Evolving Management with Molecular-Targeted and Bone-Targeted Medicine in Patients with Advanced Non–Small Cell Lung Cancer

In the field of advanced non-small cell lung cancer (NSCLC), the driver mutations such as epidermal growth factor receptor (EGFR) mutation andanaplastic lymphoma kinase (ALK) fusion gene havebeen discovered in recent years. Of the mutated genes in cancer, driver gene with oncogene addiction is strongly involved in the development and progression of cancer and dependent on tumor survival. Crizotinib which is ALK tyrosine kinase inhibitors (TKI)is recommended for the patients with previously treated advanced NSCLC with ALKrearrangement [1] and erlotinib is recommended for the patients with EGFR mutated advanced NSCLC [2,3] in National Comprehensive Cancer Network (NCCN) guidelines 2013. Gefitinib is also used for the patients with EGFR mutated NSCLC in Japanand several countries on the basis of large scale phase III trials [4-6]. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to benefit patients with untreated NSCLC in addition to carboplatin and paclitaxel [7]. More recently, new driver genes such as RET fusion [8], ROS1 rearrangement [9], BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, and DDR2 mutations were also identifiedand these driver mutations are expected as a target for new therapeutic medicines. Novel molecular targeted medicines such as afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases [10], and CH5424802, selective ALK inhibitor [11], are studied in clinical trials. “Next Generation DNA Sequencer” has been developed and Analyzing nucleotide sequence of the gene is faster than before and rapid identification of key drivermutations in advanced NSCLC is becomingmore and more important.


Introduction Molecular targeted medicine
In the field of advanced non-small cell lung cancer (NSCLC), the driver mutations such as epidermal growth factor receptor (EGFR) mutation andanaplastic lymphoma kinase (ALK) fusion gene havebeen discovered in recent years. Of the mutated genes in cancer, driver gene with oncogene addiction is strongly involved in the development and progression of cancer and dependent on tumor survival. Crizotinib which is ALK tyrosine kinase inhibitors (TKI)is recommended for the patients with previously treated advanced NSCLC with ALKrearrangement [1] and erlotinib is recommended for the patients with EGFR mutated advanced NSCLC [2,3] in National Comprehensive Cancer Network (NCCN) guidelines 2013. Gefitinib is also used for the patients with EGFR mutated NSCLC in Japanand several countries on the basis of large scale phase III trials [4][5][6]. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to benefit patients with untreated NSCLC in addition to carboplatin and paclitaxel [7]. More recently, new driver genes such as RET fusion [8], ROS1 rearrangement [9], BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, and DDR2 mutations were also identifiedand these driver mutations are expected as a target for new therapeutic medicines. Novel molecular targeted medicines such as afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases [10], and CH5424802, selective ALK inhibitor [11], are studied in clinical trials. "Next Generation DNA Sequencer" has been developed and Analyzing nucleotide sequence of the gene is faster than before and rapid identification of key drivermutations in advanced NSCLC is becomingmore and more important.
The personalized medicine based on genetically identified oncogenes in advanced NSCLC is going to be standard in daily clinical practice. Elucidation of these oncogenic drivers and development of molecular-targeted agents will cause the expansion of knowledge about molecular pathways including genesis of the lung cancer and result in a radical change of treatment strategies leading to improved overall survival and quality of life in the future.

Bone-targeted medicine
It has been reported that the incidence of bone metastases in lung cancer patients is approximately30-40% [12]. Bone metastasis causes skeletal-related events (SREs) such as fracture, need for radiation, and surgery to bone, spinal cord compression, and hypercalcemia. These complications lead to decreased performance status (PS), quality of life (QOL), and shortening of overall survival (OS). It is very important to delay and prevent SREs in clinical practice with bone-modifying agents (BMA) such as zoledronic acid and denosumab.
Denosumab is a kind of molecular targeted medicines and a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody. Stimulation of osteoblasts by tumor increases the expression of RANKL in bone metastasis and leads to increased bone resorption. Denosumab interrupts this vicious cycle by binding to RANKL and preventing the formation and function of osteoclasts [13]. In a phase III trial, denosumab was non-inferior to zoledronic acid in delaying time to first on-study SRE in patients with advanced cancer metastatic to bone (excluding breast and prostate) or myeloma [14]). Overall survival and disease progression were similar between groups. By the two randomized trial, Denosumab was superior to zoledronic acid in delaying time to first on-study SRE in patient with advanced breast cancer and prostate cancer [15,16]. A combined analysis of 3 pivotal, randomised, phase 3 trials showed denosumab's superiority to zoledronic acid in preventing SREs [17]. Even if there is a subgroup analysis, Scagliotti et al. showed denosumab was associated with improved overall survival compared with zoledronic acid in patients with metastatic lung cancer [18]. Denosumab has the merits that there is no need to adjust the dose according to renal function and we can give by subcutaneous injection. But, the death due to hypocalcemia was reported and monitoring of serum calcium is necessary.
Although Strontium-89 and samarium-153 are beta-emitting radioisotope radiopharmaceuticals approved already for palliation of bone metastases [19], the results of ALSYMPCA study has been published recently [20]. In this phase III study, radium-223 chloride which is a kind of alpha-emitting radioisotope delayed SREs and significantly improved OS as compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In NSCLC, future trials with radium-223 may reveal its decrease of SREs and survival effectiveness.
The purpose of the treatment with bone-targeted agents is decrease of SREs in patients with bone metastases now. We must start treatment early when bone metastasis became clear and also continue bonetargeted agents as long as possible to draw a maximum effect.

Communication
Even if molecular targeted treatment causes good response against advanced NSCLC, radical cureis not obtained in the current medical standard. It goes without saying that the development of the further medicine is necessary, but communication with patients is very important in the choice of treatment. For example, to think either cytotoxic chemotherapy or EGFR-TKI therapy in patients with EGFR mutated advanced NSCLC as first line treatmentis very important