December 5, 2012 1 Comment
As I read through the November 10 issue of the Journal of Clinical Oncology there were two very different but highly instructive reports.
They first examined the impact of gemtuzumab ozogamicin for patients with acute myeloid leukemia. The second involved the incorporation of bevacizumab and erlotinib into the treatment of Stage III NSCLC in combination with radiation.
By way of introduction, gemtuzumab ozogamicin (GO) is an anti CD33 antibody linked to the highly toxic chemical calicheamicin. Calicheamicin, a member of enendyne class, is among the most toxic substances known to man. By linking this poison to an antibody directed against leukemia cells, it was reasoned that this novel conjugant would provide an effective therapy for leukemia. And indeed it did. But despite compelling science and what appeared to be initially good results (particularly in older patients with AML), and FDA approval for the agent, the drug was withdrawn from the market. Now, with the publication of a new study from the United Kingdom, GO is once again in the limelight as its inclusion in induction therapy resulted in a statistically significant three-year relapse-free survival advantage (p=.0007) and three year overall survival advantage (p=.05).
It appears, with regard to GO, that the clinical trial process failed to identify the clinical utility of an active and novel form of therapy for a potentially lethal disease.
The second article of interest regards a pilot study that incorporated an anti-VGEF antibody (bevacizumab) with EGFR TKI (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.
While these two reports are very different, they represent similar failings of the contemporary clinical trial process. The GO experience reflects the failure to identify efficacy due to contemporary clinical trial’s dilution of the benefit in select candidates, mixed in the overall population, with limited responsiveness to the agent. The second trial represents clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens.
On one hand, laboratory models that accurately identify responders can segregate those most likely to benefit from those who will not. GO represents just one of many interesting new classes of drugs for whom selective methodologies could prove highly valuable. The 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 in our laboratory for more than a decade. For example, we observed antagonism between platins and the EGFR antagonists (gefitinib and 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 we successfully identified favorable interactions between erlotinib and VGEF inhibitors in individual patients that have provided durable responses in our 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.