Although the results for E1505 were negative, “overall survival and disease-free survival are not the only things we can learn from this trial,” said Paul Bunn, Jr, MD, Distinguished Professor in the Division of Medical Oncology at the University of Colorado, Denver, who formally discussed the study. “These investigators made a tremendous effort to conduct a randomized trial with 1,500 patients. We are going to learn a lot from this story,” he said.
For instance, future analyses may help to answer these questions: Was there a difference in any of the chemotherapy doublets in efficacy or toxicity when bevacizumab was present or absent? Is there a potential for a biomarker to emerge for benefit from bevacizumab?
Correlative studies for E1505 will involve proteomic and microarray analysis of tissue; immunohistochemistry staining for vascular endothelial growth factor and intercellular adhesion molecule; and examination of serum, plasma, and whole blood for a number of tumor-related factors.
“This study has the clinical and experimental data to answer questions. We still don’t know who to give antiangiogenic therapy to, and we hope to learn something from this negative trial in the future,” he said.
Comparing Study Designs
Moving forward, Dr. Bunn asked whether large, randomized adjuvant trials are the best approach to these questions. “Is this where we should be putting our money and effort?” The current E1505 study design was developed more than 10 years ago. “Before embarking on future such studies, we should ask whether the findings will even be relevant 10 years later,” he suggested.
Regardless, he noted that many adjuvant trials are underway, mostly studying epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant populations. “My dime says that 5 years from now, we will have another round of negative trials,” he predicted.
Instead, Dr. Bunn proposed that the lung cancer community follow the lead of the breast cancer community and conduct smaller, more short-term neoadjuvant trials. In a recent meta-analysis, neoadjuvant chemotherapy was shown to improve overall survival by an absolute 5% at 5 years (hazard ratio = 0.87, P = .007),1 which was essentially the same benefit shown in the adjuvant LACE trial.2
Neoadjuvant trials could lead to pathologic complete responses in patients (not previously seen) and could hasten drug development, he added, noting that neoadjuvant studies of rociletinib and also the programed cell death ligand 1 (PD-L1) antibody atezolizumab are underway. “In my opinion, this is where we should be going,” Dr. Bunn said. ■
Disclosure: Dr. Bunn has consulted for Amgen, AstraZeneca, Bayer, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, Eli Lilly, GSK, Merck, Novartis, OSI/Genentech/Roche, and Sanofi-Aventis.
References
1. NSCLC Meta-analysis Collaborative Group: Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data. Lancet 383:1561-1571, 2014.
2. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-3559, 2008.
