Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies

Patients with non–small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non–small-cell lung cancer, with a focus on SqCLC.     

非小细胞肺癌的分子靶向治疗

与传统细胞毒性化疗相比,分子靶向治疗能更特异性作用于肿瘤而毒性反应较轻。新的靶向治疗药物得到发展,并相继在晚期非小细胞肺癌一线、二线治疗中进行临床试验,其中有的药物显示了较好的疗效。本文对近年来关于非小细胞肺癌靶向治疗的临床试验进行回顾。     

Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wild-type non-small cell lung cancer?

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a world-wide annual incidence of around 1.3 million. The majority of patients are diagnosed with advanced disease and survival remains poor. However, relevant advances have occurred in recent years through the identification of biomarkers that predict for benefit of therapeutic agents. This is exemplified by the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the treatment of EGFR mutant patients. These drugs have also shown efficacy in unselected populations but this point remains controversial. Here we have reviewed the clinical data that demonstrate a small but consistent subgroup of EGFR wild-type patients with NSCLC that obtain a clinical benefit from these drugs. Moreover, we review the biological rationale that may explain this benefit observed in the clinical setting.     

NSCLC的疫苗治疗研究进展

近年来,非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的生存率因手术、放疗、化疗及靶向治疗等各方面治疗的进展而均取得了很大的进展,但NSCLC患者总的5年生存率仍然不理想。免疫治疗利用免疫系统来控制、杀灭和清除肿瘤细胞,已成为肿瘤治疗的一种重要手段。肿瘤免疫学和分子生物学等各方面的最新进展,不仅推动了免疫治疗中非抗原特异性治疗的发展,比如,以T淋巴细胞的免疫检查点为靶点的单克隆抗体,还推动了抗原特异性免疫治疗或者说是疫苗方面的发展,使得免疫治疗成为十分有前景的治疗方式。这里仅对NSCLC的疫苗治疗最新研究进展进行综述。     

非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的机制和治疗

肺癌是当前死亡率最高的恶性肿瘤之一。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）明显提高了晚期非小细胞肺癌（NSCLC）患者的生活质量,延长了生存期。EGFR基因优势突变的NSCLC患者临床获益明显,然而由于耐药产生,患者的中位无进展生存期（PFS）仅1年左右。最近,有文献报道EGFR TKIs耐药的机制之一是NSCLC转化为小细胞肺癌（SCLC）。本文对这种现象进行了分析总结,探讨了其转化的可能机制。根据EGFR-TKIs耐药后的处理方法和病理表型转化患者的治疗报道,探讨NSCLC EGFR-TKIs耐药后转化为SCLC患者的治疗策略。     

The role of new agents in the treatment of non-small cell lung cancer

Lung cancer is one of the most frequent causes of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of cases and no curative treatment is available for the advanced stages of disease (stages III and IV), which comprise the majority of cases. Current treatment regimens with standard chemotherapy offer only a limited survival benefit, and, therefore, the development of new therapeutic strategies is needed. Novel chemotherapeutic drugs such as the epothilones, MEN 10755 and S-1 are being studied in patients with advanced stages of disease. Furthermore, a large number of therapies targeted against critical biological abnormalities in NSCLC are being investigated in clinical trials. The latter approach includes inhibition of growth factors, interference with abnormal signal transduction, inhibition of angiogenesis and gene replacement therapy. Promising results have thus far been obtained with some of these therapies. This review describes the role of new therapeutic agents in the treatment of NSCLC.     

Neoadjuvant treatment in non-small cell lung cancer: New perspectives with the incorporation of immunotherapy

The aim of neoadjuvant treatment in non-small cell lung cancer (NSCLC) is to eliminate micrometastatic disease to facilitate surgical resection. Neoadjuvant chemotherapy (ChT) in localised NSCLC has numerous advantages over other therapeutic modalities and is considered standard treatment in resectable disease. Treatment with immune checkpoint inhibitors (ICI) improves long-term survival in advanced disease and has a better toxicity profile than conventional therapies. These immunotherapy agents (anti-PD1/PD-L1), administered with or without ChT, are currently being evaluated in the preoperative setting, with initial results showing better pathological response rates and more long-term benefits. Importantly, these drugs do not appear to increase the rate of severe adverse effects and/or postoperative complications. However, several questions still need to be resolved, including the identification of predictive biomarkers; comparative studies of immunotherapy alone vs combined treatment with ChT and/or radiotherapy; the optimal duration of treatment; the timing of surgery; the need for adjuvant treatment; appropriate radiologic evaluation and mediastinal staging; and the correlation between pathological response and survival outcomes. Here we review the current evidence for immunotherapy from a multidisciplinary perspective and discuss current and future controversies.     

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Objectives

Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC.

Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents.     

Five‐year lung cancer survival

BACKGROUND:

The core strategy of American College of Chest Physicians lung cancer guidelines is identification of the earliest symptoms of lung cancer and the immediate initiation of diagnosis and treatment. In the absence of screening, most symptomatic lung cancer is discovered at advanced stages, with the goal of long‐term survival entirely dependent on effective treatment of stage III and IV lung cancer.

METHODS:

In a retrospective review, all patients diagnosed with stage IIIA, IIIB, and IV nonsmall cell lung cancer (NSCLC) between the years 1986 and 2001 at City of Hope National Medical Center who survived 5 years or longer were analyzed to identify parameters that might predict long‐term survival.

RESULTS:

Of 846 patients presenting with stage III or IV disease, 56 (6.6%) survived 5 years or longer. Sixteen patients died of primary tumor progression beyond 5 years. Two 5‐year survivors died of second tobacco‐caused neoplasms, and 16 died from medical conditions potentially related to prior treatment. A substantial majority of survivors were from specific pathologic subsets including: 1) resectable N2 disease (n = 17, 30.4%), 2) multiple lung tumors (n = 7, 12.5%), 3) T3N0 (n = 5, 8.1%), and 4) single site distant metastasis (n = 8, 14.2%).

CONCLUSIONS:

Despite aggressive multimodality therapy, 5‐year survival in patients with advanced stage NSCLC was very poor and limited to small pathological subsets. Patients with advanced stage NSCLC who did not belong to 1 of these subsets had a small chance of long‐term survival. Cancer 2010. © 2010 American Cancer Society.     

非小细胞肺癌的免疫治疗策略及研究进展

非小细胞肺癌（NSCLC）是一种高发病率和死亡率的恶性肿瘤。近年来以手术、放疗、化疗和靶向治疗为主的综合治疗均取得了一定进展,但晚期NSCLC患者的远期生存率仍然较低。免疫治疗主要通过特异性地增强机体的抗肿瘤免疫应答来杀伤肿瘤细胞。以免疫检查点抑制剂、抗原特异性肿瘤疫苗等为代表的多种新型免疫治疗药物在近期临床试验中显示出较好的疗效,从而使得NSCLC的治疗取得突破性进展。免疫治疗将成为NSCLC重要的治疗新模式。     

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century—that is, two‐drug combinations consisting of either cisplatin or carboplatin plus a third‐generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)—remain the primary treatment option for advanced non‐small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin–pemetrexed over cisplatin–gemcitabine as first‐line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single‐agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta‐analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy‐naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum–docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Currently, a combination of chemotherapy and radiotherapy is the standard treatment approach for locally advanced non-small cell lung cancer (NSCLC). However, the clinical outcomes are still disappointing, with the 5-year survival rate being only approximately 20%. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Increasing attention has focused on the integration of targeted agents into current therapies. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signaling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proof-of-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarize the present state-of-the-art of this particular combination in NSCLC.     

Recent improvement in the survival of patients with advanced nonsmall cell lung cancer enrolled in phase III trials of first-line, systemic chemotherapy

BACKGROUND: Few studies have assessed formally whether treatment outcomes have improved substantially over the years for patients with advanced nonsmall cell lung cancer (NSCLC) enrolled in Phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. METHODS: The literature was searched to identify trials that addressed the role of chemotherapy regimens in the first-line setting for the treatment of advanced NSCLC. Trends were tested by using multiple regression analysis. RESULTS: In total, 121 Phase III trials were identified that involved 42,768 patients with 263 chemotherapy arms and 11 best supportive care (BSC) arms, all of which were initiated between 1982 and 2002. Although the number of randomized patients and the proportion of patients with metastatic disease had increased over the years, the number of patients with a poor performance status who were accrued into the trials had decreased. Cisplatin-based chemotherapy was been investigated most frequently during the period. The multiple regression analysis revealed a significant improvement in median survival and in the median time to disease progression over the years, with annual prolongations of 0.1203 months (3.609 days) and 0.0617 months (1.851 days), respectively (P< .0001 and P < .0130, respectively). In addition, the use of cisplatin and carboplatin was associated significantly with survival prolongation. The median survival for patients who received BSC also increased progressively over the years (P = .0487). CONCLUSIONS: The survival of patients with NSCLC in Phase III trials improved slowly but steadily over time, although the main factors responsible for this improvement remain unknown. Nonetheless, the current results also suggested that novel targets and new agents will be required in the future fight against advanced NSCLC.     

Biological Agents in Non-small Cell Lung Cancer: A Review of Recent Advances and Clinical Results with a Focus on Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor

Despite improvements in conventional therapy for non-small cell lung cancer (NSCLC) with surgery, radiotherapy, and cytotoxic chemotherapy, survival remains poor and further improvements are needed. Targeted therapy with biologic agents offers a novel treatment strategy. In the first-line treatment of advanced disease, the most promising results to date have been reported with bevacizumab [an antivascular endothelial growth factor (anti-VEGF) antibody] plus chemotherapy, with significant improvement in survival, compared with chemotherapy alone, in a selected population of patients with nonsquamous histology. Trials incorporating epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors with chemotherapy failed to produce a survival benefit. Nevertheless, cetuximab (an anti-EGFR IgG1 monoclonal antibody) plus chemotherapy has shown promising results in initial studies and continues to be evaluated in larger trials. The benefits of EGFR and VEGF inhibitors in advanced disease have propelled them into evaluation in early stages of NSCLC. Integration of these agents into bi- and tri-modality treatments is currently under investigation in these settings. Finally, emerging data combining EGFR and VEGF inhibitors suggest that multiple pathway inhibition may be more effective than targeting a single pathway.     

Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer

Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcinoma histology, with manageable toxicity. Here, we present an analytical review of literature regarding nintedanib and we focus on its particular importance in NSCLC treatment.     

Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; Systematic review and comparison with a surgical cohort

Background and purpose

To assess the efficacy of stereotactic ablative radiotherapy (SABR) for the treatment of non-small cell lung cancer (NSCLC) through a systematic review of all relevant publications from 2006 to the present compared to controls treated with surgery. In the absence of Grade I evidence, the objective outcome data should form the basis for planning future studies and commissioning SABR services.

Materials and methods

Standard systematic review methodology extracting patient and disease characteristics, treatment and outcome data from published articles reporting patient data from populations of 20 or more Stage I NSCLC patients treated with SABR with a median follow up of minimum of 1 year. The individual outcome measures were corrected for stage and summary weighted outcome data were compared to outcome data from a large International Association for the Study of Lung Cancer (IASLC) cohort matched for stage of disease with survival as the principal endpoint and local control (local progression free survival – local PFS) as the secondary endpoint.

Results

Forty-five reports containing 3771 patients treated with SABR for NSCLC were identified that fulfilled the selection criteria; both survival and staging data were reported in 3171 patients. The 2 year survival of the 3201 patients with localized stage I NSCLC treated with SABR was 70% (95% CI: 67–72%) with a 2 year local control of 91% (95% CI: 90–93%). This was compared to a 68% (95% CI: 66–70) 2 year survival of 2038 stage I patients treated with surgery. There was no survival or local PFS difference with different radiotherapy technologies used for SABR.

Conclusions

Systematic review of a large cohort of patients with stage I NSCLC treated with SABR suggests that survival outcome in the short and medium term is equivalent to surgery for this population of patients regardless of co-morbidity. As selection bias cannot be assessed from the published reports and treatment related morbidity data are limited, a direct comparison between the two treatment approaches should be a priority. In the meantime, SABR can be offered to stage I patients with NSCLC as an alternative to surgery.     

吉西他滨治疗晚期非小细胞肺癌的现状

吉西他滨是近年来治疗晚期非小细胞肺癌的有效新药。国外大量临床试验已经证实其单一用药有效率稳定在20%以上,中位生存34周,可明显改善肿瘤相关症状,毒性易耐受,本文综述吉西他滨治疗晚期非小细胞肺癌的临床结果。     

Targeting Angiogenesis with Multitargeted Tyrosine Kinase Inhibitors in the Treatment of Non‐Small Cell Lung Cancer

It has been >35 years since the link between angiogenesis and the growth of tumors was first reported. Targeting angiogenesis became feasible with the availability of bevacizumab, an anti–vascular endothelial growth factor monoclonal antibody. Initial studies revealed that the combination of bevacizumab and chemotherapy led to longer overall survival times than with chemotherapy alone in patients with advanced colorectal cancer. Since then, drug development strategies have added small molecule tyrosine kinase inhibitors to the panel of antiangiogenic agents under evaluation; data from numerous trials are now available. The challenge now is to identify the optimal antiangiogenic agent for specific patient groups and to understand not only the mechanistic differences between agents, but also the variability in their antitumor activity across different tumor types and their differing side‐effect profiles. As in other solid tumors, angiogenesis contributes to the development of non‐small cell lung cancer (NSCLC), and this review summarizes the role of angiogenesis in this disease. We review the current developmental status of antiangiogenic tyrosine kinase inhibitors (including vandetanib, sunitinib, axitinib, sorafenib, vatalanib, and pazopanib) in NSCLC and conclude by briefly discussing the need for optimal patient selection and potential future directions.