For years it has been generally accepted that the choices for the second drug in a platinum doublet for treating metastatic non-small cell lung cancer (NSCLC) were pretty much interchangeable. The question of whether cisplatin is better than carboplatin is a separate question, one which GRACE’s own Dr. Sanborn recently reviewed quite nicely. For the second drug, as long as the choice was a “newer generation” drug, oncologists would mix and match cisplatin or carboplatin with Taxol (paclitaxel), Taxotere (docetaxel), Gemzar (gemcitabine), or Navelbine (vinorelbine) based mostly upon which drug they liked the best or had the most experience with.

This perception that the specific second drug was irrelevant was not just pulled out of a hat; there has been reason to think they are all equally good. The most often quoted study to make this point has to be the ECOG 1594 trial (Comparison of Four Chemotherapy Regimens for Advanced Non–small-cell lung cancer), which randomized NSCLC patients to one of 4 arms: cisplatin/Taxol, carboplatin/Taxol, cisplatin/Gemzar, and cisplatin/Taxotere. The survival curves were essentially identical (see below), as were the response rates of the tumors.

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   With all this recent talk about never-smokers with lung cancer, and the interest in stories of patients with so-called “oligometastatic” cancer (minimal metastatic burden to perhaps a single site), I thought I would describe a recent case in my clinic as an illustration of how I use this information in everyday decision making.

   Mrs. D, a very fit 36 year-old woman with a young child at home, presented to her family doctor last year with back pain. It didn’t seem to be getting better, so her doctor ordered an x-ray of the back which showed a very nasty-looking spot in the lower spine. An MRI confirmed that there was a large tumor in the lower spine, and a surgeon went in and took a piece of the bone to determine the cause. The result was a metastatic adenocarcinoma, with special tests pointing to a primary site from the lung.

   She had never smoked, nor had her spouse. A PET scan showed a very small spot in her lung, with no evidence of spread to local lymph nodes, and no evidence of metastatic disease outside of the single metastasis in the spine. An orthopedic surgeon opined that she probably could resect the entire vertebrae involved, but this would be a major undertaking.

   This type of case, aside from the heartbreaking anguish of having to tell a young mother she has lung cancer, causes all of us in the oncology world fits. How could such a small tumor, less than 1cm in size, be the cause of the spine tumor? Was it worthwhile to discard what we intellectually know about metastatic lung cancer (incurable) and treat her aggressively for cure, and if so would we be putting her through Hell only to make ourselves feel better about not giving up on such a young patient?

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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

   One of the issues that we’ve commonly discussed and debated here is the question of when a local approach like surgery and/or radaition may be appropriate for I recently saw a patient of mine who I first met more than four years ago. At that time, he was only 37 years old and had just been diagnosed with stage IIIA NSCLC with several N2 nodes involved, after having quit smoking a couple of years earlier. He had actually initiated treatment with another local oncologist, a plan of chest radiation along with concurrent weekly carbo and taxol. He had also met with one of the expert thoracic surgeons I work very closely with, Dr. Eric Vallieres, who felt that he would be a good candidate for surgery after chemo and radiation. In truth, the extent of his disease in his mediastinum (midchest) was enough that I felt that an alternative approach of aggressive chemotherapy and radiation without surgery was a reasonable alternative. But Rob was one of the most informed and proactive patients I’ve encounted in my own practice and came to learn as much about the controversy around how to manage stage IIIA NSCLC as his physicians. Not only did he shape the plan that led him to surgery after “induction” chemo and radiation, he pushed for post-operative prophylactic cranial irradiation (PCI), though that isn’t a standard approach at this time (and I had expressed some misgivings despite the compelling rationale). He had also received a few doses of post-operative chemo with gemcitabine and navelbine, which was as much as even an aggressive-minded man in his late 30s could take after chemo, radiation, and surgery.

   Of note, he had received this care through another oncologist, but he transferred his care to me about a year after he had completed these treatment. However, before he came to me, he had undergone a repeat PET/CT that showed an upper abdominal lymph node that lit up on PET, with no other abnormalities. In fact, he had just undergone an exploratory where they found and removed that node, which was recurrent cancer. He came to me for consideration of post-operative therapy, and the entire team had an extensive discussion of the possibilities (this team definitely including the patient, along with surgeon, radiation oncologist, and myself). Though we were without any real precedent and a potential of making him feel worse for no clear benefit, he was young, aggressive, knowledgeable of the balance of potential risks and benefits, and we thought it might still be possible to cure him. He had gone a year and had a single lymph node recurrence, with no evidence of any disease elsewhere. In fact, due to some manipulations that the surgeons had done at the time of his surgery, that lymph node was felt to potentially have drained directly from the surgical bed, so there was a chance that this area of disease hadn’t spread through the bloodstream.

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A quick point on the importance of biology over treatment. Years ago, I highlighted the results in the TRIBUTE trial of chemo with placebo or combined with erlotinib (tarceva) at the same time (biomarker study abstract here), which showed that patients with EGFR mutations had a much better survival whether they received an EGFR inhibitor or not:

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   Here, biology was the prevailing factor. We’ve also recently seen that the patients on the IPASS trial of Asian never-smokers or light former smokers who were then randomized to first line chemo or an EGFR inhibitor had a far better survival if their tumor had an EGFR mutation compared to those who did not (see prior post). Similarly, the IPASS trial also showed that patients with EGFR mutations had nearly double the response rate to chemotherapy that patients without EGFR mutations demonstrated. So maybe the benefit of unique biological factors applies to standard chemotherapy as well as “targeted therapies”. Chemotherapy is also targeted and only benefits a subset of patients: we’re just further behind at understanding the relevant targets and discriminating the beneficiaries from others with standard chemo than with agents like EGFR inhibitors.

    The recently published trial of cisplatin/alimta (pemetrexed) vs. cisplatin/gemzar (gemcitabine) (abstract here) showed an interesting result among enrolled never-smokers, who comprised 14-15% of the patients on the 1725 patient trial overall. Although we think of never-smokers as doing especially well with EGFR inhibitors, this trial also showed that never-smokers had a markedly longer median overall survival in both chemotherapy arms compared to current or former smokers (15.9 vs. 10.0 months in the cis/alimta arm; 15.3 vs. 10.3 months for the cis/gem arm).

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   The improvement in median survival of 1.2 months with the monoclonal antibody to EGFR erbitux (cetuximab) in the FLEX trial that I’ve previously described was statistically significant, but there’s plenty of room to debate whether it’s really clinically significant (see prior post).  What If we could add some way to refine our predictions of who will benefit from the addition of erbitux?

   At the Chicago Lung Cancer meeting in November 2008, Dr. Ulrich Gatzemeier presented results of a planned subset analysis of the FLEX trial, in which the results compared the outcomes of patients randomized to receive cetuximab by whether they developed an acne-like rash within three weeks of starting this treatment.  This was based on a growing and rather consistent experience that patients who receive EGFR inhibitors, whether oral tyrosine kinase inhibitors or IV antibodies, generally show a a strong trend or significantly better survival than patients who develop no rash (see prior post).  The investigators found that there was a very significant difference in efficacy with cetuximab among the patients who developed a rash (of any severity) after two weeks (56%) compared with those who didn’t (44%).  The difference in median survival was a near doubling: 15.0 months for the patients with any rash, compared with 8.8 months for those who didn’t:

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