Double Trouble: A Case Series on Concomitant Genetic Aberrations in NSCLC

Several oncogenic drivers have been identified in non–small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene. We also include an unpublished case report on a patient with an epidermal growth factor receptor L858R and cMET exon 14 skipping.     

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.     

Acquired Resistance to Targeted Therapies Against Oncogene-Driven Non–Small-Cell Lung Cancer: Approach to Subtyping Progressive Disease and Clinical Implications

In the emerging era of targeted therapy for advanced-stage non–small-cell lung cancer, it is becoming increasingly important to anticipate underlying driver oncogene alterations at the time of initial diagnosis and tumor-tissue acquisition, so that patients can be selected in a timely fashion for first-line tyrosine kinase inhibitor (TKI) therapy if their cancers are found to harbor tyrosine-kinase-activating mutations in the epidermal growth factor receptor gene or gain-of-function rearrangements in the anaplastic lymphoma kinase gene. However, despite the clear benefits of TKI therapy over chemotherapy in these settings, the eventual emergence of acquired resistance and progressive disease (PD) is universal. How to best approach oncogene-driven non-small-cell lung cancer at the time of acquired resistance to initial TKI therapy is an increasingly complex question because of variability in mechanisms of resistance, extent of PD, and inter- and intrapatient tumor heterogeneity. Here we propose an approach to subtyping PD in the setting of acquired resistance as well as subsequent clinical implications.     

Update on systemic therapy of advanced non-small-cell lung cancer

In the last decade, major progress in the treatment of advanced non-small-cell lung cancer has been made through the better understanding of the molecular biology of lung cancer, identification of new oncogene drivers and development of oncogene-directed drugs. Oncogene-directed therapies with EGFR or anaplastic lymphoma kinase tyrosine kinase inhibitors became standard practice in patients with activating EGFR mutations or anaplastic lymphoma kinase rearrangements, improving median survival rates to up to 35 months. Encouragingly, there are still numerous other targeted drugs and treatment strategies under development. In addition, nowadays chemotherapy can be tailored based on histology of the primary tumor and response to induction chemotherapy, raising median survival rates up to 13 months. These major developments, both in oncogene- and non-oncogene-directed therapies is presented in this review, together with a further designation of the most relevant future strategies, such as immunotherapy.     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的应用

特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。     

Present and future evolution of advanced breast cancer therapy

Although the introduction of novel therapies and drug combinations has improved the prognosis of metastatic breast cancer, the disease remains incurable. Increased knowledge of the biology and the molecular alterations in breast cancer has facilitated the design of targeted therapies. These agents include receptor and nonreceptor tyrosine kinase inhibitors (epidermal growth factor receptor family), intracellular signaling pathways (phosphatidylinositol-3-kinase, AKT, mammalian target of rapamycin) angiogenesis inhibitors and agents that interfere with DNA repair (poly(ADP-ribose) polymerase inhibitors). In the present review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with cytotoxic agents.     

Moving from histological subtyping to molecular characterization: new treatment opportunities in advanced non-small-cell lung cancer

Over the last 10 years, the systemic treatment of advanced non-small-cell lung cancer has progressively moved away from the ‘one-size-fits-all’ approach to histological subtyping. Currently, there is a progressive implementation of targeted therapies based on specific molecular characteristics such as the EGF receptor sensitizing mutations and the anaplastic lymphoma kinase rearrangements. Despite the availability of effective agents against these abnormalities, acquired resistance is still a major issue. A new generation of tyrosine kinase inhibitors for EGF receptor and anaplastic lymphoma kinase targeting acquired resistance mechanisms have been recently investigated. Several promising tyrosine kinase inhibitors that hit other targets are also in clinical development, including: rat sarcoma gene/MEK, BRAF1, PIK3A, c-mesenchymal-epithelial transition, c-ros oncogene 1, rearranged during transfection, human EGFR 2, FGFR, VEGFR, PDGFR and discoidin death receptor 2. Furthermore, new advances in immunology have been achieved through the discovery of vaccines and immune checkpoint pathways such as the cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1 and its ligands.     

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.     

Targeted therapies for lung cancer: clinical experience and novel agents

Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography-based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene "addictions" as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer-targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review.     

First-line treatment for advanced non-small-cell lung cancer

With best supportive care alone, patients with metastatic non-small-cell lung cancer (NSCLC) have a median survival of 4 to 5 months and a 1-year survival rate of approximately 10%. Trials carried out in the 1980s and 1990s comparing chemotherapy to best supportive care reported variable efficacy results; however, a pivotal meta-analysis of these data indicated that cisplatin-based chemotherapy provided a survival benefit in advanced NSCLC. In the past decade newer agents such as gemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere) have all demonstrated activity in NSCLC as single agents; consequently these agents have been combined with cisplatin or carboplatin. Randomized phase III trials comparing these "newer" platin-based doublets have failed to identify an optimal platinum-based doublet therapy regimen. Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there a sense in which the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understanding of cancer biology has revealed numerous potential therapeutic strategies, including targeting the epidermal growth factor receptor, protein kinase C, rexinoid receptors, and the angiogenesis pathway. The Eastern Cooperative Oncology Group study E4599 comparing paclitaxel/carboplatin with/without bevacizumab is the first phase III randomized trial to show a survival advantage with the addition of a molecularly targeted agent to chemotherapy in the chemotherapy-naive patient population. Future studies will involve the evaluation of additional targeted agents plus chemotherapy as well as looking at combinations of these targeted agents alone or with chemotherapy.     

Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC

Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.     

Targeting the epidermal growth factor receptor. Trials in head and neck and lung cancer

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.     

Ligand‐triggered resistance to molecular targeted drugs in lung cancer: Roles of hepatocyte growth factor and epidermal growth factor receptor ligands

Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor ( EGFR ) mutations and echinoderm microtubule‐associated protein‐like 4 (EML4) – anaplastic lymphoma kinase (ALK) fusion gene, in lung cancer. Dramatic response has been achieved with EGFR inhibitors (gefitinib and erlotinib) and an ALK inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand‐triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. Moreover, EGFR ligands activate EGFR and downstream pathways and trigger resistance to crizotinib in EML4‐ALK lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR ‐mutant lung cancer and ALK signaling in EML4‐ALK lung cancer) and ligand‐triggered bypass signals (HGF‐Met and EGFR ligands‐EGFR, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer. (Cancer Sci 2012; 103: 1189–1194)     

Perspective on the development of new agents in thoracic cancers

The development of several targeted agents that play a critical role in the growth and survival of carcinomas has paved the way for a new era in the treatment of patients with thoracic malignancies. The novel antimetabolite pemetrexed has emerged as a key agent in the treatment of advanced malignant pleural mesothelioma (MPM). Inhibitors of the epidermal growth factor receptor (EGFR) are one of many promising targeted therapies for non-small-cell lung cancer (NSCLC). By utilizing agents that specifically target the biochemical and molecular changes underlying cancer, it is possible to envision a future in which combinations of therapies treat cancer on multiple fronts, significantly enhancing tumor responses and improving survival beyond current expectations.     

Preface

Non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the USA and worldwide. Most patients present with advanced disease, and treatment options for these patients are generally limited to platinum-based chemotherapy and a few targeted therapies. Targeted agents currently in use for NSCLC inhibit oncogenic receptor tyrosine kinase pathways, such as the epidermal growth factor receptor (EGFR) pathway. While current EGFR-targeted agents, including erlotinib and gefitinib, may result in dramatic responses, they demonstrate efficacy in only a fraction of patients, and resistance to these agents frequently develops. In order to select patients most likely to benefit from blockade of EGFR pathways, investigators have focused on identifying molecular correlates of response to anti-EGFR therapy. New strategies to minimize the risk of resistance to EGFR inhibition have been employed in the development of next-generation EGFR tyrosine kinase inhibitors, such as PF00299804 and BIBW 2992; these include irreversibility of target binding, inhibition of multiple EGFR family receptors, and/or simultaneous inhibition of EGFR and other oncogenic pathways.     

Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy

Non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the USA and worldwide. Most patients present with advanced disease, and treatment options for these patients are generally limited to platinum-based chemotherapy and a few targeted therapies. Targeted agents currently in use for NSCLC inhibit oncogenic receptor tyrosine kinase pathways, such as the epidermal growth factor receptor (EGFR) pathway. While current EGFR-targeted agents, including erlotinib and gefitinib, may result in dramatic responses, they demonstrate efficacy in only a fraction of patients, and resistance to these agents frequently develops. In order to select patients most likely to benefit from blockade of EGFR pathways, investigators have focused on identifying molecular correlates of response to anti-EGFR therapy. New strategies to minimize the risk of resistance to EGFR inhibition have been employed in the development of next-generation EGFR tyrosine kinase inhibitors, such as PF00299804 and BIBW 2992; these include irreversibility of target binding, inhibition of multiple EGFR family receptors, and/or simultaneous inhibition of EGFR and other oncogenic pathways.     

Molecular approaches to prevention and therapy of aerodigestive tract cancers.

We describe studies defining several molecular events in human non-small-cell lung cancer (NSCLC). These include increased growth factor and growth factor receptor expression and oncogene alterations. The epidermal growth factor receptor (EGFR) and erbB2 are expressed by NSCLC cells. Transforming growth factor-alpha (TGF-alpha) is produced by NSCLC and may mediate autocrine growth stimulation. Specific inhibition of K-ras oncogene expression by an antisense K-ras construct reduces the growth rate and tumorigenicity of NSCLC cells. Studies with antisense p53 in NSCLC with a homozygous p53 mutation suggest that the presence of the mutant form contributes to the transformed state.     

Gefitinib (iressa) in oncogene-addictive cancers and therapy for common cancers

Activating mutations in the epidermal growth factor receptor (EGF-R) predict response to gefitinib. How does this recent discovery affect our outlook on selective (targeted) cancer therapy? It allows us to compare mutant EGF-R with Bcr-Abl as anticancer drug targets and to discuss the nature of oncogene addiction. It emphasizes molecular diagnostics to identify oncogene-addictive cancers. It also re-enforces the notion that most cancers with multiple oncogenic alterations (common cancers) will unlikely respond to selective drugs alone. In such cancers, one strategy is targeting cancer-non-specific, universal and vital structures, essential for life of all cells: microtubules, topoisomerases, histone deacetylases, the proteasome. But in order to be cancer-selective, these chemotherapeutic agents need to be combined with selective agents. Such combinations can be effective and selective in common cancers.     

Critical update and emerging trends in epidermal growth factor receptor targeting in cancer.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non-small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.     

Personalized treatment of advanced non-small-cell lung cancer in routine clinical practice

Personalized treatment of patients with advanced non-small-cell lung cancer based on clinical and molecular tumor features has entered clinical routine practice. The 2015 pathological classification of lung cancer mandates immunohistochemical and molecular analysis. Therapeutic strategies focused on inhibition of angiogenesis and growth factor receptor signaling. Inhibitors of angiogenesis and monoclonal antibodies directed against the epidermal growth factor receptor have shown efficacy in combination with chemotherapy. Mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase have become clinically relevant therapeutic targets. Immune checkpoint inhibitors are also entering routine clinical practice. Identification of predictive biomarkers is essential and faces several challenges including tumor heterogeneity and dynamic changes of tumor features over time. Liquid biopsies may overcome some of these challenges in the future.