The FLEX trial, a European study of cisplatin/Navelbine (vinorelbine) with or without the monoclonal antibody against EGFR Erbitux (cetuximab), was a technically positive study that was initially reported at ASCO 2008.  However, showing an improvement in median survival of just 1.2 months, most oncologists came away feeling that the trial illustrated the difference between a statistically vs. clinically significant result.   Currently, the use of Erbitux in clinical practice is just a very small percentage of potentially eligible patients, though I think this would change if we could identify patients who are significantly more likely to benefit substantially and spare the others who actually don’t benefit from the cost, weekly infusions, and side effects of it.  A recent report suggests that there may be such a method.

One of the most prominent presentations from the World Conference on Lung Cancer last month was a retrospective analysis of the results from the FLEX trial that divided patients based on the extent to which their tumor expressed EGFR protein on cancer cells as measured by the technique of immunohistochemistry (IHC).  The investigators developed an “EGFR IHC score” that was a product of the percentage of cancer cells positive for EGFR protein on the cell surface multiplied by the overall intensity of staining (ranging from 0 to 3+), producing a number from 0 to 300.

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Here’s the second talk from our recent webinar, partnering with LUNGevity Foundation to cover the ASCO Highlights in Lung Cancer, and this talk followed after the presentation by Dr. Mary Pinder on highlights in SCLC, early stage NSCLC, and mesothelioma and covered developments in advanced NSCLC.   Dr. Nasser Hanna, an international leader in the field from Indiana University, summarized the most important new data in this arena.

Below you’ll find links to the audio and video versions of the podcast, as well as the transcript and figures from his talk.

hanna-asco-2011-highlights-advanced-nsclc-audio-podcast

hanna-asco-2011-highlights-advanced-nsclc-transcript

hanna-asco-2011-highlights-advanced-nsclc-figures

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Podcast: Play in new window | Download

The Importance of Identifying Molecular Markers in Non-Small Cell Lung Cancer

To understand the importance of molecular markers in the current and future treatment of lung cancer, one should first understand how lung cancer was classified up until the beginning of this decade. Pathologists would look at a sample of a patient’s lung tumor under a microscope, and then make a judgment of whether the cells represented small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Although that is an oversimplification, for all practical purposes, that is what oncologists cared about when it came to choosing treatment. If the diagnosis was NSCLC, then oncologists treated the patient with platinum doublet chemotherapy using one of many standard regimens that were felt to be equally effective. Unfortunately we knew that these regimens only worked in a certain proportion of patients, but we had no way to predict ahead of time who would benefit and who would not.

At the same time pathologists and molecular biologists have know for some time that NSCLC is not really just one disease, but rather a constellation of many diseases that all share the distinction of starting in the lung. For example, major subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma were often reported in pathology reports but did not influence treatment choice. Since 2004 we have taken this one step farther, asking pathologists to tell us not just that the lung cancer is non-small cell but also that it is non-squamous cell, for purposes of safety with Avastin (bevacizumab) and efficacy with Alimta (pemetrexed), but that is the topic for another chapter.

As our understanding of the molecular basis of cancer has grown, we have developed a number of new molecularly-targeted agents with promise in the treatment of lung cancer. However, targeted drugs tend to have limited or no effect on cancers that lack the “target” of the drug, creating a need for markers to guide us.

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In the last decade, the treatment of NSCLC has evolved very significantly, and one of the leading ways has been that we’ve gone from having no established role for treatment after initial, first line therapy to having multiple agents with a proven benefit.

It’s worth clarifying that as maintenance therapy is increasingly being considered as an option after first line therapy, a distinction between this and second line therapy. Maintenance therapy is given to prolong the period before someone who has achieved a response or stable disease on first line treatment demonstrates progression for the first time, while second line therapy is the term more commonly reserved for treatment after someone has demonstrated evidence of progression for the first time after first line therapy.

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The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).

Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.

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   The third and final part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a presentation of an Asian never-smoking woman with an advanced lung adenocarcinoma, the demographic picture most closely associated with potentially but not necessarily having an EGFR mutation or ALK rearrangement.

   We cover the question of whether, in someone with a significant probability of one of these particular molecular markers, it’s worth obtaining tissue and delaying treatment to tailor treatment on the basis of these results.  We also discuss the range of options for maintenance therapy in someone who has many alternatives for continuing one or more agents from the first line setting or switching to a new treatment.  Finally, we turn to the question of managing treatment for a patient who has a prolonged response to an EGFR inhibitor and then develops an acquired resistance to that therapy.

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   The second part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a case of a relatively young, generally healthy woman diagnosed with a lung adenocarcinoma that turned out to be stage IV.  

   Here, we discuss our priorities for molecular testing and how the results of EGFR, KRAS, and EML4-ALK testing would alter our clinical recommendations.  We then discuss the options for this patient, with special focus on how long to continue first line therapy and when and how to transition off of first line treatment into either observation or maintenance therapy.

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   Over three and a half years ago, I wrote a post about about early work looking at the possibility that a PET scan done anywhere from three days to a month out from the start of a new systemic therapy (chemo or EGFR inhibitor)  for advanced NSCLC could be predictive of a good outcome or not.  Despite the increasing use of PET scans not only for staging but also for follow-up to assess response in patients with NSCLC, there hasn’t been a lot of new information since then.  However, a study presented at ASCO 2010, coming from several Australian hospitals in collaboration with a couple in southern California, compared PET scans done after two weeks and then  two months of  Tarceva (erlotinib) therapy with the more established standard measure of response assessment, CT scans after two months of therapy.

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The negative trials don’t get a lot of discussion, but the ZEPHYR trial, a phase III study that directly compared Zactima (vandetanib), an oral inhibitor of EGFR and angiogenesis, vs. placebo, was one that merits some follow-up after my reporting that it failed to show a survival benefit, which was essentially the only thing we learned about the trial prior to ASCO this year.  A more complete report of the ZEPHYR trial was presented at ASCO, and though it suffered the indignity of being the rare phase III trial that didn’t get presented during an oral session, I think the results are important enough in trying to assess the real value of Zactima that the results merit being reviewed.

ZEPHYR was the last of four major lung cancer trials with Zactima to be completed and reported.  The others are summarized in a prior post, and they showed at best equivocal results.   The others are discussed in a point-counterpoint fashion by GRACE member and moderator Neil Berch (arguing that the Zactima glass is half full) and me (taking the less beloved view that the benefits are extremely marginal and probably not enough) — let the record show that, at the present time, his post has been more favored by the people who have added a rating.

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Continuing with the webinar discussion I had with Dr. Pennell, here is a summary I did of a randomized phase II trial of the novel agent ARQ-197 combined with the EGFR inhibitor Tarceva (erlotinib):

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Dr.  West: We’re going to shift gears and move into the metastatic setting, and this is a new agent called ARQ197 that is orally available, which was tested in combination with erlotinib(Tarceva) compared with Tarceva alone.  And this was actually in the patients who had received one or more prior lines of chemo and could not have received prior Tarceva or another EGFR inhibitor, directly comparing these two groups that randomized one-to-one. Also, patients who had been assigned to placebo could actually go on the combination at the time of progression, and we did get some interesting information from that.

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