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How does the diagnosis of BAC shape systemic therapy considerations today?
It’s not uncommon for a question here to be about the a pathologist’s terminology on a report that equivocates about whether a lesion is bronchioloalveolar carcinoma (BAC) or another form of adenocarcinoma, perhaps “well-differentiated adenocarcinoma”, especially if it has a radiographic appearance of a hazy infiltrate or many small ground glass opacities. Meanwhile, there’s a new classification of lung cancer subtypes that obliterates the term BAC, instead favoring a definition of adenocarcinoma in situ, classifying small non-invasive lesions previously called BAC as a pre-malignant condition. How have the changes over the past few years changed how we should approach BAC?
I would have to say that the new reassignment of BAC as adenocarcinoma in situ hasn’t taken the lung cancer world by storm and that I still think of the clinical entity as BAC. For the preceding decade, the definition the pathologist’s used technically excluded a lesion with even 1% or 5% of the lesion being invasive as being called BAC, even if it acted for all the world like BAC. Clinicians learned not to be too hung up on a pathologist’s technical definitions and tended to define BAC more functionally/operationally. General oncologists and expert lung cancer specialists alike managed BAC based on the overall picture of how it behaved if it looked like a BAC pattern.
HSP 90 Inhibitors: Another Rational Choice for Patients with Acquired Resistance to EGFR Inhibitors
Continuing Dr. West’s theme discussing new therapies for patients with acquired resistance, I’d like to answer a few questions about HSP 90 inhibitors that have caught my attention on GRACE over the past few weeks, and in particular, highlight my “pet” targeted agent, AUY922. HSP 90 inhibitors are drugs that many of you already know about-they are being studied in patients with ALK(+)lung cancer and as a 2nd line therapy option for all patients with lung cancer with Taxotere. But what you might not have known previously is that there is pre-clinical evidence that they may be also useful for patients with EGFR (+) lung cancer, with acquired resistance to Tarceva.
HSP 90 proteins are “chaperone proteins“-they form partnerships with other proteins-“client proteins”-- in order to guide the folding or bending of client proteins into the shapes necessary for normal protein activity. Although many, many proteins require HSP 90 chaperones for normal metabolism (ie., making a cell’s world “go round”), in particular those proteins which activate cancer development (“onco-client proteins“) can form complexes with HSP 90 chaperones -and they stay bound 100x more tightly once snuggled into their chaperone-client complexes. As a result, the onco-clients can remain “stable”, or focused on their mission of driving malignant cells to form tumors.
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Above you’ll see a cartoon illustrating a number of different proteins responsible for driving cancer cell survival and metastasis. All the proteins shown in red are onco-clients that require HSP 90 chaperones. You’ll notice that both EGFR and MET require HSP 90 chaperones (ALK does too, though not illustrated here) in order to fold and function. Therefore, you might ask “what happens if you get rid of that chaperone?”
Enter HSP 90 inhibitors. There are many HSP 90 inhibitors in development that you may have heard of: AUY922, IPI504, STA9090, SS-2248 to name a few. (Geldanamycin, 17 AAG, and 17 DMAG are older “parent” compounds of the same thing). When mice with EGFR (+) tumors with T790M or EGFR (+) tumors with MET amplification were treated with HSP 90 inhibitors, the tumors shrunk. We thought it would be interesting to study HSP 90 inhibitors and Tarceva in humans, and Novartis agreed to partner with us to study their HSP 90 inhibitor AUY922 in patients with acquired resistance.
Why continue the Tarceva in patients with acquired resistance? There are lots of anecdotal reports (and a couple of published papers) describing a disease “flare” for patients who stop their Tarceva after developing acquired resistance-either in terms of worsening clinical symptoms or in rapid radiographic progression of disease. The current hypothesis of acquired resistance is that it is a heterogenous syndrome that develops in different patients at difference places in the body, and not likely all of a sudden, but more gradually. As a result, many of us lung oncologists will continue Tarceva even as we start a 2nd line treatment in patients who have developed acquired resistance– to avoid any disease flare, and to capitalize on any remaining benefit from Tarceva.
For this reason, I wanted to test AUY922 added to Tarceva. However, this combination had not been tested before in humans. Therefore, the first step was to submit an IND (Investigational New Drug) application to the FDA for permission to study AUY922 and Tarceva in combination. Next, we opened the dose-escalation phase I study to find the “best” dose of each drug when given at the same time.
Currently, we’ve treated 3 patients at each of the 1st and 2nd dose levels. We’re hoping to step up to the 3rd dose level in mid-November. One of the side effects we were most worried about was the diarrhea– since both AUY922 and erlotinib can cause this. It was out of concern for causing horrible diarrhea that we had to start each drug at a lower dose than it would have been given individually. Fortunately, all diarrhea patients have reported has been manageable so far.
Based on prior experience with other HSP 90 inhibitors, we were also worried about whether AUY922 would cause any abnormalities in the heart’s electrical “firing”, or conduction system, and whether AUY922 would cause visual changes such as “floaters”, and/or difficulties accommodating (going from light places to dark places). No problems yet with anybody’s heart rates. The first hint of visual changes came just last week in one patient—and so we’ll be watching that closely going forward.
In order to be enrolled in this trial, patients all undergo a re-biopsy at a site of disease that has grown while on Tarceva alone. This tumor tissue will be tested for T790M, MET amplification and HGF (a partner with MET in cancer cells). This “side-car” project will help us figure out which mechanism of acquired resistance is/are being affected with inhibition of HSP 90.
This trial is open at Northwestern University in Chicago and at Memorial Sloan-Kettering in NYC. I am excited to say that accrual has been going really well, considering only three patients can be enrolled at once– on a dose-escalation trial, safety is the paramount focus. If the phase I study continues like it’s going now, I am hopeful that we’ll open a larger phase II study more focused on efficacy sometime next year. Stay tuned!
Afatinib vs. Placebo in EGFR-TKI Treated Patients: Efficacy in the Eye of the Beholder
It was almost exactly a year ago that I described the basic results of the global LUX Lung-1 trial that enrolled 585 patients with advanced NSCLC who had gone at least 12 weeks without progression on Tarceva (erlotinib) or Iressa (gefitinib) in a 2:1 fashion to either the oral targeted therapy afatinib (an irreversible inhibitor of the human epidermal receptor (HER) family, of which EGFR and HER2/neu are members, also known as a “pan-HER inhibitor”) or placebo. This trial was intended to enroll patients who had developed acquired resistance to an EGFR tyrosine kinase inhibitor (TKI) like Tarceva or Iressa, but the eligibility criteria were frankly a little too loose to really have enrolled a uniform population of patients who we think of as classic “acquired resistance” patients, who should have an EGFR activating mutation and would often have a very good response in terms of tumor shrinkage, or at least very prolonged stable disease. Requiring just stable disease for at least three months of an EGFR TKI allows the study to become a combination of 1) people with true acquired resistance after a very strong clinical benefit, and 2) people with slowly progressing cancer that didn’t happen to meet criteria for progression within 12 weeks on an EGFR TKI.
To review the highlights, the median age of patients was 58-59 years old, 60% of the patients were women, nearly two thirds were never-smokers, the median duration of response was about 10 months, and the objective response rate to prior EGFR TKI was about 45%. This is lower than the response rate to EGFR TKIs that is typically 60-75% for trials exclusively of patients with an EGFR mutation, and the median duration of response is a little on the low side, so my estimate is that only about one of every three or four patients squeaked into the trial but wasn’t really the target patient for the population that this trial was intending to study. However, this study was designed just before trial results like IPASS made it clear that molecular selection (identifying patients for trials based on the presence of a particular mutation) is clearly superior to clinical selection (identifying a patient based on clinical characteristics like race, sex, and smoking status).
Prevalence of EGFR Mutations in Patients with Adenocarcinoma: Moving Beyond Never-Smokers
The question of “who should be tested?” for an epidermal growth factor receptor (EGFR) mutation and potentially other molecular markers is among the most timely questions in lung cancer management today. The field has changed dramatically since the initial description of the mutation, associated with a high probability of an impressive and often prolonged response to EGFR tyrosine kinase inhibitor (TKI) therapy, back in 2004. For several years after that, mutations had been known to be neither absolutely necessary (occasional patients would have phenomenal responses despite not having a mutation identified) nor sufficient (response rates to EGFR TKIs among patients with an EGFR mutation have been in the 65-75% range, not 100%) to see a gratifying response. Moreover, it was also known that certain clinical/demographic characteristics, such as being Asian, female, a never-smoker, and having an adenocarcinoma or bronchioloalveolar carcinoma (BAC) tumor histology was associated with a higher probability of a significant response to EGFR TKIs as well, and that these characteristics are associated with a higher probability of having a lung cancer with an activating EGFR mutation (it has been clarified in the last few years that particular mutations in exons 19 and 21 are far more common than others and are the ones most consistently associated with a dramatic response, as discussed in Dr. Pennell’s terrific review of the subject).
Though I had previously felt there to be a potential role to be played by “clinical selection” of patients who might be best served by starting with an EGFR TKI inhibitor, such as for a never-smoker presenting with a lung adenocarcinoma, or potentially anyone with a BAC, the IPASS trial clearly illustrated that EGFR mutation status was a reliable means of selecting which patients are better served by prioritizing an EGFR TKI over standard chemotherapy, while clinical selection failed: as I described in my post “Confessions of a Former Clinical Selector“, the trial highlighted that even Asian never-smokers with a lung adenocarcinoma did better with chemotherapy than an EGFR TKI if they didn’t have an EGFR mutation.
Since then, multiple trials have confirmed that while a difference in overall survival (OS) hasn’t been clearly demonstrated, patients with an EGFR mutation have a very significantly improved progression-free survival (PFS) after starting an EGFR TKI compared with standard chemotherapy. Accordingly, testing for EGFR mutations has become far more common, though not a uniform practice. The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) now call for EGFR mutation testing in all patients who don’t have a squamous NSCLC tumor (since mutations are known to be unlikely — though are still seen rarely — in patients with a squamous tumor). Surveys of oncologist practices in the US over time have shown that more oncologists are testing than previously, but only perhaps a third to 40% of patients are being tested, and the probability of someone being tested having an EGFR mutation is about 40%, quite a bit higher than the 10-15% prevalence of the EGFR mutation among NSCLC patients in North America. This means that oncologists are being selective about who to test, and they’re focusing on patients who have a higher probability of testing positive.
Quick Update from ASCO
I apologize if it seems that the updates about ASCO have been slow in coming. This is mostly because the lung cancer program this year has most of the higher profile presentations occurring in the second half of the meeting, which we’re just getting into. And, truth be told, this isn’t going to be a blockbuster year for developments in lung cancer. But let’s review what we’ve found out about thus far.
Q&A With Dr. Sequist
The third and last podcast from our discussions with Dr. Lecia Sequist, of Massachusetts General Hospital and Harvard Medical School, covers the question & answer session that followed her excellent webinar on acquired resistance to EGFR tyrosine kinase inhibitors, as well as the update I did with her on the latest information from their experience of re-biopsying lung tumors over the course of treatment.
Here are the audio and video versions of the podcast, as well as the transcript.
sequist-qa-session-audio-podcast
Podcast: Play in new window | Download (35.1MB) | Embed
FAQ: I started an EGFR inhibitor two weeks ago but haven’t developed a rash. Does this mean it’s not working?
The short answer is no.
Since the introduction of the targeted agents that inhibit the epidermal growth factor receptor (EGFR), both the oral EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) or Tarceva (Erbitux), and the monoclonal antibody therapies against EGFR like Erbitux (cetuximab) have been identified as often having a rash as a leading side effect. Though often annoying and sometimes very difficult to manage, the development of a rash has also been identified as somewhat of a double-edged sword, as several early trials identified development of a rash as being associated with a better result on oral EGFR inhibitors, and even that there may be a correlation with best outcomes in patients who develop a more severe rash. Moreover, this same trend has also been seen in patients who receive Erbitux for lung cancer as well as for colon cancer.
Meanwhile, other corroborating tangents included the finding that smokers on Tarceva had fewer side effects and have also been consistently identified to not do as well with oral EGFR inhibitors as never-smokers or ex-smokers, very possibly related to faster metabolic breakdown of these agents in current smokers. It remains a possibility, though still not well studied and unproven, that a higher dose of EGFR TKI therapy may be more effective in current smokers.
Heterogeneity in Population of NSCLC Patients with Acquired Resistance to EGFR Inhibitors: T790M is Key Predictor
Over the past several years, probably the biggest development in the field of NSCLC has been the recognition of the importance of molecularly-defined subgroups that help define the clinical patterns of how patients are likely to do with various treatments. We’ve seen this clearly illustrated with EGFR mutations vs. EGFR wild type (no mutation), and more recently with the very uncommon but clinically important ALK rearrangements.
One newly defined clinical setting that has emerged has been the group of patients who experience a very good response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib) or Iressa (gefitinib), generally but not necessarily those with an activating EGFR mutation (most typically on exon 19 or 21, as described in this great summary by Dr. Nate Pennell) who respond for a period of months or years and then develop resistance. Why does it happen, and what are the leading options for managing this situation?
Early work on this problem of acquired resistance (as opposed to primary resistance, which is the situation in which a person starts out by not being very responsive to an EGFR TKI), largely out of the Harvard hospitals in Boston and Memorial Sloan-Kettering Cancer Center in New York City, have shown that about half or slightly more develop a resistance mutation called T790M on exon 20 (and a minority of people with an activating EGFR mutation also have this from the beginning, likely helping to explain why the response rate with one is not 100% but more like 70-75%). Another 10-20% or so are found to have over-expression of c-MET (targeted by agents like ARQ-197), reflecting a pathway that can bypass the EGFR signaling cascade as a mechanism for resistance.
Trifecta of Clinical Trials Show Major PFS Benefit for First Line EGFR Inhibitor Over Chemo for EGFR Mutation-Positive Patients with Advanced NSCLC
The IPASS trial that randomized never-smoking Asian patients with a previously untreated advanced lung adenocarcinoma to either standard chemo with carboplatin/Taxol (paclitaxel) or the oral EGFR inhibitor Iressa (gefitinib) was a pivotal study that changed how many of us thought about NSCLC. Clinical factors such as patient race, smoking status, tumor histology, and potentially patient sex have historically been useful in predicting which patients are most likely to benefit from an oral EGFR inhibitor (with Asian, never-smoking status, adenocarcinoma and especially bronchiooloalveolar carcinoma (BAC), and women being prevalent features of major responders). However, the IPASS study showed that the molecular marker of EGFR mutation is clearly more important than these clinical factors: in those patients who have an EGFR mutation, Iressa was associated with a far better response rate (RR) and progression-free survival (PFS), as well as a trend toward a more favorable overall survival (OS). On the other hand, in those who don’t have an EGFR mutation, even among Asian never-smoking women with an adenocarcinoma, chemotherapy was a clearly superior option. It is worth noting that this is specifically for the question of first line therapy, for which chemotherapy is the default standard therapy — the results comparing chemo to EGFR inhibitor therapy as second line treatment have been very comparable in broad populations.
Eligibility on the IPASS trial was based on clinical selection for patients more likely to benefit from EGFR inhibitor therapy, and it was only in a planned retrospective analysis that the importance of the very different results by EGFR mutation status became apparent. A slightly different question emerges if you know that a patient has an EGFR mutation before you start treatment. The IPASS trial strongly suggests that patients with an EGFR mutation will be better served by receiving first line EGFR tyrosine kinase inhibitor (TKI) therapy, and this has now been confirmed in three independent prospective randomized trials.
One pivotal study of this concept was done by the North-East Japan Study Group, performing a remarkably similar trial to that done by IPASS: carbo/Taxol or Iressa as first line therapy in patients with a prospectively identified EGFR mutation, using PFS as the primary endpoint. Though it was designed to enroll 320 patients, it closed early, when an interim analysis showed such a remarkably superior improvement in PFS that the Data Safety Monitoring Board considered that continuing to randomize patients on the trial would be unethical:
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TITAN Trial: Comparison of Chemo and Tarceva in Patients Who Progressed Early on First Line Chemo for Advanced NSCLC
One of the trials presented at the Chicago Multidisciplinary Symposium in Thoracic Oncology last month was the TITAN trial, one of a pair of studies conducted in Europe to test the oral EGFR inhibitor Tarceva (erlotinib) in patients with chemotherapy pre-treated advanced NSCLC. The other trial, SATURN, was designed to test Tarceva as a maintenance therapy vs. placebo in patients who had shown a response or stable disease after four cycles of first line chemotherapy (without the VEGF inhibitor Avastin (bevacizumab)) has been summarized previously and ultimately led to the approval of Tarceva as a maintenance therapy in this patient population. But what happened to the significant fraction of patients who progressed by the time of the repeat imaging after four cycles of first line platinum-based doublet chemotherapy? They were directed to the TITAN trial, which was a head to head comparison of Tarceva vs. either Taxotere (docetaxel) or Alimta (pemetrexed), both well studied and commonly used second line agents for advanced NSCLC. The trial looked for an improvement in overall survival with Tarceva.
The trial closed earlier than planned, due to slow enrollment, with just 424 patients, which leaves it quite underpowered to detect a difference even if there really is one between the two treatment approach. Still, there may be some conclusions that can be drawn from what they saw, even if limited by smaller numbers than needed to say anything definitive.
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