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The Role of Chemotherapy and Predictive Markers in Early-stage Non-small-cell Lung Cancer


in patients with early-stage NSCLC who had only undergone resection with no adjuvant chemotherapy.20


In this study, patients with high


RRM1 expression had a median disease-free survival exceeding 120 months compared with patients with low RRM1 expression who had a median survival of 54.5 months (HR for disease progression or death in the high expression group, 0.46; p=0.004). The overall survival was more than 120 months for patients with tumours with high levels of RRM1 expression and 60.2 months for those with low levels of RRM1 expression (HR for death, 0.61; p=0.02).


RRM1 is the molecular target of gemcitabine and high levels of RRM1 have been linked to gemcitabine-resistance in advanced NSCLC. A small prospective phase II clinical trial in patients with locally advanced, non-resectable NSCLC revealed that RRM1 expression was significantly (p=0.002) and inversely correlated (r = -0.498) with disease response to platinum plus gemcitabine.21


A randomised phase III trial of 170 patients


who received either gemcitabine versus gemcitabine plus carboplatin revealed that low RRM1 and ERCC1 expression was significantly correlated with disease response (r = -0.41; p=0.001 for RRM1; r = -0.39; p=0.003 for ERCC1). A model for response prediction that included RRM1, ERCC1 and the treatment arm was highly predictive of the treatment response observed (p=0.0005). RRM1 expression appears to correlate with ERCC1 expression (p<0.001) in both early- and late-stage NSCLC and improves the prognostic utility.17,19


The SWOG S0720 trial


listed below will use the levels of both RRM1 and ERCC1 expression in patients with resected stage I NSCLC to determine whether or not they should receive cisplatin plus gemcitabine as adjuvant chemotherapy versus observation.


Epidermal Growth Factor Receptor


The utility of single-agent tyrosine kinase inhibitors (TKIs) as first-line therapy in patients with advanced NSCLC (stage IIIB or IV) was demonstrated in the Iressa pan Asia study (IPASS) trial. IPASS was a phase III study that randomised never/light ex-smoking Asian patients who had never received therapy to receive either gefitinib or carboplatin/paclitaxel. It demonstrated a significant progression-free survival benefit for the gefitinib arm (HR = 0.74; p<0.0001).22


This


Another TKI, erlotinib, was originally approved for second- or third-line monotherapy in advanced NSCLC after a randomised, placebo-controlled, phase III study (BR.21) demonstrated an increase in survival for these patients from 4.7 to 6.7 months.24


revealed that in carefully selected patients with advanced disease, gefitinib may be superior to chemotherapy. By contrast, a phase III trial using gefitinib (Iressa survival evaluation in lung cancer [ISEL] trial) as second- or third-line therapy in patients with advanced NSCLC did not reveal a statistical advantage over placebo in an unselected population.23


Following on from the mixed success of the use of TKIs as a therapy in patients with advanced NSCLC, their use in maintenance and adjuvant therapies was tested. The SWOG 0023 trial enrolled unresectable stage III NSCLC patients to evaluate gefitinib as a maintenance therapy following definitive concurrent cisplatin/etoposide and consolidative docetaxel.25


High RRM1 or high ERCC1


Eligible: n=55


Resected IA–IB (IA ≥2cm)


Stratified:


• RRM1 expression • ERCC1 expression


Low RRM1 or low ERCC1


Primary end-point: feasability of pharmacogenomics-based treatment. SWOG = Southwest Oncology Group


showed that KRAS mutation status, epidermal growth factor receptor (EGFR) by fluorescence in situ hybridisation (FISH) or EGFR sensitising mutation status were neither prognostic nor predictive of survival. The focus has now shifted from gefitinib to erlotinib. The Randomised double-blind trial in adjuvant NSCLC with Tarceva® (RADIANT), which requires EGFR overexpression to be detected by IHC, will investigate the role of erlotinib in the adjuvant setting. In addition, there are ongoing non-randomised studies exploring the use of adjuvant erlotinib in patients with EGFR mutations in resected NSCLC (TASTE and Massachusetts General Hospital trials discussed below). Despite the promising results seen with use of the EGFR TKIs as first-line therapy in those with EGFR mutations, their role as adjuvant therapy even in this setting remains investigational.


Although EGFR mutations are being used to predict who will respond to TKIs,26


the utility of evaluating EGFR expression using IHC or FISH analysis is controversial. Although there are data to suggest that increased EGFR copy number detected by FISH predicts responsiveness to antibody therapy, there is no clear predictive value of EGFR FISH for treatment with TKIs.27–30


Although FISH is not being explored in the adjuvant setting, EGFR copy number or increased EGFR expression detected by IHC are undergoing further evaluation in phase III biomarker validation studies for erlotinib (NCCTG-N0723 – closed) and cetuximab (SWOG S0819) in patients with advanced NSCLC.


This trial was a randomised, placebo-controlled trial in an unselected patient population and resulted in an unexpected survival detriment for gefitinib. Owing to the negative gefitinib trials SWOG 0023 and ISEL, the double-blinded, prospective randomised placebo- controlled phase III trial JBR.19 using gefitinib was closed early. This study was designed to investigate the role of adjuvant gefitinib in resected stage IB–IIIA NSCLC. In this under powered study, gefitinib did not improve disease-free and overall survival. Subgroup analysis


EUROPEAN ONCOLOGY & HAEMATOLOGY p53


The mutation or loss of p53 can lead to genomic instability resulting in an aggressive tumour with a poor prognosis. There have been many meta-analyses looking at both p53 protein levels and mutational status as a prognostic marker. In the JBR.10 trial, overexpression of p53 protein detected by IHC was a marker for poor prognosis but the p53 mutational status was not prognostic for survival.31 Overexpression of p53 protein evaluated by IHC predicted survival


111


Chemotherapy/ gemcitabine x4 cycles


Observation


Eligible: n=1,620


Resected stage I–II (≥2 but ≤7cm)


≥Lobectomy


>3 years since last chemotherapy No planned XRT


Stratified:


• ECOG (0 versus 1) • Stage (I versus II) • Chemotherapy regimen:


(Investigator choice) Cisplatin/vinorelbine Cisplatin/docetaxel Cisplatin/gemcitabine Cisplatin/pemetrexed


Primary end-point: overall survival.


CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; XRT = radiotherapy.


Figure 2: SWOG S0207 Trial Overview


Chemotherapy x4 cycles


Randomised Observation Figure 1: CALGB 30506 Trial Overview


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