EGFR-TKI in the second-, third- and first-line treatment of advanced NSCLC has been established, the exploration of maintenance therapy after first-line conventional chemotherapy has also been conducted, and the more representative ones are the EORTC08021, WJTOG0203, SATURN and INFORM trials;
None of these trials selected patients with EGFR mutations as a prerequisite for enrollment, and although retrospective studies of the relationship between EGFR mutation status and clinical outcomes have been conducted, and prolonged PFS after EGFR-TKI maintenance therapy has been demonstrated in patients with EGFR mutations, the number of patients is small. Unfortunately, to date there are no prospective clinical studies on the use of EGFR-TKI for maintenance therapy in patients with EGFR gene sensitive mutations.
4. Adjuvant therapy: Whether EGFR-TKI therapy can extend PFS and overall survival (OS) in advanced EGFR-sensitive mutated lung cancer to improve the cure rate of patients undergoing surgery is a research direction of great interest. The NCIC CTG BR19 study, which began in 2002, showed no significant difference in OS or DFS in the overall population at 2 years of gefitinib adjuvant therapy compared to placebo.
The SELECT study presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting showed that the median DFS rate for 2 years of adjuvant treatment with erlotinib was 89%. In a phase II exploratory study of a small sample of EGFR-sensitive mutated stage IIIa patients with N2 lymph node metastases in China, the PFS difference between the control group was pemetrexed combined with carboplatin adjuvant chemotherapy and the trial group was pemetrexed combined with carboplatin chemotherapy followed by 6 months of oral gefitinib, with a significant difference in PFS between the two groups (39.8 vs. 27.0 months).
A prospective study is being organized at the Cancer Hospital of the Chinese Academy of Medical Sciences to enroll patients with stage II-IIIa surgically resected NSCLC with EGFR-sensitive mutations who receive conventional adjuvant chemotherapy followed by erlotinib or placebo for 2 years to investigate the long-term benefit of such patients (clinical trial number: NCT01405079).
5. Treatment of EGFR-TKI-resistant patients: EGFR-TKI resistance is divided into two conditions: primary resistance, which refers to the absence of clinical benefit after the use of EGFR-TKI; and acquired resistance, which refers to the deterioration of EGFR-TKI after receiving effective EGFR-TKI treatment.
Currently, the mechanisms of acquired resistance to EGFR-TKI include EGFR gene T790M point mutation, MET gene amplification, phosphatidylinositol-3-kinase (PIK3 CA) gene mutation, EGFR gene amplification, and transformation to small cell lung cancer (SCLC), but the mechanisms of resistance in some patients are still unclear.
AZD9291 is a 3rd generation EGFR-TKI developed for T790M, and its preliminary results show that AZD9291 has an objective remission rate (ORR) of 69% in NSCLC patients with acquired resistance after EGFR-TKI treatment, and has shown better efficacy in patients with T790M mutation.
Drugs targeting other resistance mechanisms such as MET amplification (Cabozantinib, LY2875358 and INC280), HER2 amplification (Dacomitinib), PIK3CA mutation (BKM1120) and ERK amplification (Selumetinib) are still in the research stage.
6. Direction of development: For patients with EGFR gene-sensitive mutation-positive advanced lung cancer, whether EGFR-TKI can be combined with chemotherapy, vascular targeting therapy, and immunotherapy to further improve the efficacy also deserves attention.
Preliminary results from NEJ005 / TCOG0902, a phase II randomized study comparing concurrent versus sequential gefitinib and chemotherapy in the first-line treatment of EGFR gene-sensitive mutation NSCLC, suggest that gefitinib alone or gefitinib-based concurrent combination chemotherapy may be a better option than post-chemotherapy gefitinib maintenance or sequential therapy for primary EGFR gene-mutation-positive patients.
Preliminary results from the J025567 study showed that erlotinib in combination with bevacizumab in advanced EGFR gene-sensitive mutation-positive NSCLC had significantly better PFS than the erlotinib monotherapy arm. A study of the safety and remission rates of erlotinib in combination with the programmed death receptor (PD-1) inhibitor Nivolumab in patients with advanced NSCLC with EGFR mutations is ongoing (clinical trial number: NCT01454102).
For patients with positive EGFR gene-sensitive mutations, EGFR-TKI-based combination with chemotherapy or other treatments may be an important research direction to further improve the clinical efficacy of such patients. It is believed that all of the above issues will gradually become clearer with the depth of research.
(II) Echinoderm-like microtubule-associated protein 4- mesenchymal lymphoma kinase (EMLA-ALK) fusion gene inhibitor
Crizotinib is an important milestone in the development of molecularly targeted therapies for NSCLC after EGFR-TKI, and was approved by the U.S. Food and Drug Administration (FDA) and the Chinese State Food and Drug Administration (CFDA) in 2011 and 2013, respectively, for the treatment of patients with locally advanced or metastatic NSCLC with EMLA-ALK expression.
Crizotinib, a potent inhibitor of cMET and ALK synthesized in 2005, was first observed in ALK-positive NSCLC patients in 2008, initiating a series of clinical studies of crizotinib in advanced ALK-positive NSCLC.
Preliminary results from the PROFILE 1014 study showed a significant increase in median PFS in the crizotinib group compared to first-line treatment with platinum-containing chemotherapy (10.9 versus 7.0 months), thus establishing the importance of crizotinib in the treatment of ALK-positive NSCLC.
China participated in the pivotal clinical trials A8081005, A8081007, A8081013 and A8081014 and approved the marketing of crizotinib in China based on the results of the A8081005 clinical study.
In 2012, the National Comprehensive Cancer Network (NCCN) NSCLC clinical guidelines recommended that patients with advanced NSCLC should be tested for EML4-ALK before starting treatment and recommended that positive patients receive crizotinib first. Approximately 40% of ALK-positive NSCLC patients are primary resistant to crizotinib. The complex and diverse mechanisms of resistance have become the biggest obstacle to targeted therapy for ALK-positive NSCLC.
The results of the phase I clinical study of cretinoin, a next-generation ALK inhibitor, have demonstrated its efficacy in patients with crizotinib resistance and central nervous system metastases. Based on these encouraging trial data, in April 2014, the FDA approved ceritinib for the treatment of ALK-positive patients with metastatic NSCLC whose disease has progressed or is intolerant to crizotinib therapy.
Alectinib, a potent selective ALK inhibitor, had an ORR of 93.5% in 46 ALK-positive patients not treated with crizotinib in a phase II clinical study, and Aectinib was approved for use in Japan in July 2014.
A number of other ALK inhibitors are also entering clinical studies, such as AP26113, TSR-011, X-396, ASP3026, CEP-28122 and AZD3463. It is believed that the clinical study data of these drugs will further promote the research process of ALK-targeted therapy.
(III) Other molecular marker-guided targeted drug therapy
In addition to EGFR gene-sensitive mutations and EMIA-ALK fusions, clinical studies of targeted drugs for BRAF mutations (dabrafenib, trametinib), KRAS mutations (semitinib, SEL, AZD6244), PI3 KCA mutations (BKM120, GDC0941) and DDR2 (dasatinib) in NSCLC are underway. It is worth mentioning that crizotinib has significant efficacy in patients with advanced ROS1-positive NSCLC, and the type of ROS1 fusion gene does not affect the efficacy, which brings a new option for such lung cancer patients.
II. Detection methods and quality control of molecular targets
(I) Detection technology
Currently, the main detection techniques for EGFR gene mutations are direct sequencing and amplification mutation suppression system (ARMS), and the common clinical detection methods for ALK are fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR), etc. The FDA approved the FISH method for the diagnosis of EMLA-ALK fusion gene and introduced the concept of concomitant diagnosis when approving the marketing of crizotinib. The concept of concomitant diagnosis was introduced.
On September 12, 2013, the CFDA approved VENTANA ALK IHC for the detection of ALK protein expression to screen lung cancer patients who are suitable for crizotinib.
(II) Quality control of assay samples
In clinical molecular marker assays, patient tumor specimens need to be obtained first, and their quality determines the accuracy of the assay results. Common types of clinical specimens include: surgical resection specimens, biopsy specimens (CT-guided fine needle aspiration, fiberoptic bronchoscopy biopsy), cytology specimens (malignant pleural fluid, pericardial effusion, bronchoscopic brushings), sputum and blood specimens, etc.
Currently, tumor tissues are the most suitable specimens for the detection of molecular targets such as EGFR and ALK. To ensure the accuracy of the test results, traditional histopathology is very important, and fresh and tumor cell-rich specimens should be selected for molecular marker testing as early as possible to effectively ensure the smooth implementation of individualized molecular targeting therapy for tumors. In recent years, significant progress has been made in the detection of EGFR mutations by circulating tumor DNA in blood, which can be used to detect EGFR mutations when tumor tissue samples are not available.
(III) Standardization of the assay
In order to establish a standardized testing process and to have rules to follow, authoritative academic institutions around the world have established testing standards and treatment guidelines. 2014, the College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) jointly released clinical practice guidelines for EGFR and ALK molecular testing in lung cancer patients.
The Chinese Anti-Cancer Association’s Oncology Clinical Chemotherapy Committee and the Chinese Physicians Association’s Oncologist Branch organized Chinese experts to develop the Chinese Guidelines for the Diagnosis and Treatment of Epidermal Growth Factor Receptor Gene Sensitive Mutation and Mesenchymal Lymphoma Kinase Fusion Gene Positive Non-Small Cell Lung Cancer.
The national health industry standard “Diagnosis of non-small cell lung cancer with epidermal growth factor receptor gene mutation and mesenchymal lymphoma kinase fusion gene-positive non-small cell lung cancer” approved by the National Health Industry Standard Committee and organized by the Department of Internal Medicine of Cancer Hospital, Chinese Academy of Medical Sciences and Beijing Key Laboratory of Clinical Research on Anti-tumor Molecular Targeted Drugs has now been officially established.
As the capacity building of laboratories related to molecular target detection and pharmacogenetic clinical studies has been strengthened, some central laboratories for multicenter clinical studies are located in the internal medicine laboratory of the Cancer Hospital of Chinese Academy of Medical Sciences.
III. Clinical molecular epidemiology
Large sample, multicenter and prospective clinical molecular epidemiology studies are very important to comprehensively understand and accurately grasp the genetic differences between NSCLC patients in China and those in western countries, and to develop a diagnosis and treatment strategy that meets the clinical characteristics of patients in China.
(I) EGFR
A molecular epidemiology study of EGFR mutations in Asian patients with advanced lung adenocarcinoma (PIONEER) was initiated in July 2010 to understand the mutations in EGFR genes in Asian patients with advanced lung adenocarcinoma. Seven countries and regions in Asia participated in this study. Seventeen hospitals in mainland China participated. Of the total detectable sample of 1482 patients, 747 patients (50.4%) were from mainland China.
The EGFR-sensitive mutation rates were 51.4% and 50.2% for the full cohort and the mainland Chinese subgroup, respectively, indicating that the EGFR-sensitive mutation rates in Asian patients were significantly higher than those reported in the literature for Caucasians, implying that 50% of Asian patients with advanced lung adenocarcinoma were able to receive EGFR-TKI therapy.
The IGNITE study, initiated in 2013, is a large international multicenter, non-invasive study comparing EGFR mutational status in locally advanced/metastatic NSCLC, adenocarcinoma and non-adenocarcinoma histology in a molecular epidemiology study (clinical trial number: NCT01788163). We are a major participant in this study in the Asia-Pacific region. The study is currently in enrollment and the results are expected.
(II) EMLA-ALK
The rate of ALK fusion gene in non-selective NSCLC patients is low, about 3-5%, but the detection rate can be increased to 30%-40% after the selection of clinicopathological characteristics such as young, non-smoker or small smoker, EGFR and KRAS gene mutation negative, and adenocarcinoma. The Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, analyzed the pathological characteristics of ALK in Chinese NSCLC patients and found that ALK fusion genes occurred mostly in dominant populations such as young, non-smoker or small smoker, adenocarcinoma, and hypofractionation.
(III) Other driver genes
In 2011, a study that examined 10 driver genes in 830 lung adenocarcinoma specimens showed that 60% of patients had driver gene mutations and about 36.4% of lung adenocarcinoma patients had unknown driver genes.
In 2012, the Cancer Genome Atlas Group (TCGA) analyzed the genetic profile of 178 patients with squamous lung cancer using second-generation sequencing and identified 11 genes with high mutation frequency and 17 genes with altered copy number.
In the same year, Paik et al. used multiplex PCR and Massarray techniques to detect known driver mutations in lung squamous carcinoma, including PI3 KCA mutation, PTEN mutation, FGFR1 amplification and DDR2 mutation, and their mutation frequencies were similar to the mutation profile reported by TCGA. A study on the gene mutation profile of lung squamous carcinoma based on Chinese population is underway.
IV. Development of molecular diagnostic reagents
The development of molecular diagnostic reagents is an important link in the healthy development of molecular targeted tumor therapy. The development of domestic standard test kits can not only save limited medical resources, but also promote the development of related industries in China.
Ltd. is a famous enterprise that develops tumor molecular target detection kits in China. Its 6 kits for EGFR, KRAS, BRAF, PIK3 CA, EMLA-ALK and ALK/ROS1 gene fusion combined detection have been awarded the CFDA Medical Device Registration Certificate and EU CE certification.
The Cancer Hospital of Chinese Academy of Medical Sciences organized 73 hospitals nationwide to conduct a multi-center clinical study on the Her-2 FISH test kit produced by Beijing Jinbojia Medical Technology Co. (HSP90α) quantitative assay kit developed by Beijing Progressive Biotechnology Development Co., Ltd. was validated, and the HSP90α quantitative assay kit was approved to enter the Chinese and EU markets, so that HSP90α can be used as a serum marker for adjuvant diagnosis of lung cancer patients and prediction of chemotherapy efficacy.
V. Summary and outlook
Over the past decade, China has become an important part of the global research on molecularly targeted therapies for NSCLC, and Chinese research has been integrated into the world and the results have been shared worldwide. Due to the difference in genetic background between East and West, the number of NSCLC patients with EGFR gene sensitive mutations in China is significantly higher than that in Western countries, so the participation of Chinese patients has positively contributed to the progress of global research on targeted NSCLC therapies.
Currently, China is developing rapidly in the development of targeted drugs for NSCLC, clinical research and application, detection methods and quality control of molecular targets, clinical molecular epidemiological studies, and development of molecular diagnostic reagents, and Chinese treatment norms are increasingly based on the findings of Chinese patients as evidence-based medicine, and the National Health and Family Planning Commission’s “Treatment Norms for Primary Lung Cancer (2015 Edition) has been promulgated. It is believed that with the joint efforts of our colleagues, lung cancer research in China will achieve greater success for the benefit of more patients.