EML4-ALK fusion gene: a new favorite for targeted lung cancer therapy!!!
2011-08-02 09:11 Source: Deng Hong, Department of Oncology, Guangdong Province Hospital of Traditional Chinese Medicine, Physician’s Daily
Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, Hu Qiong, Zhou Cai Cun
Lung cancer is the most common cause of tumor-related death, and 85% of these patients have non-small cell lung cancer (NSCLC), and most of them are in the progressive stage when diagnosed, which is incurable with available treatments. For those patients with advanced NSCLC, chemotherapy is the primary treatment with an average survival of 8 to 10 months. In recent years, the continuous advancement of molecular biology research has opened up avenues for targeted therapy for lung cancer treatment. Dissecting the EML4-ALK fusion gene The EML4-ALK fusion gene is seen in a variety of tumors, such as mesenchymal large cell lymphoma, inflammatory myofibroblastoma, neuroblastoma and NSCLC, and it is caused by insertion of the short arm of chromosome 2. There are at least 10 EML4-ALK fusion genes depending on the EML4 gene breakpoints.EML4-ALK fusion genes form an intricate signaling network that affects cell proliferation, differentiation and apoptosis through the activation and delivery of downstream substrate molecules and the mutual crossover and overlap of each transduction pathway.EML4-ALK fusion genes affect cell proliferation, differentiation and apoptosis through the extracellular helix of fusion partners structural domain, the kinase regions of the two EML4-ALK molecules bind to each other to form a stable dimer that activates the downstream MAPK, PI3K/AKT, and JAK/STAT3 pathways through auto-phosphorylation, thereby causing cellular transformation to malignancy.
Phase I clinical study of EML4-ALK inhibitor ALK inhibitor PF-02341066 (Crizotinib), a dual target small molecule inhibitor of ALK/C-met, was reported in a phase I clinical study at the 2010 ASCO Annual Meeting by Bang, Seoul National University School of Medicine, Korea. The study enrolled 82 patients with EML4-ALK-positive NSCLC and showed that more than 90% of patients treated with Crizotinib experienced tumor shrinkage and 57% achieved objective remission, the results of which further validated the report by Kwak et al. At this year’s ASCO annual meeting, Professor Shaw updated the clinical data from the trial: 82 patients receiving Crizotinib had a 1-year survival rate of 77% and a 2-year survival rate of 64%; median OS was not available at this time. Patient survival was not significantly correlated with their gender, ethnicity, smoking history or age. In this phase I clinical trial, 37 ALK-positive patients were not treated with Crizotinib, and this group had 1- and 2-year survival rates of 73% and 33%, respectively, with a median OS of 20 months. The investigators then performed a subgroup analysis comparing data from 24 ALK-positive patients not treated with Crizotinib with 32 patients treated with ALK inhibitors, showing that among ALK-positive patients, 1-year survival was significantly higher in those treated with Crizotinib than in those not treated with Crizotinib, and 2-year Survival rates were also significantly different (Table 1). Patients receiving ALK inhibitors in second line had 1-year and 2-year survival rates of 49% and 33%, respectively, with a median OS of 11 months. From this, the investigators concluded that treatment with Crizotinib resulted in a significant survival benefit for patients in the ALK-positive group.
EML4-ALK inhibitor phase II clinical studies Based on the above findings, the US FDA has approved Crizotinib to enter phase II/III clinical studies, with the PROFILE1005 study and PROFILE1007 study currently underway. At this year’s ASCO Annual Meeting, Kim et al. reported on the results of the ongoing Phase II single-arm clinical trial of the ALK inhibitor PROFILE1005. The study enrolled ALK-positive advanced/relapsed NSCLC patients who had failed first-line chemotherapy from 57 centers in 12 countries. 136 patients have been enrolled, and 93% have received at least 2 or more chemotherapy regimens. All patients were given Crizotinib 250 mg bid in a 21-day cycle, administered orally. Patients were evaluated for disease every 2 cycles according to RECIST 1.1 criteria. The existing enrolled patients had received an average of 3 cycles of treatment, 88% of them were still on treatment, 63 patients had shrunken lesions, 41 of them had >30% tumor shrinkage, and only 7 patients had disease progression. The overall effective rate (RR) was up to 51%, with a disease control rate (DCR) of 85% at 6 weeks and 74% at 12 weeks. Common adverse reactions included grade 1/2 nausea, visual abnormalities, vomiting and diarrhea. Treatment-related grade 3/4 toxicities accounted for approximately 15% of the cases, mainly elevated ALT, dyspnea and neutropenia. There were only 2 treatment-related deaths. Clinical symptoms such as pain, cough, dyspnea and malaise were significantly improved in most patients. The overall quality of life of the patients also improved. However, patients’ constipation may have worsened during the course of treatment. From this, the investigators concluded that Crizotinib is safe and effective and well tolerated in patients with ALK-positive NSCLC who have failed first-line therapy, and that their clinical symptoms can be significantly improved. Another study, 1007, enrolled ALK-positive NSCLC patients who had previously received a platinum-containing regimen with Crizotinib and pemetrexed or docetaxel, respectively, for which no data have been published.
EML4-ALK positives do not benefit from EGFR-TKI-targeted therapy Shaw et al. concluded that EML4-ALK represents a molecular subtype of NSCLC with unique clinical features in this group of patients, but it is noteworthy that although some features of EML4-ALK positives are similar to those of EGFR mutants, the former do not benefit from EGFR-TKI-targeted therapy The first of these is the EML4-ALK-positive group. The results of a retrospective study reported by Kim et al. from Korea at this year’s ASCO Annual Meeting validate Shaw’s view. The study analyzed the clinical data of 1,100 patients with non-squamous stage IIIB to IV NSCLC treated at the investigators’ hospital between 2003 and 2009, 257 of whom were EGFR wild-type or had previously received EGFR-TKI therapy without benefit. The investigators divided the patients into three groups: ALK-positive, EGFR mutant, and both ALK and EGFR wild type. The results showed a significant difference in median OS of 10.4 months and 28 months in the ALK-positive and EGFR-mutant groups, respectively (P = 0.012). There was no difference in PFS among the three groups of patients receiving first-line chemotherapy with platinum-containing regimens, but the PFS rate was lower in ALK-positive patients treated with EGFR-TKI than in the EGFR mutation group (P < 0.001) and the ALK/EGFR wild-type group (P = 0.048). It is suggested that wild-type patients treated with EGFR-TKI may be more prone to develop drug resistance compared with ALK-positive patients in the latter group.
Conclusion The discovery of EML4-ALK has led to a step toward “individualization” of lung cancer treatment. It has been suggested that stepwise detection of genetic variants such as KRAS, EGFR, and EML4-ALK in NSCLC patients could be performed to fine-tune the differentiation of patient groups and maximize the benefits for different subgroups of patients. However, most of the current studies are small sample studies, and EML4-ALK faces the same dilemma as previous EGFR mutations, which urgently needs to be validated in large sample prospective studies, and in addition, it must be clarified which detection method is more accurate, such as immunohistochemistry, FISH, and RT-PCR, and then the detection method should be standardized. The EML4-ALK gene is undergoing a similar research journey as the EGFR gene, but there is no doubt that the EML4-ALK fusion gene will become a new favorite for targeted therapy in the future.
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