Targeting the PD-1/PD-L1 axis in non–small cell lung cancer

The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non–small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting; however, nivolumab failed to show a survival benefit possibly relating to patient selection based on PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research focuses on the development of PD-1 and PD-L1 inhibitor monotherapy in neoadjuvant and adjuvant NSCLC. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities including cytotoxic chemotherapies in the first-line NSCLC, other immunotherapies such as cytotoxic T-lymphocyte–associated protein 4 antagonists, molecularly targeted agents including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest owing to the potential for the abscopal effect, using radiotherapy to facilitate systemic treatment.     

FDA analyses of survival in older adults with metastatic non–small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies

Background

Among patients with newly diagnosed non–small cell lung cancer (NSCLC), approximately 70% occur in those above 65 years of age and more than half are metastatic or locally advanced NSCLC.

Therapeutic revolution for inoperable stage Ⅲ non-small cell lung cancer in the immune era

<正>The PACIFIC study ushered in a “tsunami-like” therapeutic revolution for stage Ⅲ inoperable non-small cell lung cancer(NSCLC) In the past, chemoradiotherapy(CRT) has been the standard of care for inoperable stage Ⅲ NSCLC. Concurrent chemoradiotherapy(cCRT), if tolerable in patients, is the optimal treatment regimen.     

Targeted therapy in non-small cell lung cancer

Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes, giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human     

Gemcitabine (Gemzar®) in non-small cell lung cancer

Of the new chemotherapeutic substances of the last decade, gemcitabine (Gemzar^®, Eli Lilly) is probably the most valuable for the treatment of early and advanced stage non-small cell lung cancer (NSCLC). When used as a single agent in both chemotherapeutically pretreated and chemotherapy-naive patients, gemcitabine shows an objective tumor regression rate of approximately 20%. Gemcitabine’s unique mechanism of action and its lack of overlapping toxicity with other cytotoxic agents also define it as an ideal candidate for combination therapy. Early clinical development has included single-agent first- and second-line treatment, doublet combination regimens and incorporation into multimodality treatment strategies for operable and inoperable locally advanced nonmetastatic NSCLC. Gemcitabine/platinum-based combination chemotherapy has become the most attractive treatment standard for NSCLC patients in good clinical condition. The role of gemcitabine in the concurrent or sequential application of chemo- and radiotherapy for inoperable locally advanced NSCLC has also been addressed in several Phase I and II studies. Based on data available, gemcitabine can be safely administered in combination with radiotherapy. This review summarizes results from representative Phase I, II and III studies in order to underline gemcitabine’s clinical importance for patients suffering from early and advanced NSCLC.     

SUVmax during 18FDG-PET scanning in small cell lung cancer: similar information as in non-small cell lung cancer?

In patients with non-small cell lung carcinoma (NSCLC) fluorine-18 fluorodeoxyglucose positron emission tomography (18FDG-PET)-scanning is shown to be of prognostic value. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis. Limited results on the prognostic and predictive value of the maximum standard uptake values (SUVmax) obtained during 18FDG-PET scanning in SCLC are available. An observational study in 75 chemonaive patients diagnosed with SCLC who underwent a 18FDG-PET scan was performed. SUVmax values of the primary tumor were related to the overall survival (OS) and the progression free survival (PFS). Significant lower SUVmax values of the primary tumor were observed in patients with stage I-III disease compared to stage IV disease. SUVmax did not discriminate for either OS or PFS in the whole group of patients. In patients with stage IV disease and treatment with chemotherapy, OS and PFS were significantly higher in patients with a high SUVmax. (p-value 0.005 and 0.002 respectively) compared to patients with a low SUVmax value. In patients with SCLC metabolic activity determined using 18FDG-PET (SUVmax) differed between stage I-III and stage IV diseases. Compared to NSCLC, the relationship between SUVmax) and prognosis seems more complex.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar^®), vinorelbine (Navelbine^®) and irinotecan (Campto^®), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20–30% and 1-year survival rates of 30–40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-α. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Radiotherapy for stage I–II non-small cell lung cancer

Background. Surgery has been regarded as the standard treatment for patients with non-small cell lung cancer in the early stage, while radiotherapy has become an effective alternative for medically inoperable patients and those who refuse surgery. Methods. We reviewed the records of 31 patients with stage I–II non-small cell lung cancer treated by radiotherapy between 1980 and 1997. There were 15 patients in stage I and 16 in stage II. The variables analyzed for influence on cause-specific survival and loco-regional control were: age, performance status, clinical stage, tumor size, tumor site, radiation field, radiation dose, and combination with chemotherapy. Results. The overall and cause-specific 1-, 2-, 3-, and 5-years survival rates were 71% and 77%; 63% and 73%; 34% and 48%; and 17% and 32%, respectively. Five-year survival rate for patients with peripheral tumor in the lung was 72%, with 70% loco-regional control, while the 5-year survival rate of patients whose tumor originated in the central region was 20%, with 25% loco-regional control. These differences had marginal significance on univariate analysis (P = 0.07), but only tumor site (central vs peripheral ) showed marginal significant influence on cause-specific survival (P = 0.08) and loco-regional control (P = 0.07) on multivariate analysis. There were no fatal complications, including radiation-induced myelopathy. Conclusion. The present series showed satisfactory results with definitive radiotherapy for patients with medically inoperable stage I–II non-small cell lung cancer, with results similar to those in recent reports of radiotherapy. The only significant variable was that patients with peripheral tumors had a better prognosis than patients with central tumors. Received: March 26, 1999 / Accepted: August 9, 1999     

Chemotherapy in non-small cell lung cancer：opportunities for advancement

Locally advanced non-small cell lung cancer (NSCLC) continues to be a challenging disease to treat. With high rates of both local and distant failures, there is significant interest in finding more biologically active chemotherapy regimens that can contribute to reduce both failures. The phase III PROCLAIM trial, recently published in the Journal of Clinical Oncology entitled“PROCLAIM: randomized phase III trial of pemetrexed–cisplatin or etoposide–cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer”, compared two different chemotherapy regimens given concurrently with radiotherapy in patients with stage III non-squamous lung cancer: pemetrexed plus cisplatin versus cisplatin plus etoposide. Both groups received con-solidation chemotherapy. After enrolling 598 of planned 600 patients, the study was stopped early due to futility as no difference was seen in the primary end-point of overall survival. Since PROCLAIM was designed as a superiority trial, these results suggest that pemetrexed regimens do not offer a clinical advantage over standard cisplatin plus etopo-side. There are some subpopulations who might still benefit from pemetrexed, especially if clinicians are concerned about myelosuppression-related adverse events. Future trials are needed to investigate novel biologic agents and irradiation techniques that can result in more durable local and distant disease control in locally advanced NSCLC.     

Optimal mediastinal staging in non-small cell lung cancer: What is the role of TEMLA and VAMLA?

Objectives

The aim of this review is to present the current role of two techniques of extensive mediastinal dissection, in the staging of lung cancer.

Materials and methods

The authors performed a search for original papers published in English language, peer-reviewed journals.

Results

According to the published evidence, definitions of VAMLA and TEMLA are given and the main elements of the operative technique are briefly presented. Extensiveness and completeness of mediastinal lymph node dissection using these techniques, their diagnostic yield as well as complications and use of hospital resources are discussed. The role of VAMLA and TEMLA in the contemporary staging of lung cancer is presented in context of other staging techniques and the current clinical practice guidelines.

Conclusion

On the basis of the evidence currently available, it may be concluded that VAMLA and TEMLA have no contemporarily use in the routine mediastinal staging of lung cancer. This is because of their invasiveness and – at least for TEMLA – high risk of complications and mortality, which renders it unacceptable as a diagnostic procedure, and also due to the development of equally accurate, but far less invasive techniques, i.e. EBUS-NA and EUS-NA.     

T-regulatory cell modulation: the future of cancer immunotherapy?

T-regulatory cells suppress anti-tumour immunity in cancer patients and in murine tumour models. Furthermore, their activity is likely to have an effect on the effectiveness of immunotherapeutic treatments for cancer. Here we describe the current status of developing clinical strategies for modulating Treg activity in cancer patients.