About 18 months ago, I wrote a post about a new technique being developed that looks at the pattern of proteins in the blood of a patient in order to determine whether a patient is likely to do well or poorly after receiving an EGFR tyrosine kinase inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. This work was the product of collaborative work among folks at Vanderbilt University, the University of Colorado, and a Colorado based company called Biodesix.

   At the time that I wrote the original post, there was a general plan to bring this test to commercial use. Earlier today, I met with some of the folks at the company, who told me that this plan is now moving forward, with a plan to launch the test, now known as Veristrat, in early March. While they didn’t have additional published or formally presented information to highlight, they told me that they have continued to do studies of the serum from patients from all over the world that has validated what their test is trying to do. Here’s the idea:

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   One of the basic concepts of oncology is that you treat patients with different drugs once they’ve shown progression on a treatment, rather than continue that a patient has presumably become resistant to.  However, there are some exceptions to this: many or most women with breast cancer continue the antibody herceptin (trastuzumab) even after progression, adding it to one chemo and then the next, and the same is often done with avastin in colon cancer and sometimes lung cancer as well.  In the past few years, there has been interest in whether the patients who respond well to an EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) should continue on it for a while or even forever after showing the first evidence of progression on an EGFR inhibitor.

    It may help for us all to take a step back and remember that the goal of improving survival and slowing the progression of a tumor may occur not only if the cancer is shrinking or even if it’s holding steady.  If the cancer might potentially be growing quickly, even slowing the progression may translate to an improvement in how a patient does.  In the lab, basic scientists examine the growth of a cancer in lab animals and consider it beneficial if the cancer progression is slower over time when a new treatment is added, compared with a placebo or some alternative approach.   But in the grading system oncologists use, we don’t discriminate between slow progression and faster progression — it’s just considered a disappointment and time to move on.

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  The point is that imperfect brakes is better than no brakes.   In fact, in some settings of especially effective treatments for other cancers, some investigators noticed that patients who were progressing slowly on a previously very effective treatment showed a rapid rebound progression when they stopped the treatment (as if they jumped from the blue line to the yellow line in the figure above).  So a few years ago, the folks at Memorial Sloan Kettering Cancer Center (MSKCC)studied a small number of patients with either EGFR mutations or a prolonged response to EGFR inhibitors who were showing some progression (abstract here).  They did CT scans and PET scans right before and right after patients took a planned three week break from their EGFR inhibitors, and they also assessed how these patients were feeling.  After restarting their EGFR inhibitors and repeating scans and checking patient symptoms, they added another novel agent called everolimus, an mTor inhibitor (see prior post for discussion of the novel agent approach of mTor inhibitors alone and combined with EGFR inhibitors).  For the more visually oriented, this is the overall design of the complicated trial:

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  With the recent publication of the Eli Lilly-sponsored phase III trial of immediate versus delayed Taxotere (docetaxel) after the completion of first-line chemotherapy in patients with advanced NSCLC (abstract of paper by Fidias and colleagues here), I think the time has come to critically evaluate this as a potentially practice-changing concept. Call it whatever you want: maintenance therapy, sequential treatment, or early/immediate second-line therapy, but whatever you do, don’t call it a fluke. The idea behind maintenance is simple: after finishing your initial 4-6 cycles of platinum-doublet chemotherapy, you move immediately on to more treatment rather than stopping and waiting for the cancer to progress. In the last year and half, we have seen four major phase III trials test some version of maintenance treatment with chemo or Tarceva, and all have generally supported a benefit. The Fidias paper is the first of these to be published, so let’s take a closer look at the design:

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In this trial, 566 previously untreated patients with metastatic NSCLC were all initially treated with carboplatin and gemcitabine. Those that finished four cycles without progression were randomly assigned to either receive Taxotere immediately and continue it for a maximum of 6 cycles, or to be followed and receive Taxotere once their cancer started to progress. The trial was designed to be large enough to see a 4 month improvement in overall survival (OS), which in retrospect seems ridiculously ambitious. To give you a comparison, the ECOG 4599 trial, which led to the approval of Avastin in lung cancer, only showed a 2 month improvement in OS.

In any case, the trial did not quite make the 4 month improvement, missing it by a little over a month (OS 12.3 months for immediate Taxotere versus 9.7 months for delayed; p=0.085), but it did have an impressive improvement in progression-free survival (PFS; 5.7 versus 2.7 months; p=0.0001), which is a measure of patients still alive without progressive cancer. Essentially what this means is that patients who started immediately on Taxotere delayed the progression of their cancer by 3 months compared to those who waited, and lived an average of almost 3 months longer. This is a pretty clinically significant improvement, although there are some important things to point out about this trial. First, only 309 patients (out of the original 566) made it to the randomization, so these were already the patients who were doing very well after first-line chemo. Second, 37% of the patients (58 of 156) who were designated to receive the delayed Taxotere never got it (as opposed to only 8 patients in the immediate arm), about half of them because their cancer progressed so much that they were unable to get more treatment. So it is unclear if the benefit of immediate Taxotere was truly better effect, or just the results of most of the patients in the immediate Taxotere group actually getting the chemo.

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   We have long noted that there is a clear association of smoking history with effectiveness of oral EGFR tyrosine kinase inhibitors (TKIs).   Part of this is because never-smokers have a high incidence of carrying activating EGFR mutations, but also potentially because current smokers actually metabolize EGFR TKIs faster (see prior post).   We’ve seen a consistent association of rash development with better outcome (see prior post), and current smokers have been disproportionately likely to develop little or no rash.  A recent study just coming out in the Journal of Clinical Oncology from a group in the UK has studied blood levels with dose escalation of  tarceva (erlotinib) among current smokers (abstract here) and suggests a possible value in giving higher than standard tarceva dosing among current smokers, so that they can achieve the same blood levels as never-smokers or former smokers.  Will this lead to better results for these patients?

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    A press release today informs us that the ATLAS trial of maintenance avastin (bevacizumab)  combined with tarceva (erlotinib) vs. avastin with placebo was positive for a significant improvement in progression-free survival (PFS).  We had already learned that the very similar SATURN, of maintenance tarceva vs. placebo in patients who weren’t on avastin was also positive for an improvement in PFS (see prior post), though we don’t have details yet.  Here’s the design of these two trials:

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    What we’ve learned so far about the ATLAS trial is that an interim planned analysis of safety and efficacy showed that there was a significant improvement in progression-free survival that led to the stopping of the trial and disclosure of these early results of more favorable PFS in the recipients of tarceva combined with avastin.  It had already enrolled 1157 patients, which was its goal, and these patients received avastin with any of several different platinum-based chemotherapy doublets (carboplatin/gemcitabine, carboplatin/paclitaxel, carboplatin/docetaxel, cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine).  If patients hadn’t progressed after four cycles of this combination, they would be randomized to avastin maintenance with either tarceva or a placebo pill.  The results apparently showed no evidence of any unexpected safety problems, which is important both for broadening our experience of different chemo agents with avastin and because patients with therapeutic doses of blood thinners were able to be enrolled, as were patients with more peripheral squamous cancers that were far from the center of the chest (a minority of squamous cancers).

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   Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.  

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Or access via web link here. 

Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images

Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript

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Podcast: Play in new window | Download

   Erbitux (cetuximab) is a monoclonal antibody to EGFR, and it’s actually made from a protein that is part mouse and part human (called a chimeric protein, named for the mythologic creature chimera that was composed of multiple parts from different animals). It’s uncommon but not rare for patients to have an allergic reaction to this protein, and in most large national and international studies show rates of hypersensitivity reactions (HSRs) in the 1-3% range. In severe cases, these reactions can be very serious, causing low blood pressure, fainting, wheezing, and shortness of breath; they can even be fatal. While that is a small but real risk, wht is fascinating and especially scary is that there is an area in the southwest US — including Tennessee, the Carolinas, northern Georgia, and perhaps other areas — in which about 20-25% of patients develop these reactions.

   Oncologists in these areas had noted over the past few years that they seemed to have a higher than expected rate of these complications, but the problem was highlighted in real terms in a 2007 article in the Journal of Clinical Oncology (abstract here) that retrospectively reviewed the experience of 88 patients on clinical trials and 55 patients off of clinical trials who received erbitux at one of three institutions in the region: Sarah Cannon Cancer Center and Vanderbilt-Ingram Cancer Center in Nashville, TN, and the University of North Carolina at Chapel Hill. They found a 22% rate of moderate to severe HSRs, ten times what we see in the rest of the country or world. These reactions occurred at the time of the first infusion but rarely afterward if someone did well the first time. They were more commonly seen in patients with a history of allergies, and it was interesting to see that reactions were more commonly seen in patients with NSCLC than other tumor types. The association of this type of reaction with lung cancer more than colon cancer is puzzling and suggests that there may be some correlation with a tobacco-related antigen, but we still need to learn more about this.

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