Integrating biomarkers into clinical trials: methodological issues for a new paradigm in nonsmall cell lung cancer- Introduction

A Special Author Introduction
Current Opinion in Oncology

ISSN: 1040-8746 • Frequency: 6/year • Subscribe Now  

By Gerard Zalcman

Despite recent advances and declining incidence in males in Western countries, lung cancer remains the main cause of cancer deaths worldwide, mainly because of tobacco smoking epidemics, and still moderate efficacy of therapeutic strategies. Stage IV non-small cell lung cancer (NSCLC) is still an incurable disease with a median survival that reached a plateau of 10 months, with available cisplatinum-based regimens. However, some subsets of patients, especially those with adenocarcinoma, benefit at best from some specific drugs, either classical cytotoxics or targeted therapies. The challenge remains to identify those subsets in order to give them the most individualized therapy for the highest survival.

Major advances in understanding NSCLC molecular biology have been made in the first decade of the 21st century. Activation of the Epidermal Growth Factor Receptor (EGFR) pathway was shown to result in signalling cascades that promote tumour growth and progression. These observation provided the rationale for developing small-molecule tyrosine kinase inhibitors (TKIs) targeting EGFR. In lung adenocarcinoma, EGFR mutations are found in around 15% of Caucasian patients, and more than 40% of Asian patients. Inhibiting EGFR signaling using TKIs (gefitinib or erlotinib) was shown to be an effective treatment for patients with tumors exhibiting such EGFR-sensitizing mutations, first in retrospective studies, in which their predictive impact was difficult to distinguish from their prognostic role.  IPASS phase III study then reported the predictive and prognostic impact of EGFR mutations in stage IV patients treated by EFGR tyrosine kinase inhibitor or platin-based chemotherapy, and was further corroborated by several other phase III prospective studies randomizing TKI versus chemo in patients with EGFR mutations.
Large phase III trials have also recently been published in resected early-stage NSCLC, with retrospective studies of biomarkers identifying subset of patients that beneficiated at best of the experimental perioperative strategy. IALT-bio study for instance, reported that ERCC1 and MSH2 DNA-repair proteins had prognostic and predictive implications. Other studies reported on prognostic role of TUBB3 expression in stage I to III NSCLC.

Whereas EGFR mutations studies received prospective validation with trials in which treatment allocation was based on biomarker status, biomarkers predicting chemotherapy (CT) efficacy still need such prospective confirmations either for limited-stage or metastatic NSCLC. Indeed, candidate biomarkers came from retrospective series of patients that only can be hypothesis-generating since many biases were encountered in those recently published studies. Markers of chemotherapy efficacy still need validation studies before coming in routine practice, and prospective clinical trials for such biomarkers are thus needed. Methodological stringent recommendations from the REMARK group should avoid most of the possible pitfalls of these studies and allow clinical applicability of predictive biomarkers to tailor treatment in NSCLC. EGFR mutations have still reached that point and future clinical research efforts will have to focus on biomarkers of chemotherapy efficacy.

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