The Meaning of Meaningful Improvement in Lung Cancer

When asked to define what constituted pornography in his 1964 Supreme Court decision (Jacobellis versus Ohio 1964) Justice Potter Stewart stated, “I know it when I see it.” When I reviewed an article on the changing landscape of clinical trials in non-small cell lung cancer (NSCLC) (Shifting patterns in the interpretation of phase 3 clinical trial outcomes in advanced non-small cell lung cancer: The bar is dropping, Sacher A. G. et al, J Clin Oncol May 10, 2014), Justice Stewart came to mind.

The authors selected 203 NSCLC trials from a total of 245 studies conducted between 1980 and 2010. They compared how often the studies met their endpoints with how often the study authors’ called the results “positive.” Among the findings, it seems that earlier studies (before the year 2000) were geared for overall survival, while later studies (after 2000) overwhelmingly favored progression free survival. Although patient survivals changed little, the number of trials reported as successful increased dramatically.

Non-small cell lung cancer

Non-small cell lung cancer

Progression-free survival measures how long it takes for a patient to fail treatment. That is, for the disease to worsen on therapy. Its use increased after 2000 when Docetaxel, for the first time, provided a survival advantage in recurrent disease.

The FDA’s willingness to accept progression-free survival for drug approval was originally based on their expectation that the benefit would be “substantial and robust” but they did not define the term. One group has suggested that improvements should be of the magnitude of 50 percent. Another went even further suggesting a doubling of the survival advantage.

Unfortunately, the trend has been just the opposite. Trials from the 1980s on average gave a 3.9 month improvement, which fell to a meager 0.9 months after 2000.

What are patients and their physicians to make of these trends? First, the large clinical trials, that are so common today, are much more likely to achieve significance. The troubling corollary is that statistical significance is not the same as clinical relevance. The “publish or perish” climate, combined with the skyrocketing cost of drug development has placed inordinate demands upon investigators and their sponsors to achieve “positive results.” Fearing failure, many pharmaceutical companies sponsor “safe” trials that provide incremental advances but few breakthroughs.

Meaningful advances in oncology are generally quite evident. The first use of Interferon alpha for the treatment of hairy cell leukemia provided a response rate of 100 percent and earned a lead article in the New England Journal of Medicine (NEJM) with only seven patients!

Similarly the 57 percent response rate for Crizotinib in ALK positive lung cancer required only 82 patients for a place in the NEJM. Unfortunately, the failure of contemporary investigators to identify more “paradigm changing therapies” has forced many to lower the bar.

The clear solution to the problem is the better selection of candidates for therapy. Despite advances in molecular biopsy a paucity of truly effective companion diagnostics exist. Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients.

While we expand our armamentarium and develop better companion diagnostics, today we can apply measures of cellular response (as found in an EVA-PCD assay)
that capture all of operative mechanisms of sensitivity for all classes of drugs. While it is not always possible to know why a patient will respond, it is possible to know that they will respond. In the words of Judge Stewart, when it comes to a responsive lung cancer patient “I know it when I see it.”

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

6 Responses to The Meaning of Meaningful Improvement in Lung Cancer

  1. Dr. Nagourney,

    Are the reports on Nivolumab as treatment for NSLC cause for near term hope or to be viewed with restraint. The drug appears to have been fast tracked, but reports have gone from relatively optimistic to less so in the last year or so.

    Bristol-Myers Squibb statistical data:

    http://web1.pharmiweb.com/PressReleases/pressrel.asp?ROW_ID=75203#.U4f9rBtOUc8

    Positive report in BusinessWeek Oct 2013:

    http://www.businessweek.com/ap/2013-10-28/bristol-myers-rises-on-new-data-for-cancer-drug

    More restrained report in Business Week May 15, 2014:

    http://www.businessweek.com/ap/2014-05-15/bristol-myers-slumps-on-cancer-drug-study-data

    Thanks for you continuing reports on the subject.

    • robert nagourney says:

      Paul,

      The PD-1 and PDL-1 work is extremely exciting and extremely important. It is a legitimate breakthrough and will be an important modality for treatment.

  2. James says:

    Dr. Nagourney,

    In your post you said, “Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients.”

    This my dilemma. I have NSCLC testing positive for the KRAS mutation, codon 12, (p.G12D, c.35G>A). Based on my research it appears the best cocktails tested thus far are getting response rates of 5% or less. Consequently, I have refused chemotherapy for 2 years. When a CT recently revealed progression from 4.9cm to 5.9cm over these 2 years, I requested and am receiving palliative shrinking of the tumor with radiation. All I have been offered are randomized clinical trials until recently, when an oncologist proposed the “standard chemo regimen” he starts with for NSCLC, He also said, “I don’t know why they’re still testing for KRAS,” which left me at a loss.

    My hope is that shrinking my tumor may give me another 2 years to look/wait for a more targeted approach.

    Do you have any thoughts on this?

    • James,

      I share your frustration. The 800 pound gorilla in the cancer research living room is RAS. Your physician is articulating a common thread, “as there is no treatment for RAS(+) tumors, why test for it?” Frank McCormick, PhD at UCSF is heading up a national task force on the topic. Unfortunately we are still only nibbling around the edges of this big problem.

      Nonetheless, downstream signals can in some instances be interrupted (mTOR, MEK, etc) with available small molecules and a not insubstantial percentage of RAS(+) NSCLC respond to conventional chemotherapy. We have experience testing some of these hypotheses and would be happy to help if we can be of assistance.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Follow

Get every new post delivered to your Inbox.

Join 117 other followers

%d bloggers like this: