Several weeks ago, we were fortunate enough to be joined by not one but two international stars in lung cancer research that is being translated directly from lab bench to bedside of the patient.  I don’t think there’s a more clear and inspiring example of good science leading to effective therapy, albeit for a limited patient population, than the story of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (recently FDA approved and commercially launched as XALKORI) for patients with an EML4-ALK rearrangement (approximately 4% of the broader NSCLC population).  Drs. Ben Solomon from Peter MacCallum Cancer Centre in Melbourne, Australia, and Ross Camidge from University of Colorado, in Denver, collaborated with a handful of other international researchers from all over the world to study crizotinib and conduct the critical trials, shepherding its development into a treatment now available to help a targeted subset of patients with this targeted therapy.

Dr. Ben Solomon spoke first, providing an overview of the (short) history of the EML4-ALK translocation and how crizotinib began to be studied in the first patients.  He then took us on a tour of the highlights of both the efficacy data for this new agent and the side effect profile.  Here’s the audio and video podcast versions of his presentation, along with pdf files of the accompanying transcript and figures:

dr-solomon-alk-inhibition-science-to-approved-therapy-audio-podcast

dr-solomon-alk-inhibition-science-to-approved-therapy-transcript

dr-solomon-alk-inhibition-science-to-approved-therapy-figures

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   It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR).  However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.

   The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done.  In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib)  and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive.  In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients.  This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.

   However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients.   In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.

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  Back when I first started doing this, one of my earliest posts (see here) was on the question of whether EGFR tyrosine kinase inhibitors (TKIs) (see introduction to this work in prior post).  My point, which is still true, is that EGFR TKIs aren’t only effective in a narrow population of patients, whether identified based on molecular or clinical variables.  But in the more limited number of patients who have the “activating mutation” in the actual receptor, who might be expected to do especially well with an EGFR TKI, how do they do?  How does a targeted therapy do in a precisely targeted population?

   There are several studies that have now tested this by identifying patients who have an EGFR mutation and received an EGFR TKI.  As shown in the table below, the results are very clear and consistent. 

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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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   We’ve seen clear evidence that patients who have tumors with certain mutations in the EGFR gene are highly likely to respond to oral EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib) – with response rates that are in the 70% range and often last for many months or even a few years (see prior post).   On the other hand, K-Ras mutations are associated with a very low probability of responding to EGFR mutations (see prior post).

   But the overall favorable or unfavorable results of these mutations may not be limited to their associations with how patients respond to EGFR inhibitors and/or other systemic therapies.  I’ve noted how patients with advanced NSCLC and EGFR mutations have a superior survival even if they don’t receive an EGFR inhibitor.  Another approach to assessing the prognostic value of mutations is to look at survival of patients with resected earlier stage NSCLC tumors.

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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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   One of my good friends in the lung cancer community, Dr. Ed Kim from MD Anderson, was in town tonight and gave a talk that I attended.  He’s one of the emerging real leaders in the field, and last week had published in Lancet one of the largest trials in advanced lung cancer, the INTEREST trial (see prior post describing it, and the link to the summary of the published article).  The trial compared the EGFR inhibitor iressa (gefitinib) to standard chemo taxotere (docetaxel) and reported that the two approaches produced identical survival results. 

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This is interesting (excuse the pun) in its own right, because some oncologists hold on to a belief that chemo is the treatment that really works and that EGFR inhibitors are a late consolation prize to offer.   Even a less effective EGFR inhibitor like iressa (compared with tarceva (erlotinib)) was absolutely comparable, truly equivalent to a chemo approach that was less well tolerated.  But we’ll cover the full results of the INTEREST trial in more detail separately. 

    Dr. Kim mentioned in passing that he wanted to see iressa return to the US market.  Read the rest of this entry »

   Actually, it’s some background information and your blood that’s needed. 

   Memorial Sloan-Kettering is running an important trial that is trying to determine some of the molecular factors that lead some never-smokers to develop lung cancer while other never-smokers don’t.   The trial is just a one-time collection of information in a questionnaire, I believe about medical history and environmental exposures, and submission of two vials of blood.  There is no cost to participants, with all packaging and mail expenses pre-paid, and the registration and additional information is online here. 

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  I just recently wrote a post (here) that describes how I became convinced that under certain circumstances there could be a genuine value in determining whether a particular lung cancer patient has a tumor with an EGFR activating mutation.  While these have seemed to predict that these patients are quite likely to respond with dramatic tumor shrinkage, correct about 70% of the time, I had previously been impressed by how correlated EGFR mutation results were with some other clinical factors, such as being Asian and especially a history of never-smoking.  But recent results that I described in my last post convince me that

1) mutations trump clinical factors

2) patients who receive EGFR inhibitors as first line therapy but don’t carry an EGFR mutation don’t seem to do as well as those who received chemo.

   I also said that this doesn’t mean that patients without mutations don’t benefit from an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) in the second or third line setting (the evidence is far stronger with tarceva, though, showing a survival benefit vs. placebo that hasn’t been shown with iressa).  Member sunnyside then asked about the evidence with regard to EGFR mutations and second/third line treatment.  Here’s what we know.

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   Those who have followed my writings over time will know that I haven’t been inclined to adopt a reflexive strategy of ordering molecular testing without good evidence that having this information will improve outcomes.  Testing tumors for EGFR mutations is advocated by a vocal minority of lung cancer experts in Boston and New York City, but this hasn’t been advocated by the broader lung cancer community yet, or adopted as routine clinical practice.  Although I’ve felt that we’ll have enough evidence to support broad use of molecular variables to individualize treatment for lung cancer patients in the next few years, I haven’t felt that they have a role yet, but I’ve now seen some results that I believe are enough for me to change that conclusion.

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