Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer

BACKGROUND: Erlotinib is an oral tyrosine kinase inhibitor, targeting the human epidermal receptor type 1/ epidermal growth factor receptor, recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after the failure of more than 1 or 2 previous chemotherapeutic regimens. OBJECTIVE: The purpose of this article is to summarize the development, pharmacology, pharmacokinetics, efficacy, and adverse effects of erlotinib. METHODS: A literature search was conducted with the MEDLINE and EMBASE (1999-2005) databases using the search terms non-small-cell lung cancer, erlotinib, and epidermal growth factor receptor inhibitor. Abstracts from the American Society of Clinical Oncology and documents submitted to the FDA also were reviewed. RESULTS: BR.21, a randomized, placebo-controlled, multinational Phase III trial demonstrated clinically and statistically improved overall survival in patients with advanced or metastatic NSCLC treated with erlotinib versus placebo as second-line therapy. The erlotinib group had a median survival of 6.7 months versus a median survival of 4.7 months in the placebo group (P < 0.001). The toxicity profile of erlotinib was moderately benign, with the most commonly documented adverse events requiring dose reductions including skin rash (12%) and diarrhea (5%). Interstitial lung disease and relative fatalities were reported infrequently (0.8%) in patients receiving erlotinib. Two randomized, placebo-controlled, multicenter Phase III trials conducted in patients with locally advanced and metastatic NSCLC showed no clinical benefit with first-line administration of erlotinib plus concurrent platinum-based chemotherapy. CONCLUSIONS: For patients with NSCLC in whom more than 1 or 2 previous chemotherapeutic regimens have failed, erlotinib is an effective therapy with significant overall survival benefits. The use of erlotinib as first-line therapy in combination with platinum-based chemotherapeutic regimens, however, has failed to demonstrate efficacy in the treatment of NSCLC.     

The 800-lb gorilla we all ignore: treatment of NSCLC in elderly and PS 2 patients

Patients with non-small cell lung cancer,NSCLC, typically have advanced disease on presentation. First-line palliative platinum-based doublet chemotherapy has emerged as the standard of care in fit, younger patients. However, patients with advanced age and/or impaired performance status have been relatively underrepresented in clinical trials. Retrospective analyses and the few existing prospective randomized trials in these populations have suggested a poorer overall prognosis, yet also provide evidence of benefit from systemic therapy. Toxicity is generally manageable, and in most cases, comparable to that of younger, healthier patients. There are clearly expanding roles for nonplatinum chemotherapy agents and newer targeted therapies, which have generally yielded decreased toxicity compared to platinum-based chemotherapy without sacrificing efficacy. Appropriate pretreatment assessment and proper patient selection is of paramount importance; it is imperative to treat patients who are most likely to garner benefit. In summary, data suggest that these relatively neglected populations of NSCLC patients can be safely treated, and can benefit from palliative systemic therapy. Single-agent chemotherapy is generally recommended over combination chemotherapy, although investigation of newer targeted therapies or alternative agents may allow for combination therapy in the near future. Further prospective investigation is absolutely warranted.     

Advances in breast cancer chemotherapy

Progress in chemotherapy for breast cancer was reviewed in the management of primary and metastatic diseases. In the metastatic setting, a survival advantage from combinations of drugs has not been proved over single agents given in sequence. Currently, active agents include anthracyclines, taxanes, vinorelbine, and fluoropyrimidines. Prospective randomized trials demonstrated that adjuvant systemic chemotherapy reduced annual odds of recurrence and death with combination therapy, regardless of age, stage, nodel status and hormone receptor status. One of the recent important questions in the adjuvant setting is the role of taxanes. Although many adjuvant taxane studies are still on going, 4 cycles of anthracycline-containing regimen sequenced with 4 cycles of a taxane appear to be the most beneficial treatment for advanced disease. Controversies and future directions are the high cost of treatment and the prediction of response to each drug for individual patients.     

Adjuvant chemotherapy in non-small cell lung cancer

Adjuvant chemotherapy is considered a standard of care for many malignancies, the most well known being breast and colon cancer. Unfortunately, less than a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease and despite resection outcomes are often poor with a median 5-year survival of 40-50%. Modern chemotherapy for NSCLC provides both a survival advantage and an improvement in quality of life in the palliative setting. Several large studies using modern platinum-based regimens have been presented since the 1995 meta-analysis. This demonstrated a nonsignificant benefit for older platinum-based regiments. These studies have consistently shown a survival benefit across all stages of resection with acceptable toxicity. The absolute magnitude of benefit is consistent with that achieved in other malignancies where adjuvant chemotherapy is offered as a standard of care.     

Pembrolizumab for the first-line treatment of non-small cell lung cancer

Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.

Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and ?189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.

Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.     

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

INTRODUCTION: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity. AREAS COVERED: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing. EXPERT OPINION: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.     

Advances in chemotherapy for non-small cell lung cancer

OBJECTIVES: To discuss the use of chemotherapy and targeted therapy for treating non-small cell lung cancer (NSCLC). DATA SOURCES: Published articles, book chapters, and research papers. CONCLUSION: Chemotherapy has improved both response and survival rates incrementally in patients with advanced NSCLC. Targeted therapy agents are now included in the treatment schema and are impacting overall survival in combination with chemotherapy for first-line therapy and as monotherapy for second- or third-line treatment. In recent years, chemotherapy has also shown efficacy in earlier stages of treatment, especially as adjuvant therapy after surgery. Additionally, elderly patients can tolerate platinum-based chemotherapy without significant toxicities; therefore, age should not be the only determining factor when deciding on treatment for an older person. IMPLICATION FOR NURSING PRACTICE: It is important for nurses to know and understand the background and rationale for many of the current treatments for NSCLC given today.     

基于基因检测的26例晚期非小细胞肺癌患者化疗疗效观察

目的观察基于肺癌化疗预测因子指导下的非小细胞肺癌(NSCLC)化疗疗效。方法 26例NSCLC患者标本行切除修复交叉互补基因1(ERCC1)、核糖核苷酸还原酶M1(RRM1)、β-微管蛋白(β-tubulin)和胸苷酸合成酶(TS)基因检测。根据检测结果选择化疗方案,每例患者至少完成2个周期化疗后评估客观疗效、无进展生存时间(PFS)及毒性反应。结果客观缓解率(ORR)为34.6%,疾病控制率(DCR)为57.7%。其中,一线治疗ORR为60%,DCR为70%;二线治疗ORR为30%,DCR为60%。总体PFS为4.9个月;其中一线、二线和三线PFS分别为6.7个月、4.5个月和1.5个月。毒性反应以血液学及消化道反应为主。结论根据肺癌化疗预测因子制定的化疗方案可提高NSCLC一线和二线治疗的疗效,延长一线治疗的PFS,毒副作用可耐受。     

Selection of chemotherapy for patients with advanced non-small cell lung cancer

Chemotherapy remains the first-line treatment for most patients with stage IV non-small cell lung cancer (NSCLC), but optimal regimens are now defined by histology. Platinum-based regimens with pemetrexed, bevacizumab, or both are reasonable first-line options for patients with nonsquamous NSCLC. The standard treatment for squamous NSCLC remains a platinum doublet with a drug other than pemetrexed. Maintenance therapy is emerging as a treatment strategy for patients who do not progress after four cycles of first-line chemotherapy. In the maintenance setting, pemetrexed and erlotinib significantly prolong overall survival compared with placebo after the completion of first-line chemotherapy.     

Adjuvant chemotherapy for early-stage non-small cell lung cancer: the past,the present and the future

Complete resection is mandatory in order to achieve a cure in patients with early-stage non-small cell lung cancer (NSCLC). However, despite complete resection, a substantial proportion of patients have disease recurrence, with distant metastases being the primary sites of failure. Recent trials have conclusively demonstrated the benefit of platinum-based adjuvant therapy in patients with resected stage IB and II NSCLC. The role of adjuvant chemotherapy in resected stage III NSCLC is less clear, with trials showing conflicting results. The role of targeted agents in this setting is being investigated. Gene expression profiling studies should help direct chemotherapy to those who would actually benefit from it, thereby saving others from unnecessary toxicity.     

Adjuvant chemotherapy for early-stage non-small cell lung cancer: the past, the present and the future

Complete resection is mandatory in order to achieve a cure in patients with early-stage non-small cell lung cancer (NSCLC). However, despite complete resection, a substantial proportion of patients have disease recurrence, with distant metastases being the primary sites of failure. Recent trials have conclusively demonstrated the benefit of platinum-based adjuvant therapy in patients with resected stage IB and II NSCLC. The role of adjuvant chemotherapy in resected stage III NSCLC is less clear, with trials showing conflicting results. The role of targeted agents in this setting is being investigated. Gene expression profiling studies should help direct chemotherapy to those who would actually benefit from it, thereby saving others from unnecessary toxicity.     

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

Introduction: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity.

Areas covered: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing.

Expert opinion: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.     

Ramucirumab for the treatment of advanced or metastatic non-small cell lung cancer

ABSTRACT

Introduction: On 12 December 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.

Areas covered: This review discusses the best treatment strategy for ramucirumab, a vascular endothelial growth factor receptor-2 inhibitor for patients with advanced NSCLC.

Expert opinion: The addition of ramucirumab to docetaxel in the treatment of patients with metastatic NSCLC who have progressed on or after platinum-based chemotherapy confers a 1.4-month improvement in overall survival, with an acceptable toxicity profile. The potential impact of the approval of the programmed death receptor-1 (PD-1)-blocking antibody nivolumab or pembrolizumab on the use of ramucirumab plus docetaxel in advanced NSCLC patient population is uncertain in clinical practice. In order to improve overall outcomes for patients with advanced NSCLC, both ramucirumab plus docetaxel and the PD-1-blocking antibody should be used in any treatment line.     

Is there still room for large registrative trials in unselected cancer patients? The case of anti-epidermal growth factor receptor antibodies in advanced non-small-cell lung cancer

Necitumumab, a monoclonal antibody directed against EGFR, is currently under development as a treatment for advanced NSCLC. Two Phase III randomized trials are ongoing, testing the addition of necitumumab to first-line platinum-based chemotherapy. In the same setting, cetuximab produced a statistically significant but clinically modest benefit in the whole study population, and no solid data have been produced about predictive factors of efficacy. Will the difference in structure between the two antibodies be enough to obtain a clinically relevant advantage, making real progress in the treatment of advanced NSCLC? Large Phase III trials in unselected patients risk demonstrating statistically significant results with debatable clinical relevance in the whole population, and the study of predictive factors is often left to subgroup analysis performed after the conduction of the trial. We do not need further 'me-too' drugs, or drugs that produce a small benefit in the unselected population. On the contrary, the oncologic community needs drugs to be used with a proper selection of patients, to obtain larger, relevant benefits in molecularly characterized subgroups. Final results of randomized trials with necitumumab in advanced NSCLC are expected in a couple of years.     

Is there still room for large registrative trials in unselected cancer patients? The case of anti-epidermal growth factor receptor antibodies in advanced non-small-cell lung cancer

Necitumumab, a monoclonal antibody directed against EGFR, is currently under development as a treatment for advanced NSCLC. Two Phase III randomized trials are ongoing, testing the addition of necitumumab to first-line platinum-based chemotherapy. In the same setting, cetuximab produced a statistically significant but clinically modest benefit in the whole study population, and no solid data have been produced about predictive factors of efficacy. Will the difference in structure between the two antibodies be enough to obtain a clinically relevant advantage, making real progress in the treatment of advanced NSCLC? Large Phase III trials in unselected patients risk demonstrating statistically significant results with debatable clinical relevance in the whole population, and the study of predictive factors is often left to subgroup analysis performed after the conduction of the trial. We do not need further ‘me-too’ drugs, or drugs that produce a small benefit in the unselected population. On the contrary, the oncologic community needs drugs to be used with a proper selection of patients, to obtain larger, relevant benefits in molecularly characterized subgroups. Final results of randomized trials with necitumumab in advanced NSCLC are expected in a couple of years.     

Platinum-based compounds for the treatment of metastatic breast cancer

The role of platinum-based compounds (PBCs) in the treatment of metastatic breast cancer (MBC) has been extensively studied. As single agents, high response rates have been observed in first-line therapy, while results in pretreated patients were discouraging. Regimens containing cisplatin/carboplatin together with taxanes showed the highest efficacy and safety as both first-line and second-line therapy. When administered with vinorelbine, the combination was also active and well tolerated in anthracycline- and taxane-pretreated patients. Combining PBCs with etoposide or nucleoside analogues showed moderate activity, yet high toxicity in the case of etoposide. The overall results for the combination with anthracyclines were disappointing. Addition of trastuzumab to PBC combinations showed remarkable activity and good tolerability in patients with HER2/neu overexpression. The use of cisplatin or carboplatin alongside novel targeted therapeutics for patients with triple-negative MBC seems promising and is being further evaluated. The use of PBCs against MBC requires careful patient selection and combination with the right chemotherapeutic agent.     

Toripalimab in an advanced non-small cell lung cancer patient with poor general condition after multiline treatment: a case report

Several clinical trials have proven that immunotherapy can improve survival and benefit non-small cell lung cancer (NSCLC) patients. In patients who progress after chemotherapy, immune checkpoint inhibitor (ICI) monotherapy can prolong overall survival compared with patients receiving single-agent chemotherapy. A 61-year-old man diagnosed with advanced NSCLC and without driver variants received first-line chemotherapy but experienced recurrence. During subsequent treatment, the disease progressed rapidly, and his general condition deteriorated; therefore, toripalimab monotherapy was initiated. Surprisingly, he responded well, and symptoms were relieved after several treatment cycles despite pseudoprogression, shown in chest images. For driver gene-negative NSCLC patients who progress after chemotherapy and who develop poor performance status (PS), ICIs are an option to alleviate symptoms and improve survival. Furthermore, immunotherapy in patients with pseudoprogression may also provide a survival benefit.     

CC4-02: Comparative Effectiveness of Chemotherapy Regimens for Advanced Lung Cancer

Background/Aims Research has demonstrated that platinum-based chemotherapy may prolong short-term survival and improve symptom control in patients with advanced (stage IIIb-IV) non-small cell lung cancer (NSCLC). Newer chemotherapy agents (e.g., taxanes, antimetabolites, monoclonal antibodies, drugs targeting EGFRs), used as singlet, doublet, or triplet regimens, may improve survival. However, these agents are expensive and may produce side effects requiring hospitalization. Little is known regarding variation in both use (singlet vs. doublet vs. triplet regimens) and outcomes (survival, hospitalizations, cost) in community practices over time for non-aged populations, adjusting for comorbidities. Aims Using information from the HMO Cancer Research Network's (CRN) Virtual Data Warehouse (VDW), we examined the impact on variation over time in use of first-line chemotherapy regimens (singlet vs. doublet vs. triplet) in stage lIIb-IV NSCLC patients on survival, hospitalizations, and costs. Methods Patients aged less than 21 years with stage IIIb-IV NSCLC diagnosed between 2000-2007 at four CRN sites were included in the analysis. Patients were followed from diagnosis date through 2008 (or death or disenrollment). Patient demographics, comorbidities, chemotherapy treatment data, and mortality were obtained from the CRN VDW. Propensity-adjusted survival and Poisson modeling were employed to examine variation in survival days and hospitalizations. Average wholesale price data were used to examine the relative difference in costs by chemotherapy regimen. Results We identified 3,072 stage lIIb-IV NSCLC patients who received first-line chemotherapy of which 24% were <65 years old at diagnosis. The distribution of first-line therapy changed significantly over time with the introduction of taxane, monoclonal antibody, and antimetabolite agents in the later years of the study period. Those receiving singlet regimens were older and had more comorbidities. Unadjusted survival rates were higher for those receiving triplet therapy, but only against singlet regimens in adjusted models. Those receiving singlet regimens had the greatest number of hospitalizations. The costs of doublet and triplet regimens were significantly higher than the singlet regimens. Discussion There was significant variation over time in chemotherapy regimens used in the CRN. Triplet therapy appeared to be associated with the best outcomes and fewest side effects. However, cost considerations for triplet therapy warrant assessments of their cost-effectiveness.     

多西他赛联合奥沙利铂治疗一线化疗失败的非小细胞肺癌的临床研究

目的观察多西他赛联合奥沙利铂二线治疗晚期非小细胞肺癌（NSCLC）的临床疗效及毒副反应,并进行安全评估。方法52例一线治疗失败的晚期非小细胞肺癌患者采用多西他赛＋奥沙利铂化疗3周期后,用世界卫生组织（WHO）的疗效及抗肿瘤药物急性及亚急性毒性反应分度评价疗效和毒性。结果52例患者均完成3周期以上化疗,完全缓解（CR）4例,部分缓解（PR）12例,总有效率30．8％,不良反应主要表现为骨髓抑制、脱发及消化道反应等,未见水钠潴留。结论多西他赛联合奥沙利铂治疗一线化疗失败的非小细胞肺癌疗效确切,可以提高生活质量,毒副反应较轻,耐受性好,值得临床排一老推广研究．     

卡培他滨联合长春瑞滨治疗复发转移乳癌的效果

目的观察长春瑞滨联合卡培他滨对蒽环、紫杉类药物治疗无效的复发转移性乳癌的疗效及毒性。方法蒽环、紫杉类药物治疗无效的复发转移性乳癌病人33例,给予长春瑞滨25 mg/m2,第1、8天,采用深静脉穿刺置管技术静脉滴注;卡培他滨每天1 000 mg/m2,分2次餐后30 min温水送服,连用14 d,间隔7 d,21 d为1周期。进展病例2周期后停止治疗;而有效和稳定病例均在治疗4周期后评价疗效。结果完全缓解（CR）1例,部分缓解（PR）6例,好转（MR）8例,稳定（SD）12例,进展（PD）6例,有效率达45.5%。常见的不良反应为骨髓抑制、恶心、呕吐和手足综合征等。结论长春瑞滨联合卡培他滨对紫杉或蒽环类药物治疗无效的转移性乳癌有较好的疗效,毒性可以耐受。