We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches. —D. Ross Camidge, MD, PhD
A countdown of the top 5 breakthrough therapies in the treatment of advanced lung cancer was presented by D. Ross Camidge, MD, PhD, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Dr. Camidge is Director, Thoracic Oncology Clinical and Clinical Research Programs, and Associate Director for Clinical Research, University of Colorado Comprehensive Cancer Center, Aurora. He is also the Director for the newly minted ATOMIC Lung Cancer Consortium. He chose the following molecular therapies as his top choices for illustrating what the future of Lung cancer treatment will involve:
Dr. Camidge chose crizotinib(Xalkori) as a breakthrough therapy “because of how it has exemplified the philosophy of one size does not fit all,” he said.
#4. Second-Generation ALK Inhibitors
The second-generation ALK inhibitors werechosen “not because of their impressive activity post-crizotinib, but because of their progress in accurately defining how we capture data on benefit in central nervous system (CNS) disease,” Dr. Camidge explained.
#3. Third-Generation EGFR Inhibitors
Dr. Camidge identified the third-generation EGFR inhibitors “because of what they are teaching us about understanding acquired resistance in order to effectively treat it,” he said.
#2. PD-1/PD-L1 Antagonists
Dr. Camidge singled out the inhibitors of programmed death receptor 1 (PD-1) and its ligand (PD-L1) as opening the door to immunotherapy but with the open question of whether they will really be a panacea or whether they have the potential to become a truly personalized medicine.
#1. Three Possible Future Breakthroughs
The number 1 spot was shared by three “mini-fantasies” about what future breakthroughs might be, based on the concepts of mining the past, intraoncogene heterogeneity, and affordable incremental benefit.
Explaining his interest in mining the past, Dr. Camidge said, “We have walked away from a large number of targeted agents because they didn’t work when given to otherwise unselected lung cancer populations. However, in almost all of these cases, no attempt at robustly exploring predictive biomarkers was conducted,” he noted.
“Consequently, the classes of drugs may not truly be ineffective, and there may have been evidence of hypersensitive subpopulations ripe for re-exploration,” he continued. “We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.”
As an example, he cited the class of drugs known as death receptor agonists. These drugs “which directly stimulate apoptosis and worked exceptionally well in various preclinical models, were all dropped when a series of randomized phase II studies adding these agents to first-line chemotherapy failed to show an advantage.” But the nonprogressors in the experimental arms approached 15% of the population in several of the studies, he said. “Unfortunately little or no tissue was collected in these studies so no predictive biomarkers could really be explored at the time.”
Dr. Camidge used KRAS as an example of intraoncogene heterogeneity. The most common mutation among adenocarcinomas of the lung, KRAS has been shown in preclinical and clinical studies to have tremendous heterogeneity. The trial design for the FAK inhibitor VS-6063 in KRAS-mutant lung cancer is “at least starting to address this heterogeneity by exploring its benefit in four KRAS-mutant cohorts that have also been characterized with regard to their INK4a and p53 status to see if these contexts alter the response to the drug, based on relevant preclinical data,” Dr. Camidge said.
To explain affordable incremental benefit, he cited the REVEL study, which looked at the addition of ramucirumab (Cyramza), an antibody against VEGFR2, to standard second-line docetaxel. “The addition of ramucirumab increased the response rate from 14% to 30% and the disease control rate from 53% to 64%, increased the progression free survival from 3.0 to 4.5 months, and increased the overall survival from 9.1 to 10.5 months,” Dr. Camidge reported.
“So with an unequivocally positive phase III study, adding a little to all major endpoints, we might want to be using this drug. But only if it, and drugs like it, are affordable, as one recurring problem has been in pricing a breakthrough as if it’s a game-changer and not just a way of offering a little incremental benefit to everyone.” If not affordable, “these minor breakthroughs will never be practical to use in the real world,” he said.
Disclosures: Dr. Camidge has received honoraria from Pfizer, Genentech/Roche, Clovis, Aria, and Eli Lilly.
Camidge DR: The top five most promising molecular therapies on the horizon. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.
Source/Complete article by Charlotte Bath (The ASCO Post) is available at: http://www.ascopost.com/issues/december-1,-2014/top-5-breakthroughs-in-the-treatment-of-advanced-lung-cancer.aspx
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