The November 10, 2012 issue of the Journal of Clinical Oncology published a highly instructive report on the incorporation of Avastin (bevacizumab) and Tarceva (erlotinib) into the treatment of Stage III NSCLC in combination with radiation for the treatment.
The article regarded a pilot study that incorporated an anti-VEGF antibody Avastin (bevacizumab) with EGFR TKI Tarceva (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced.
The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.
According to Dr. Robert A. Nagourney of Rational Therapeutics, the trial represented clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens. This lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.
Combinations of chemotherapy with target therapies have been the subject of investigation at Rational Therapeutics in Long Beach, California for more than a decade. For example, they observed antagonism between platins and the EGFR antagonists Iressa (gefitinib) and Tarceva (erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.
All four of these trials combined platin based doublets with EGF-TKI’s. More recently Rational Therapeutics successfully identified favorable interactions between Tarceva (erlotinib) and VEGF inhibitors in individual patients that have provided durable responses in their NSCLC patients as first line therapy, now out to four and five years since diagnosis.
These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures. In the recent JCO, a good treatment was missed while a bad treatment was advanced.
Functional profiling through use of the EVA-PCD assay may represent the critical path from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.
Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial
http://jco.ascopubs.org/content/30/32/3953.abstract