Opportunities and obstacles of targeted therapy and immunotherapy in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive malignant tumour which accounts for approximately 13–15% of all newly diagnosed lung cancer cases. To date, platinum-based chemotherapy are still the first-line treatments for SCLC. However, chemotherapy resistance and systemic toxicity limit the long-term clinical outcome of first-line treatment in SCLC. Recent years, targeted therapy and immunotherapy have made great breakthrough in cancer therapy, and researchers aim to exploit both as a single agent or in combination with chemotherapy to improve the survival of SCLC patients, but limited effectiveness and the adverse events remain the major obstacles in the treatment of SCLC. To overcome these challenges for SCLC therapies, prevention and early diagnosis for this refractory disease is very important. At the same time, we should reveal more information about the pathogenesis of SCLC and the mechanism of drug resistance. Finally, new treatment strategies should also be taken into considerations, such as repurposing drug, optimising of targets, combination therapy strategies or prognostic biomarkers to enhance therapeutic effects and decrease the adverse events rates in SCLC patients. This article will review the molecular biology characteristics of SCLC and discuss the opportunities and obstacles of the current therapy for SCLC patients.     

Emerging drugs for small-cell lung cancer

Small-cell lung cancer (SCLC) is a rapidly progressing tumor in which chemotherapy has a limited impact on survival. Unfortunately, little progress has been made in the medical management of SCLC during the last 30 years, which is best exemplified by the fact that standard first-line chemotherapy has remained platinum-based over time. On the other hand, improvements in survival have been obtained only with the introduction of innovative radiation strategies such as accelerated hyperfractionation to the thorax for limited-stage disease and prophylactic cranial irradiation for both limited- and extensive-stage disease. However, recent advances in the understanding of SCLC biology have renewed the interest in the clinical development of active drugs for SCLC. In this review, we address the most promising agents under clinical evaluation, discussing both novel chemotherapeutic agents and targeted agents. Particularly, amrubicin, a fully synthetic anthracycline, is a very active agent for SCLC, and ongoing Phase III trials are evaluating this agent either in the first-line setting of extensive-stage or relapsed disease. Among targeted agents, anti-angiogenic strategies and Bcl-2 inhibitors represent the most promising approaches, and they are being specifically tested in combination with and/or as maintenance therapy after first-line platinum-based chemotherapy.     

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens.

Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed.

Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.     

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit.

Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy.

Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

Currently available first-line drug therapies for treating pancreatic cancer

ABSTRACT

Introduction: Pancreatic adenocarcinoma is the 9th most common cancer in the United States and the 4th most common cause of cancer-related death given its poor prognosis.

Areas covered: The authors have performed a literature search for pertinent published clinical trials, ongoing Phase 3 clinical trials, and current treatment guidelines using PubMed, Clinicaltrials.gov, and NCCN, ASCO, ESMO, and JPS websites. The review itself discusses landmark studies and ongoing research into the chemotherapy regimens recommended by each oncologic society. The authors also examine drugs that were promising but failed in Phase 3 trials and those currently being investigated. Finally, the authors provide their expert opinion on the subject and provide their future perspectives.

Expert opinion: While advances in chemotherapy for pancreatic cancer have been limited in comparison to other cancers, there have been improvements in survival. Combination therapy and a goal of R0 resection are key elements to extend life. Novel agents directed at the unique properties of pancreatic cancer are promising.     

Optimal drugs for second-line treatment of patients with small-cell lung cancer

Introduction: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed.

Areas covered: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials.

Expert opinion: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Afatinib in squamous cell carcinoma of the head and neck

Introduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.

Areas covered: We searched the literature for published and ongoing studies with afatinib in HNSCC.

Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.

Expert opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.     

Cancer drug related cardiotoxicity during breast cancer treatment

ABSTRACT

Introduction: Breast cancer (BC) is the most common cancer in women. Although therapeutic armamentarium like chemotherapy, endocrine and target agents have increased survival, cardiovascular side effects have been observed. A comprehensive risk assessment, early detection and management of cardiac adverse events is therefore needed.

Areas covered: In this review we focus on cardiotoxicity data deriving from Phase III randomized trials, systematic reviews and meta-analysis in BC patients. We provide insight into advances that have been made in the molecular mechanisms, clinical presentation and management of such adverse event.

Expert opinion: Despite the large number of data from Phase III trials about cardiac events incidence, there are poor evidences for detection, monitoring and management of cardiotoxicity during BC treatment. Future cardiotoxicity-oriented clinical cancer research can help to predict the risk of cardiac adverse events and improve patients’ outcome. Multidisciplinary approach as well as integration of blood biomarkers with imaging will be desirable.     

Therapeutic advances in small cell lung cancer

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.     

Therapeutic advances in small cell lung cancer

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.     

Pharmacotherapy targeting the EGFR oncogene in NSCLC

Introduction: The EGFR plays a central role in regulating cancer cell growth and survival, representing an attractive therapeutic target in NSCLC.

Areas covered: For the purpose of this review article, data from Phase II and III trials with anti-EGFR agents, including EGFR-tyrosine kinase inhibitors (TKIs) and mAbs, were collected and analysed.

Expert opinion: Eight large Phase III trials demonstrated that EGFR-TKIs are the best option we can offer today as front-line therapy exclusively in EGFR mutant NSCLC. In patients with EGFR wild type or unknown lung cancer, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of an anti-EGFR treatment. In pretreated NSCLC, EGFR-TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy with docetaxel or pemetrexed in terms of survival has been demonstrated. New agents targeting EGFR are under investigation, particularly in individuals with squamous cell histology and those with acquired resistance to EGFR-TKIs.     

Update on new drugs in small cell lung cancer

INTRODUCTION: Small cell lung cancer (SCLC) will account for 25,000 to 32,000 new lung cancer cases in the USA in 2010. Current treatmenta pproaches include platinum-based chemotherapy and etoposide with or without radiation therapy depending on stage and performance status. Five-year survival is approximately 25% for patients with limited stage disease and 1 -- 2% for patients with extensive stage disease and has noti mproved in almost two decades. AREAS COVERED: This article reviews the results of recent clinical trials that have evaluated targeted agents and novel cytotoxic agents alone or in combination with standard chemotherapy in the treatment of patients with SCLC. EXPERT OPINION: The lack of a targeted approach to the treatment of patients with SCLC has led investigators to evaluate a multitude of agents with overwhelmingly negative results. A more systematic approach to clinical trials in patients is needed to improve outcomes for patients with this disease.     

An update on the pharmacotherapy for endometrial cancer

Introduction: Endometrial cancer (EC) is the seventh most common malignancy in women. Most cases have a favorable prognosis because they present an early stage disease at diagnosis. Treatment currently comprises surgery with or without adjuvant approaches. A combination of radiation therapy, chemotherapy or hormonal therapy (HT) is usually administered. This article gives an update concerning the role of synthetic drugs in EC, reviewing the most recent data from Phase III randomized-controlled trials onwards.

Areas covered: Over the years, chemotherapy has become the treatment mainstay in both high-risk or locally advanced EC and in metastatic or recurrent disease. Carboplatin plus paclitaxel is currently considered the standard chemotherapy regimen with a well-tolerated toxicity profile. HT is an alternative option in women with advanced EC and important co-morbidities, and in young women with very early stage disease.

Expert opinion: Basic results of EC treatment during the last decade were collected. There is a need of more advances in treatment. The use of biomarkers, necessary for the success of a therapeutic strategy, and the identification of an ad-hoc population, are two important goals. In the authors' opinion, the development of comprehensive tumor bio-banks and international networks represent the right approach to foster translational studies and obtain improvement in patient outcomes.     

Emerging drugs in endometrial cancers

Importance of the field: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving.

Areas covered in this review: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers.

What the reader will gain: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents.

Take home message: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas.     

Emerging pharmacotherapeutic strategies for cholangiocarcinoma

Introduction: Although of limited clinical benefit, chemotherapy represents the cornerstone of management for patients with inoperable cholangiocarcinoma. The literature on chemotherapy in advanced cholangiocarcinoma is difficult to interpret because of the heterogeneity of cholangiocarcinoma, the use of various chemotherapeutic agents in different combinations and dosing regimens, and the small size of existing patient cohorts.

Areas covered: The authors discuss the major advances in the therapy of cholangiocarcinoma over the past decade. The audience will become familiarized with the contemporary medical management of cholangiocarcinoma and potentially useful agents/combinations for the therapy of this entity in the future.

Expert opinion: In recent years, gemcitabine-based chemotherapy has improved overall survival in advanced cholangiocarcinoma. Although gemcitabine–cisplatin combination represents the largely accepted standard for biliary cancers at present, very few studies so far have looked at the results in cholangiocarcinoma patients only. Therefore, large multicenter, randomized clinical trials are essential to identify the optimal treatment strategy for this rare tumor. In addition, regimens employing gemcitabine with oxaliplatin and/or fluoropyrimidines have shown promising results and warrant additional investigation in cholangiocarcinoma. The efficacy of a variety of newer agents is also now being tested in clinical trials.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.