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.1 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 singled out the following molecular therapies:
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.
“Before the phase I study, preclinical work had already clarified that crizotinib had particular activity only in some cell lines, which could be characterized by their evidence of either MET or ALK activation,” Dr. Camidge stated. Clinical trial results showing overall response rates exceeding 60% among patients with ALK-positive non–small cell lung cancer (NSCLC) “led to the initial licensing of crizotinib and the defining of ALK-positive lung cancer as a clinically relevant subtype of disease,” he added.
This was followed by publication a few months ago of the ROS1-positive lung cancer cohort data “showing equally impressive efficacy,” Dr. Camidge noted. “And at this year’s ASCO Annual Meeting, we saw data for the first time on crizotinib’s activity in the MET-amplified lung cancer cohorts showing a 67% response rate and a median duration of response of over a year in the highest amplified cohort.”
#4. Second-Generation ALK Inhibitors
The second-generation ALK inhibitors were chosen “not because of their activity postcrizotinib, but because of their progress in accurately defining how we capture data on benefit in central nervous system (CNS) disease,” Dr. Camidge explained.
The benefit of crizotinib in the central nervous system is limited, Dr. Camidge noted. “Patients with ALK-positive disease who receive or never receive crizotinib have very similar lifetime incidences of brain metastases; nearly 50% of patients on crizotinib have a first progression within the brain, with it being the sole site of progression in most cases,” he said.
Second-generation ALK inhibitors shown to be clinically active following an initial tyrosine kinase inhibitor include ceritinib (Zykadia), which has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with metastatic NSCLC, and alectinib and AP26113, which have both received Breakthrough Therapy designations from the FDA for use in patients with metastatic NSCLC who have had disease progression on crizotinib. Magnetic resonance imaging (MRI) has shown responses of CNS lesions occurring with second-generation ALK inhibitors, but Dr. Camidge cautioned that hard data are still lacking on the proportion of patients with CNS responses to these newer agents and the duration of the responses.
“The good news is that the brain is now achieving appropriate recognition as a relevant battleground, and robust CNS data are now being generated prospectively,” Dr. Camidge said. The ongoing ALEX study is “comparing alectinib head-to-head with crizotinib in the [tyrosine kinase inhibitor]–naive setting, with time to CNS progression as a prominent secondary endpoint in the study,” he reported.
#3. Third-Generation EGFR Inhibitors
Dr. Camidge chose the third-generation EGFR inhibitors “because of what they are teaching us about understanding acquired resistance in order to effectively treat it,” he said.
“From multiple elegant rebiopsy series we know that the T790M exon 20 mutation drives acquired resistance in 50% to 60% of cases. But inhibiting T790M has been a problem,” according to Dr. Camidge. Second-generation drugs “could not achieve tolerable enough levels to inhibit T790M due to their lower IC50 [half maximal inhibitory concentration] for the wild-type form of the EGFR. The third-generation drugs were not screened against the wild-type form of the enzyme, but rather, against the mutant forms present in the cancer,” he said.
“The two most notable third-generation drugs, AZD9291 and CO-1686 (now called rociletinib), both have significant activity against the standard activating EGFR mutations and T790M while relatively sparing the wild-type EGFR.” Both rociletinib and AZD9291 “are now showing robust response rates in known T790M-positive disease,” Dr. Camidge added, with skin and gut toxicity appearing to be significantly less than with earlier generation drugs.
#2. PD-1/PD-L1 Antagonists
Dr. Camidge singled out the inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1) with the open question of whether they will be a panacea or whether they have the potential to become a truly personalized medicine.
“From the earliest nivolumab data it was clear that responses could be very long lasting in lung cancer, but benefit doesn’t occur in everyone,” Dr. Camidge said. Objective response rates have been relatively modest and progression-free survival short. Low median progression-free survival has also been seen with pembrolizumab (Keytruda) in the pretreated population, although treatment-naive patients may do well. The rate of response to MPDL3280A has been higher among those with a smoking history and among those with specific mutations. “Who exactly is deriving benefit from these agents and why remain a work in progress,” Dr. Camidge stated.
“Perhaps the biggest challenge to the idea of PD-1/PD-L1 inhibitors as a panacea is the recognition that the PD-1/PD-L1 axis is only one of multiple immune stimulatory and inhibitory pathways that will be exploited as drug targets in the next few years,” he added. The excitement about PD-1 and PD-L1 inhibitors needs to be tempered “with the reality that they don’t work in everyone, and many new immune modulatory agents are on the horizon, suggesting the one-size-does-not-fit-all philosophy will also extend into the realm of immunotherapies.”
#1. Three Possible Future Breakthroughs
Dr. Camidge’s 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, Dr. Camidge 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. ■
Disclosure: Dr. Camidge has received honoraria from Pfizer, Genentech/Roche, Clovis, Aria, and Eli Lilly.
1. Camidge DR: The top five most promising molecular therapies on the horizon. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.