The rate of our progress in lung cancer and other settings in medicine reaches a bottleneck in the slow rate at which clinical trials are completed.  Nevertheless, only about 3% of patients with cancer in the US participate in clinical trials, and the number is even a little lower for people with lung cancer.   There are many reasons for this: many patients don’t have access to clinical trials without traveling significant distances, and others may object to participating in research (misleadingly sensational magazine covers showing a person in a cage, with a headline titled “Are you a guinea pig?” make me cringe), but another factor is that many patients are simply not eligible for our clinical trials.  Some recent research looked at this question, important for its relevance for the rate of our progress and the generalizability of clinical trial results in a narrow subset to a much broader population of real world patients.

    Dr. Lou Fehrenbacher is a medical oncologist in the large Kaiser Permanente network of Northern California (KPNC) who also conducts a significant amount of important clinical research there.  He and collagues there took advantage of the breadth of this network to capture data on 326 consecutive patients diagnosed with advanced NSCLC just in the first quarter of 2005, comparing them to 196 patients who were enrolled on any of the randomized clinical trials that KP participated in over the preceding 10 years.   They then presented the results on the differences between these two populations at the ASCO 2009 meeting. 

Read the rest of this entry »

    Occasionally at meetings, oncologists are confronted with a marketing study done by the pharmaceutical industry that reveals that something like half of patients diagnosed with lung cancer never receive any treatment.  In fact, epidemiologic studies using the massive Surveillance, Epidemiology, and End-Results (SEER) database suggest that only a minority of patients receive chemotherapy for advanced lung cancer (see here and here for examples).  Most oncologists find it hard to believe that so many people fail to receive a treatment that has a consistently demonstrated survival benefit.  Yet these results are out there.

    Among the potential explanations for a gulf between what we perceive and what the data tell us are that at least the SEER database is linked to Medicare data and therefore represents older patients who may be less likely to receive treatment than younger patients, and also that there is a lag of many years between the data included in SEER and its subsequent reporting, so that the data may be obsolete compared to more current practice.

Read the rest of this entry »

   One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (”whole body”) therapy and chest radiation to all of the visible cancer.  The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.  

   The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients).  So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease.  And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.

   Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects.  Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable.  And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.

Read the rest of this entry »

  I’ll get back to the storyline of our growing understanding of the differences of individuals based on pharmacogenomics very soon.   But I wanted to give people some breaking news that just came out.  The first line ESCAPE trial of chemo with the anti-angiogenic and multi-kinase inhibitor nexavar (introductory post here) or placebo is apparently negative according to a press release, and it even shows a harmful effect of the study drug in patients with squamous cancers, who were included in the trial.

  The trial was designed very similar to the ECOG trial with avastin that led to its subsequent FDA approval.  Over 900 first line, previously untreated patients with advanced NSCLC were randomized to receive standard carbo/taxol chemotherapy IV every three weeks for up to six cycles, with either nexavar (introductory post here) by mouth twice daily or a placebo on the same schedule.  As in the avastin trial, patients who did not progress after six cycles of chemo continued on “maintenance” nexavar or placebo until progression or prohibitive side effects.  The trial design is summarized here:

(Click on image to enlarge) Read the rest of this entry »

   Member Wendy asked me about a drug called picoplatin that I had heard of but really didn’t have much familiarity with.  This gave me an occasion to flesh out some background on this agent, which is being developed as a potential therapy for patients previously treated for lung cancer.  Developed by Poniard Pharmaceuticals in South San Francisco, picoplatin is a variant platinum drug, which cause cell death by binding to DNA and interfering with its ability to make copies and divide, which in turn leads to programmed cell death (a self-destruct program), also known as apoptosis.  It was designed to have a slightly different shape from cisplatin or carboplatin that would make it overcome resistance to these other platinum drugs, and early studies suggest that it has some activity in platinum-pretreated patients, and also a lower risk for kidney damage and neuropathy that can accompany platinum use, particularly cisplatin. 

(Click on image to enlarge) Read the rest of this entry »

    Many of us who work in the field of lung cancer, whether as doctor, patient, friend, or family member, bemoan that lung cancer is too often viewed as a black sheep among cancers – little attention and too few resources.  But one of the key ways in which lung cancer has lagged behind has been in terms of clinical trials participation, and this is something that we can control, and our underperformance (on both the physician and patient side) has hurt the field. 
 
   The field of oncology is used to seeing trials with thousands of patients with breast cancer and colon cancer, to name two other common cancers, and the pace of clinical research in those fields has led to major momentum and rapid advances.  The field of lung cancer has certainly had advances too, but the question is how far we’re falling behind our potential, with 200,000 new cases in the US alone, and with pharmaceutical companies recognizing the size of that market and falling over each other to get their new drugs used in lung cancer.  Despite these factors, the pace of progress in the field is maddeningly slow, in large part because of the slow pace of clinical trial completion that drives our development of new diagnostic and prognostic tools, and of course also new treatments.

    Lung cancer patients make up a far smaller percentage of the clinical trial populations in the US (9% of male patients on cancer trials are on a lung cancer study, and 4.6% of women) than they do overall US cancer patients (14% and 12.6% of cancers in men and women, respectively) (abstract here).  Even more acute is the under-representation of older and sicker patients, as well as minorities.  In many countries, minority patients do poorly compared with Caucasians.  As we learn more about relevant differences among different racial/ethnic groups based on genetic differences in how cancer behaves or treatments work in patient subsets, it becomes increasingly clear that we need to include diverse populations in our lung cancer trials.

   There’s no doubt that there are multiple causes for low trial participation.  Historically, there have been times when there were not interesting clinical trials.  Now there is a broad range of interesting trials, but certainly access is a problem.  Others have done work suggesting that lung cancer patients may feel more hopelessness about changing their plight than people with other cancers (abstract here).  People may see the offer of a clinical trial as a “last resort” and be less inclined to pursue clinical research because of that.  And even among highly proactive and educated participants on OncTalk, 73% of the 107 respondents here who participated on a recent online poll said they would not participate in a placebo-controlled trial that included standard of care treatment (with placebo) on the control arm.  I realize that people would prefer the new agent, but we can only determine the value of a new treatment if we compare it properly to a standard treatment arm. 
 
     I’m certainly interested in people feeling the “guinea pig syndrome” in trying new treatments, but I think that while some people fear the new, for many people the objection to a trial is in not getting the new approach.   Regardless, at the present time some of our problems controlled by investigators/physicians who write protocols that are too restrictive and “cherry picking”, or they don’t prioritize trial options when speaking with patients.   Other obstacles are controlled by patients reluctant to try anything “investigational”, or else unwilling to accept being randomized to a treatment and not receiving the non-standard treatment they have decided is critically important.
 
    But we all need to do better if we’re going to move the field forward and improve our survival results in the next five years compared to the last five years.  Clinical trials, including randomized ones and even placebo-controlled ones, are an important driver of the evolution of our understanding of cancer and its best treatment.

   In my last post I described a new study that will be randomizing previously treated advanced NSCLC patients with a current or prior smoking history to receive either tarceva or a new chemotherapy called pralatrexate.  Now it’s time to provide a little background on this new agent.

   The name pralatrexate may not roll off the tongue, but its full name is just plain painful: 10-propargyl-10-deazaaminopterin.  Mercifully, this is abbreviated PDX, which is what how we’ll refer to it from now on.  It’s one of a class of drugs in the family called antifolates, descendants of the venerable chemo methotrexate, and they work by interfering with the cell’s ability to make purines, one of the building blocks of DNA.  Alimta, with the full name pemetrexed, is a newer member of the antifolate class as well.  A chemical modification on pralatrexate leads to increased cellular uptake and maximal concentrations in cells.  This agent is very effective in lab models of breast or lung cancer cells (references here and here).

   The earliest phase I studies in human cancer patients were done at Memorial Sloan Kettering Cancer Center in NYC, led and reported by Dr. Lee Krug there (abstract here).  The first included 33 patients with advanced NSCLC who had received a median of two lines of prior treatment and then received PDX either weekly or every two weeks by vein.  They were only able to get up to a dose of 30 mg/m2 IV every week (6 patients in total), before being limited by mouth sores and other side effects, but they were able to get much higher doses with an every two week schedule.  Among the 27 who received PDX every two weeks, they got up to a dose of 170 mg/m2 before the point of prohibitive side effects, and they recommended moving ahead with a dose of 150 mg/m2 IV every two weeks as the best dose for future study.  Importantly, two of the patients in the study had partial responses.  While this may not sound like a high rate of response, I’ll remind you that our current FDA-approved best agents for previously treated patients – taxotere, alimta, and tarceva – have response rates below 10% in the larger trials of pre-treated patients. Read the rest of this entry »

  I’ve described in a prior post and many of my comments here how tarceva and iressa, oral targeted therapies against EGFR, have been pretty consistently impressive in never-smokers.  Not infallibly great, but these agents have shown high response rates in the 25-50% range for never-smokers, and have also been pretty favorable for remote and minimal smokers.  These groups have a high incidence of their tumor having an EGFR activating mutation.  In the randomized trial that compared tarceva to placebo and showed a significant survival benefit, known as the NCI-Canada BR.21 study, tarceva more than doubled the survival of never-smokers compared with placebo.  Among current or former smokers, the trend for tarceva was in the right direction, but it was much less dramatic, with an approximately 13% improvement in survival over the time course of the study.  So far I’ve talked a lot about the favorable results for EGFR inhibitors in lifelong nonsmokers or minimal prior smokers, but the flipside of this is to focus on the less impressive results among smokers, who comprise more than 80% of the lung cancer population.  One new trial is attempting to take advantage of that potential weakness and test a new standard chemotherapy against tarceva in smokers in hopes of proving that the standard chemo is superior (link here).

    I’ll cover the details and available history on the new drug, pralatrexate, in my next post.  What’s really interesting, adding a personal dimension to the story, is that this drug is being developed by Allos Therapeutics, where the Chief Medical Officer is Dr. Pablo Cagnoni.  That doesn’t mean anything to you yet, but the interesting part is that Dr. Cagnoni’s prior job was as Vice President of Medical Affairs and Translational Research at OSI Pharmaceuticals, which developed tarceva and the BR.21 trial.  So clearly he has an intimate knowledge of tarceva and some ideas about its strengths and weaknesses.  And after leaving the old job, he and the folks at Allos are taking aim at a potential Achilles’ heel for tarceva, figuring that beating it in the large population of current or ex-smokers may be easy pickings. 

   The trial will be a randomized phase IIb, which to me means that it will be basically like a phase III trial but with too few people to really be done exactly the way you’d do it with enough money.  Enrolling second line advanced NSCLC patients who have previously received platinum-based chemo, the trial will accrue 160 patients from 50 sites internationally.  This is too small to expect the FDA would approve it, but it could certainly boost interest in the new drug pralatrexate if the preliminary trial is positive.  The trial is being run by Dr. Karen Kelly, who heads the oncology program at the University of Kansas and is a world leader in lung cancer, and also a very nice friend who gave us a sweet baby gift of a cool shirt that says “The Future of Rock & Roll”:  

 (But I digress).

    I must say that I think this is a smart and promising strategy for trying to get a new chemo drug approved for lung cancer.  Most oncologists perceive that chemo is a little bit more active than EGFR inhibitors like Tarceva or Iressa, or they’re at least more comfortable giving it, with the decades of experience with conventional chemotherapy.  But some recent trials suggest that iressa performed comparably to single agent taxotere (prior post here) or navelbine (prior post here) in head to head comparisons.   Interestingly, those trials didn’t indicate that there are subsets that do much better with chemo or EGFR inhibitor, which countered our expectations (mine, at least).  So it remains to be seen whether tarceva will be more or less comparable to pralatrexate, or a currently available standard chemo, in a smoking population.  For now, I think this is a very interesting and new approach to drug development, with the added intrigue of a the backstory that Dr. Cagnoni left OSI and is now thinking about the potential weaknesses of a drug that he helped develop several years ago. 

   Of course, what is most important is that this line of research could very possibly lead to a new drug for lung cancer.  I’ll describe what we know about pralatrexate next. 

   Several trials have recently opened up for never-smokers with any lung adenocarcinoma or those with BAC (or adeno/BAC mix, invasive adenocarcinoma with BAC features) with any smoking status.  Both of these groups have only recently gained recognition as likely being a distinct clinical entity with a different natural history (clinical behavior outside of treatment) and pattern of responsiveness to treatments that is different from other types of lung cancer.
 
   The Southwest Oncology Group (SWOG) has just recently activated a pair of trials that I wrote and will lead, each giving the combination of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) tarceva and the anti-angiogenic (attacking tumor blood supply) avastin at current standard doses to patients who we think may fare very well with this combination as an early, potentially first-line therapy.  These are single arm phase II trials, so every patient will know what they are receiving, and there is no randomization or placebo treatment.  SWOG trial 0635 will give this combination to patients with BAC or adeno/BAC, whether they have smoked or not, while SWOG trial 0636 will give this combination to never-smokers with invasive adenocarcinoma or BAC (never-smokers with BAC will preferentially be enrolled to SWOG 0636 if both are available at an institution).  Tumor tissue is also built into these trials, so that we can have the tumor reviewed by expert pathologists in one central place, and so that we can check molecular variables like EGFR gene amplification by FISH, mutation analysis for FISH and RAS, and several other potentially relevant makers that we can then correlate with how individual patients did.  Read the rest of this entry »

   In my recent post on the JMDB trial that randomized patients between cisplatin/alimta and cisplatin gemcitabine in first line treatment of advanced NSCLC, the take home conclusions were that overall efficacy was very similar, with the cis/alimta arm looking a little better in several side effect parameters, most notably a less significant decline in blood counts and lower risk for fevers with a low white blood cell count.  Also, the study showed the quite intriguing finding that those with adenocarcinoma and large cell tumors did signficantly better with cisplatin/alimta, while those with squamous cell carcinomas did notably (not quite statistically significantly) better with cisplatin/gemcitabine.

   So a central question, first, is does this make sense?  Actually, it very well might, because alimta works partly and potentially substantially by blocking a cellular enzyme called thymidylate synthase (or synthetase) (TS).  There was a recent publication (abstract here) that demonstrated that levels of both messenger RNA (the code that is between the DNA and the protein it builds) and TS protein are significantly higher in squamous lung cancers than in adenocarcinomas, and also that the levels were higher in high grade cancers than lower grade ones.   Higher TS levels would be expected to be associated with more resistance to alimta, while lower levels would be expected to correlate with sensitivity, as has been shown in some preclinical (lab-based) studies. Read the rest of this entry »