Benjamin Besse

2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response.

In the genomics era, our main goal should be to identify large and meaningful differences in small, molecularly selected groups of patients. Classical phase I, II and III models for drug development require large resources, limiting the number of experimental agents that can be tested and making the evaluation of targeted agents inefficient. There is an urgent need to streamline the development of new compounds, with the aim of identifying “trials designed to learn”, which could lead to subsequent “trials designed to conclude”. Basket trials are often viewed as parallel phase II trials within the same entity, designed on the basis of a common denominator, which can be a molecular alteration(s). Most basket trials are histology-independent and aberration-specific clinical trials. Umbrella trials are built on a centrally performed molecular portrait and molecularly selected cohorts with matched drugs, and can include patients’ randomisation and strategy validation. Beyond new designs, new end-points and new evaluation techniques are also warranted to finally achieve methodology and clinical improvements, in particular within immunotherapy trials.

The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: The case of the Institut Gustave Roussy

Research with high throughput technologies has propitiated the segmentation of different types of tumors into very small subgroups characterized by the presence of very rare molecular alterations.

KRAS oncogene in lung cancer: focus on molecularly driven clinical trials

KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp

Management of Extensive Small-Cell Lung Cancer

The treatment of patients with extensive SCLC still remains palliative. In this setting, it is highly important to include patients in clinical trials that evaluate new drugs. For patients who can not be included in trials, the treatment should be tailored according to performance status and patients’ wishes. Three options can be discussed: a four-drug combination when performance status is unaltered, a standard etoposide/cisplatin regimen when there is a minimal alteration of performance status, and when the patient asks for a good quality of life. The combination of carboplatin and etoposide should be given only to patients who present an important performance status alteration or a contraindication to a standard chemotherapy.