Abstract
Improved understanding of the molecular mechanisms involved in development, growth and spread of cancer have led to develpment of targeted therapies for many cancers. Based on their superior tolerability and efficacy, targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib are preferred first-line treatments over platinum-based chemotherapies in patients whose tumours harbour EGFR-activating mutations and anaplastic lymphoma kinase (ALK) translocations, respectively. Active areas of research in EGFR-mutant and ALK-translocated NSCLC include identification of mechanisms of resistance and overcoming them. Therapeutic targeting of several other targets including ROS, RET and discoidin domain receptor 2 (DDR2) tyrosine kinases are in early phases of clinical evaluation. Despite the advances in tumour genomic sequencing, a substantial fraction of patients with non-small cell lung cancer (NSCLC) do not have any targetable genetic alteration. Ongoing research is focused on identifying mechanisms of carcinogenesis in these patients. Targeted therapies in small cell lung cancer (SCLC) and thymic malignancies have not yielded meaningful clinical benefits, and platinum-based therapies remain the cornerstone of treating patients with advanced disease.
Thoracic malignancies represent a major health problem worldwide. Lung cancer is one of the most common types of cancer in the world, with more than 1.6 million new cases in 2008, comprising 13% of all newly-diagnosed cancers (1). Lung cancer was responsible for 1.4 million deaths from cancer in 2008, accounting for 18% of all cancer deaths (1). Traditionally, lung cancer is divided in two groups: non-small cell lung cancer (NSCLC), which represents approximately 85% of all cases, and small cell lung cancer (SCLC). Although lung cancer has been associated largely with cigarette smoking (2), lifestyle, diet, passive smoking, and occupational exposure have also been found to play important roles (3-5).
On the contrary, thymic neoplasms are rare: the incidence is 0.13 per 100,000 individuals per year (6). Thymic malignancies are the most common type of tumor located in the anterior mediastinum (6). There are no known environmental risk factors for the development of thymic malignancies, although some reports describe an association between Epstein-Barr virus and human T- cell lymphotropic virus type-1 and thymoma (7, 8).
The poor prognosis of thoracic malignancies has not changed significantly over the past 30 years. The histological and molecular heterogeneity of thoracic malignancies makes our understanding of carcinogenesis, as well as treatment challenging. The ‘One size fits all’ treatment strategy has proven insufficient in recent years as it lost its battle against biomarker-driven targeted treatment strategies (9). This review focuses on the development of treatment for advanced thoracic malignancies from platinum-based therapy to personalized treatments.
Platinum-based Therapies
The vast majority of NSCLC is locally advanced or metastatic at the time of diagnosis, and thus remains incurable with fewer than 15% of patients alive at five years after diagnosis. Platinum-based cytotoxic chemotherapy has been the mainstay of treatment for patients with advanced NSCLC for decades. Median survival almost doubled from five months, with cisplatin and vinblastine (10), to 10 months with third-generation cytotoxic agents such as paclitaxel, gemcitabine and docetaxel in combination with platinum (11). Selection of patients who would benefit from chemotherapy is crucial to maximise efficacy and limit toxic effects. In the past five years, we have learnt that tailoring chemotherapy regimen according to histology can improve efficacy, and thus improve outcomes. Patients with adenocarcinoma of the lung showed improved overall survival with combination of pemetrexed and carboplatin (12), or when bevacizumab was added to paclitaxel and carboplatin (13)
Prognosis of patients with SCLC is poor. Despite being chemosensitive, these tumors usually recur quickly and metastasize early. In contrast to NSCLC, very little progress has been made in SCLC treatment. The treatment of choice remains cisplatin with etoposide, leading to a mean overall survival of less than 10 months (14).
Chemotherapy is the backbone of treatment in patients with unresectable, advanced, metastatic or recurrent thymic malignancies. Disease control is achievable in these patients but complete remission is rarely possible. Due to their rarity, current treatments are informed mainly by retrospective studies, non-randomized trials or expert opinions. Many monotherapy and combination protocols have been investigated, with most protocols containing platinum (15-20). Although response rates to platinum-based combination chemotherapy regimens were high, ranging from 30 to 90%, overall survival was not impressive, at around 17 months (17-20).
Targeted Treatments in Non-small Cell Lung Cancer
Improved understanding over the molecular mechanisms involved in development, growth and spread of cancer have led to advances in the treatment of NSCLC. These advances made it possible to focus on specific pathways active in NSCLC, which enabled development of new drugs which target these cancer cell-specific alterations. Clinical characteristics alone have proven insufficient to predict the presence of these cancer cell-specific alterations. Hence detection of these alterations is crucial in order to identify specific drugs because targeted drugs gave maximum effect in patients whose cancer cells harbour specific molecular alterations (21). Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) were found to pedict patients who responded to EGFR tyrosine kinase inhibitors (TKIs) (22). It is estimated that nearly 16% of Caucasians and up to 50% of Asians with advanced-stage NSCLC harbour activating EGFR gene mutations (21, 23). Mutations in EGFR result in the constitutive activation of several downstream signaling pathways leading to cellular proliferation, growth and spread of cancer. To date three EGFR TKIs have been approved for treament of patients with NSCLC which harbour activating mutations in EGFR: gefitinib, erlotinib and afatinib.
Erlotinib and gefitinib are reversible and highly specific small-molecule TKIs that competitively block the binding of adenosine triphosphate (ATP) to its binding site on the EGFR tyrosine kinase domain, thereby inhibiting autophospho-rylation and blocking downstream signaling. In selected chemonaive patients with advanced NSCLC, four phase III open-label, randomized trials in East Asian patients demonstrated superior overall response rates (ORR) and progression-free survival (PFS) when gefitinib was compared with standard first-line platinum-based chemotherapy (24-27). Patients in IPASS and First-SIGNAL trials conducted in East Asia were selected according to clinical characteristics to increase probability of response: never-smokers/former light smokers and adenocarcinoma histology (24, 27), while WJTOG3405 and NEJ002 populations were defined based on the presence of EGFR-activating mutations (25-26).
Similarly designed trials were conducted with erlotinib. OPTIMAL was conducted in China in patients with advanced NSCLC harbouring EGFR-activating mutation (exon 19 deletion or exon 21 L858R point mutation) receiving either erlotinib or gemcitabine plus carboplatin (28). Median PFS was significantly longer in erlotinib-treated patients than those treated with chemotherapy [13.1 vs. 4.6 months; hazard ratio (HR)=0.16, 95% confidence interval (CI)=0.10-0.26; p<0.0001]. EURTAC, a phase III randomized study conducted in Europe that compared erlotinib with platinum-based chemotherapy in 174 chemonaive Caucasian patients with EGFR-activating mutations (exon 19 deletion or exon 21 L858R mutation). Median PFS almost doubled with erlotinib compared to chemotherapy (9.7 months vs. 5.2 months; HR=0.37, p<0.0001). However, there was no benefit in overall survival (29).
Second-generation EGFR TKIs include irreversible inhibitors that simultaneously target multiple members of the EGFR family. Irreversible EGFR TKIs may overcome resistance to gefitinib or erlotinib by covalently binding to EGFR. Most extensively studied among such agents is afatinib. The results of LUX–LUNG 3 trial have lead to FDA approval of afatinib for treatment of patients with EGFR-activating mutations. In the trial, afatinib was compared to combination of pemetrexed and cisplatin in 345 chemonaive patients with EGFR mutation. Afatinib in this molecularly-selected population significantly prolonged PFS compared to chemotherapy (11.1 vs. 6.9 months; HR=0.58; 95% CI=0.43-0.78; p=0.0004) (30), and delay in time-to-deterioration of cancer-related symptoms of cough and dyspnoea (31).
Echinoderm microtubule-associated protein-like 4 (EML4)–ALK translocation was identified as a driver mutation of lung carcinogenesis in 2007 (32). Several fusion partners of ALK have been described, but the most common one is the N-terminal portion of the protein encoded by the EML4 gene with the intracellular signaling portion of the receptor tyrosine kinase encoded by the ALK gene. The chimeric protein, EML4–ALK, has strong oncogenic activity both in vitro and in vivo (33). EML4–ALK transloclocation is found in 4-5% of patients with lung adenocarcinoma and is mutualy exclusive with EGFR and Kirsten rat sarcoma viral oncogene (KRAS) mutations (34-35). ALK inhibitor crizotinib received accelareted FDA approval based on results of phase I and phase II trials in previously treated patients with ALK translocation (36-37). Results were confirmed in a phase III trial of 347 patients with ALK translocation who were previously treated with one prior platinum-based chemotherapy. Crizotinib was compared with pemetrexed or docetaxel. Crizoinib significantly prolonged PFS compared to chemotherapy (7.7 months vs. 3.0 months, p<0.001) and improved symptoms and quality of life (38).
Targeted Therapies in Small Cell Lung Cancer and Thymic Malignanices
Different targeted agents have been investigated in SCLC, but unlike NSCLC, none of these drugs have shown meaningful clinical efficacy. In a phase III trial of patients with advanced SCLC, addition of thalidomide to standard therapy did not improve survival but did increase the risk of thrombotic events (39). Several phase II trials with TKIs showed no benefit in patients with advanced SCLC (40). A probable reason for failure of these agents was that patients were not selected according to target expression.
Similarly, no targeted agents have been approved for clinical use in patients with thymic malignancies. The most studied were EGFR and tyrosine-protein kinase Kit (c-KIT) pathways due to significant overexpression detected by immunohistochemistry. The lack of efficacy of agents that target EGFR (erlotinib) and c-KIT (imatinib) can be explained by the absence of drug-sensitizing mutations in thymic malignances (41).
Ongoing Research
Besides EGFR and EML4–ALK gene alterations, several other potentially targetable alterations are discovered in patients with NSCLC such as KRAS, v-ros UR2 sarcoma virus oncogene homolog (ROS1), v-raf murine sarcoma viral oncogene homolog B (BRAF), v-erb-b2 avian erythroblastic leukemia viral oncogene homolog-2 (HER2), hepatocyte growth factor receptor (c-MET) and MAP kinase-ERK kinase (MEK).
KRAS mutations are the most common mutations in patients with NSCLC and have been reported in 15-20% of all patients with NSCLC and approximately in 30-50% of patients with adenocarcinoma histology (42). KRAS mutations in NSCLC are associated with decreased response to EGFR TKIs (43). Although there is no direct inhibitor of KRAS, a phase II trial of MEK inhibitor selumetinib, in combination with docetaxel showed promising effects in patients with KRAS mutation (44).
The frequency of HER2 mutations is relatively low in patients with NSCLC, around 2%, and is increased in patients with NSCLC who are women, never-smokers and in patients of Asian origin, and are more frequent to adenocarcinoma than in other subtypes of NSCLC (45). TKIs that block both EGFR and HER2, such as lapatinib and afatinib, showed promising results in patients with lung adenocarcinoma positive for the HER2 mutation (46-47).
In NSCLC, 1-3% of adenocarcinoma have BRAF mutations which are mostly non-Val600Glu mutations (48), unlike melanoma, where V600E mutations, highly sensitive to vemurafenib are more frequent (49). Vemurafenib, and several other BRAF inhibitors are in early-phase clinical trials.
ROS1 is a member of the RTK of the insulin receptor family. A recent study demonstrated that approximately 2% of patients possess ROS1 translocation and the patients typically have a similar profile to patients with EML4–ALK translocation (50). Crizotinib, an ALK and MET inhibitor, showed in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC (50).
Several growth factor pathways have been implicated as mediators of carcinogenesis in SCLC, including growth hormone-releasing hormone, insulin-like growth factor I, bombesin, hepatocyte growth factor, and fibroblast growth factor 2 (40). Inhibitors of several of these growth factor pathways are in clinical development, although in early phase.
Several targeted drugs with different mechanisms of action are under investigation in patients with thymic malignancies. Most studied are inhibitors of vascular endothelial growth factor pathway, such as sunitinib (51) and sorafenib (52), histone deacetylase inhibitor belinostat (53), monocolonal antibody against insulin-like growth factor-1 receptor, cixutumumab (54) and src inhibitor saracatinib (55). Targeted therapies have shown only modest results in the treatment of thymic malignancies.
- Received October 31, 2013.
- Revision received November 24, 2013.
- Accepted November 26, 2013.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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