Drs. Bob Doebele, Ross Camidge, and their colleagues at the University of Colorado just published an interesting and clinically relevant paper in Clinical Cancer Research that looked in detail at the mechanisms of resistance in ALK rearrangement positive patients to the ALK inhibitor XALKORI (crizotinib).   Evaluating 14 patients with a known ALK rearrangement who were resistant to XALKORI, either from first treatment (in the case of two patients), or after a period of response (for the other 12), they performed repeat tissue biopsies after resistance was documented, in order to determine whether the ALK rearrangement was still present, whether there were additional copies of the ALK gene, or whether there were new mutations documented that might now be an alternative mechanism of driving the cancer.

Of the 11 patients who had sufficient tumor tissue for analysis, they found a wide range of apparent mechanisms of progression.  Four of the 11 (36%) developed new mutations in the ALK gene that conferred resistance, and in two cases this was associated with a particular mutation(known as G1269A) that has been associated with resistance to crizotinib in lab-based work.  Two patients (18%), including one who had an ALK resistance mutation, were now found to have developed additional copies of the ALK gene in their cancer cells, which could overcome the inhibitory effect of crizotinib. Three patients (27%) no longer had the ALK rearrangement present in their tumor tissue, of whom one had developed a new EGFR mutation, one had developed a KRAS mutation, and one had developed an unknown mutation (they tested for a limited panel of known high yield ones). Another patient (9%, in case you haven’t figured out the pattern) developed a KRAS mutation but continued to have an ALK rearrangement detectable.  The final two continued to have an ALK rearrangement present and no detectable mutation or other changes that could explain the development of resistance.  The summary of mechanisms of recurrence is as shown on the left in the figure below:

(click on image to enlarge) Continue reading →

Thanks (and congratulations) to GRACE member Craig, who highlighted the just-published report that is the first to characterize the frequency and clinical features of the newly identified ROS1 rearrangement, identified in 2007, similar in structure to an ALK rearrangement, and found to also be responsive in preclinical cell lines to ALK inhibitor therapy.  Craig has a special perspective on this new target, since a ROS1 rearrangement was detected in his tumor.   Importantly, very early but quite promising work is showing that patients with a ROS1 rearrangement may respond very well to the oral ALK inhibitor XALKORI (crizotinib), Craig being one of the beneficiaries of this treatment.

He’s one of a very limited number who we’re only beginning to learn about.    The article looks at the molecular features of 1073 tumors from patients mostly from Massachusetts General Hospital and Vanderbilt University, reporting that 18 (1.7%) had a ROS1 rearrangement and 31 (2.9%) had an ALK rearrangement.  Both groups share the some clinical features, specifically skewing toward a much younger median age than the broader NSCLC population (around 50 in both ROS1- and ALK-positive patients, compared with 62 in the larger NSCLC population), being seen predominantly in never-smokers (in whom a ROS1 rearrangement was seen in 6% of the group), and being seen predominantly in patients with an adenocarcinoma (in fact, all 18 patients with a ROS1 rearrangement had an adenocarcinoma).  The adenocarcinomas included many different subtypes and tended towards being more poorly differentiated and higher grade (correlated with a more aggressive appearance). Continue reading →

Several weeks ago we did a webinar, co-sponsored with LUNGevity Foundation, with Dr. Mark Millard, pulmonologist at Baylor University in Dallas, TX, who provided a brief summary of tobacco’s uptake in the US and worldwide, then covered the controversy over its association with lung cancer.   These are the subject of the first podcast covering his webinar, and part two will cover current approaches to smoking cessation.

Here’s the audio and video versions of the podcast, as well as the transcript and figures:

millard-on-tobacco-and-lung-cancer-audio-podcast

millard-on-tobacco-and-lung-cancer-transcript

millard-on-tobacco-and-lung-cancer-figures

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Dr. Pinder previously covered the potentially clinically relevant target of HER2/neu (HER2) mutations for lung cancer.   Specifically, she noted that Herceptin (trastuzumab), an antibody against the HER2 receptor (in the same family as EGFR, which is also known as HER1), but it hasn’t been especially impressive in NSCLC thus far.  For example, an ECOG phase II study by Dr. Langer (who was a mentor of Dr. Weiss’s at the University of Pennsylvania) looked at a target population of patients with advanced NSCLC and HER2 protein expression by immunohistochemistry (IHC).  This captures a large proportion of people with NSCLC, but it may be so broad a population that it dilutes the subset whose cancer is especially driven by HER2.  Instead, mutations in the HER2 gene, similar to mutations in EGFR that are far better studied in NSCLC, appear to be present in about 3-4% of patients with NSCLC.  While this population may be far more likely to benefit greatly from HER2-targeted therapy, this is an essentially completely untested hypothesis.

An article by Li and colleagues out of Shanghai was just published in the Journal of Thoracic Oncology evaluates and attempts to better characterize this population of patients with a HER2 mutation a little more.  They reviewed tissue from the cancers of 224 consecutive patients with a lung adenocarcinoma in their tumor registry, looking for EGFR, KRAS, and HER2 mutations.  It should be noted that this population, which is evenly split between men and women but is 62% never-smokers, only 5% stage IV, and entirely Chinese, is clearly a clinically distinct population from the more heterogeneous NSCLC populations seen in Europe or North America, but it’s interesting that they saw a HER2 mutation in 3.6% of patients.  This is in contrast with a 64.4% prevalence of an EGFR mutation (wow!) and a 4.5% prevalence of a KRAS mutation — and these were all mutually exclusive of each other: (click on image to enlarge) Continue reading →

One of the longstanding ideas in lung cancer management is that you exhaust the benefit of first line combination chemotherapy after 4-6 cycles of treatment.  This is based on a few trials that showed no survival benefit for treating beyond that point, as summarized in this early post I wrote all the way back in my first few months of doing this (OncTalk days, pre-GRACE). This standard of care is based in part on the premise that the incremental adverse effects may escalate faster than any incremental benefit for a platinum-based doublet.  With cisplatin, cumulative nausea, fatigue, risk of significant kidney damage, neurotoxicity, and overall “platinum blues” tend to make treatment beyond 6 cycles infeasible and disproportionate to any potential added benefits of ongoing therapy.  With carboplatin, cumulative cytopenias (low blood cell counts) and a rapidly escalating risk of a severe and potentially dangerous hypersensitivity reaction (which can also occur with ongoing cisplatin but is notorious and almost inevitable with carboplatin) make indefinite carboplatin too challenging and inadvisable.

In the last few years, the concept of maintenance therapy for patients who haven’t experienced progression or prohibitive side effects after 4-6 cycles of first line combination chemotherapy has taken hold.  Initially, this default strategy was baked into the development of Avastin (bevacizumab): the trial that led to approval of Avastin gave six cycles of carbo/Taxol (paclitaxel)/Avastin, followed by maintenance Avastin.  It showed a survival benefit for the whole program, but it was not possible to say whether the benefit was from the addition of Avastin with chemo, from the maintenance Avastin, or both components.

Meanwhile, many trials over the last few years have shown a clear improvement in progression-free survival (PFS) and a suggestion of improvement in overall survival (OS) with addition of switch maintenance therapy, where a new treatment is initiated after 4-6 cycles of first line combination chemotherapy is completed in non-progressing patients.   This work is discussed in more detail elsewhere and led to a general standard of at least considering maintenance therapy in this setting for appropriate patients, even if the data supporting a survival benefit are flawed enough to leave most experts considering maintenance therapy far from a mandate.

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   A few months ago I wrote about the preliminary reported results from the AVAPERL trial, which started patients with previously untreated  advanced nonsquamous NSCLC up to four cycles of cisplatin/Alimta (pemetrexed)/Avastin (bevacizumab), then randomized patients who hadn’t progressed after four cycles to either maintenance Alimta/Avastin or Avastin alone.  At the Eurpean Society for Medical Oncology (ESMO) 2011 meeting, the investigators (Barlesi and colleagues) presented early results that showed a very significant improvement in progression-free survival (PFS) from the beginning of all treatment, at 10.2 vs. 6.6 months (HR 0.50, p < 0.001).  For those of you who understand things better visually, here’s the curve plotting the PFS outcome for the two different groups, with a very impressive difference:  

  (click on image to enlarge)

   The same results, plotted from the time of randomization to combination vs. single agent Avastin as maintenance therapy, are even more striking:

   I didn’t have any information about overall survival (OS) back in September, but here’s the preliminary OS results, with numbers from the time of starting all treatment:

So while these are only preliminary results, the difference of a 25% better OS with continuation of Alimta is impressive to me, especially considering that the arm with the worse outcome, receiving maintenance Avastin alone, has a median survival of nearly 16 months, which we would consider to be quite excellent compared the outcome of other advanced NSCLC trials (12 months for cisplatin/Alimta on one large phase III randomized trial, 12 months with carboplatin/Taxol (paclitaxel) with Avastin in another).  So the inferior arm on AVAPERL has still done very well: the superior arm is just doing meaningfully better.

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It’s been a while since we released another podcast from the recording I did with Drs. Jyoti Patel from Northwestern and Bob Doebele from University of Colorado earlier this year.  In that session, we covered a series of real life scenarios in managing lung cancer that are at the outer limits of what we can say we know and leave us relying more on our best judgment than on evidence. Along with the comments by Drs. Patel and Doebele, we’ve then added responses from a collection of additional great lung cancer experts (Drs. Suresh Ramalingam, Jonathan Goldman, Julie Brahmer, Heather Wakelee, and Karen Reckamp) when presented with the same case.  Here, you can see the convergence of principles but also how we sometimes struggle in our varied recommendations.

Here is a podcast of an important topic that comes up here all too often: What do we do for a patient with advanced NSCLC  and a known EGFR mutation who has responded very well and for a long time to an EGFR tyrosine kinase inhibitor (TKI), but now demonstrates rather slow but clear progression compared to their best response?  Should we continue on the EGFR TKI without any changes for a while? When we decide a change is needed, how do we approach that? Do we stop the EGFR TKI temporarily or for good, or do we continue it and add a chemotherapy-based regimen in addition?  And when we reach a point of clear acquired resistance, how valuable is it to do a repeat biopsy? Is this just an arguably a nice thing to consider or an approach that the experts would clearly pursue?

Below you’ll find the audio and video versions of the podcast, as well as the transcript and figures (in truth, this isn’t a very video-oriented presentation, so you won’t miss much by concentrating on the audio and/or the transcript only):

grace-cases-acquired-resistance-to-EGFR-TKI-audio-podcast

grace-cases-acquired-resistance-to-egfr-tki-transcript

grace-cases-acquired-resistance-to-egfr-tki-figures Continue reading →