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Randomized Prospective Biomarker Trial of ERCC1 for Comparing Platinum and Nonplatinum Therapy in Advanced Non–Small-Cell Lung Cancer: ERCC1 Trial (ET)

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posted on 2019-09-18, 13:45 authored by SM Lee, M Falzon, F Blackhall, J Spicer, M Nicolson, A Chaudhuri, G Middleton, S Ahmed, J Hicks, B Crosse, M Napier, JM Singer, D Ferry, C Lewanski, M Forster, S-A Rolls, A Capitanio, R Rudd, N Iles, Y Ngai, M Gandy, R Lillywhite, A Hackshaw
Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non–small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 (P = .32), and XPF, 1.08 (P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.


Supported by Eli Lilly and sponsored by University College London (endorsed by Cancer Research UK, C1438/A9947, with S.M.L. supported by the University College London/University College London Hospitals Biomedical Research Centre). Eli Lilly also provided free pemetrexed. Aprepitant (Emend) was provided by Merck Sharpe & Dohme. Eli Lilly and Merck Sharpe & Dohme had no role in the study design, data collection, data analysis, data interpretation, or report writing, although they saw a draft of the paper.



Journal of Clinical Oncology, 2017, 35 (4), pp. 402-411

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European Society for Medical Oncology 2014 Congress, Madrid, Spain


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