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


early-stage NSCLC. Proteomic signatures still need validation using prospective studies.


Prospective Clinical Trials Using Biomarkers to Predict Utility of Adjuvant Therapy Cancer and Leukemia Group B 30506 Trial The Cancer and leukemia group B (CALGB) 30506 trial is a randomised phase III trial to determine the potential overall survival benefit of adjuvant chemotherapy in patients with NSCLC of 2–7cm without nodal involvement randomised to chemotherapy compared with observation (see Figure 1). Patients in the trial will be randomised to observation or to three cisplatin-doublet chemotherapies. High-quality fresh frozen lung cancer tumour tissue will be collected and processed from multiple institutions for gene expression array generation. The primary objective is to determine whether any gene expression patterns can be correlated with the effect of adjuvant chemotherapy for overall survival. Other biomarkers are also being investigated.


Southwest Oncology Group S0720 Trial The Southwest Oncology Group (SWOG) S0720 is a phase II clinical trial using the expression of ERCC1 and RRM1 to determine adjuvant therapy in patients with stage IA or IB NSCLC (see Figure 2). After surgery patients are assigned to one of two arms based on RRM1 and ERCC1 gene expression analysed using automated quantitative analysis (AQUA) technology. Arm I includes patients who have high RRM1 and ERCC1 expression who will be observed post-operatively. Arm II includes patients who have low RRM1 and ERCC1 expression who will receive gemcitabine and cisplatin for four cycles. The primary objective is to assess the feasibility of assigning adjuvant treatment based on tumoural RRM1 and ERCC1 gene expression and to estimate the two-year disease-free survival of these patients. The trial will also to explore the relationship between RNA and RRM1 and ERCC1 protein expression, and the relationship between RRM1 and ERCC1 expression in the formalin-fixed and paraffin-embedded tumour specimens.


Eastern Cooperative Oncology Group 1505 Trial The Eastern Cooperative Oncology Group (ECOG) 4599 and Avastin in lung cancer (AVAiL) phase III clinical trials for patients with advanced NSCLC demonstrated a benefit from the addition of bevacizumab to first-line chemotherapy.46–48


Based on these positive results in


advanced NSCLC, the ECOG 1505 trial is an ongoing clinical trial to investigate the role of bevacizumab in the adjuvant setting for patients with resected stage IB (at least 4cm in size) to IIIA NSCLC (see Figure 3). The trial is not based on any biomarkers for enrolment stratification because none have been validated for the antivascular endothelial growth factor treatment strategies, but extensive correlates are planned and all patients will have tumour tissue collected and blood drawn and banked from multiple time-points.


Melanoma-associated Antigen 3 Adjuvant Non-small-cell Lung Cancer Immunotherapy Trial The role of vaccines in NSCLC is as yet unproven and remains an area of active investigation. Melanoma-associated antigen 3 (MAGE-A3) is a tumour antigen in 30–50% of resected lung cancers. The MAGE-A3 adjuvant NSCLC immunotherapy trial (MAGRIT) is investigating the use of the MAGE-A3 vaccine in patients with completely resected stage IB, II and IIIA NSCLC that express the MAGE-A3 antigen (see Figure 4). The target accrual is 2,270 patients to find over 1,400 who will be eligible for the vaccination based on MAGE-A3 expression. The vaccination will be given 13 times over 27 months. Patients will be followed every


EUROPEAN ONCOLOGY & HAEMATOLOGY


High TS Low TS


High ERCC1


Eligible: n=700


Resected II-IIIA


No prior chemotherapy No prior XRT


Stratified: • ERCC1 and


TS levels by IHC and qPCR • Adjuvant chemotherapy


Low ERCC1


High TS Low TS


Cisplatin/pemetrexed x 4 cycles


Control* x 4 cycles


Primary end-point: overall survival. *Control = Investigator choice of a Cisplatin- based doublet.


ITACA = International tailored chemotherapy adjuvant trial; mRNA = messenger RNA; qPCR = quantitative PCR; TS = thymidylate synthase; XRT = radiotherapy.


113


Pemetrexed x 4 cycles


Control* x 4 cycles


Cisplatin/gemcitabine x 4 cycles


Control* x 4 cycles


Figure 6: TASTE Trial Overview


Eligible: n=108


Resected II–IIIA non-N2


Histology other than squamous cell


Cisplatin/pemetrexed x 4 cycles


Stratified:


• ERCC1 levels • EGFR status • Chemotherapy regimen


Randomised


EGFR mutant EGFR wild-type


High ERCC1 Low ERCC1


Erlotinib 150mg PO every day x 1 year


Observation


Cisplatin/ pemetrexed x 4 cycles


Primary end-point: feasibility followed by disease-free survival. EGFR = epidermal growth factor receptor; PO = orally; TASTE = Tailored post-surgical therapy in early stage NSCLC.


Figure 7: SCAT Trial Overview


Eligible: n=432


Resected II–IIIA


No prior chemotherapy No prior XRT


Cisplatin/docetaxel x 4 cycles


Stratified:


• BRCA mRNA • Adjuvant chemotherapy


High BRCA1 Medium BRCA1 Low BRCA1


Randomised


Docetaxel 4 x cycles


Cisplatin/docetaxel x 4 cycles


Cisplatin/ gemcitabine x 4 cycles


Primary end-point: overall survival.


BRCA1 = Breast cancer 1; mRNA = messenger RNA; SCAT = Spanish customised adjuvant trial; XRT = radiotherapy.


Figure 8: ITACA Trial Overview


Taxane x 4 cycles


Control* x 4 cycles


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