GRACE :: Lung Cancer

driver mutation

Denise Brock

Lung Cancer Video Library – Role for Immunotherapy for Patients with Driver Mutations

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We welcome Dr. Luis Raez, MD FACP FCCP, Chief of Hematology/Oncology and Medical Director at Memorial Cancer Institute, and Clinical Associate Professor of Medicine at Florida International University with 2017 updates to our Lung Cancer Video Library.  In this recent video for GRACE, Dr. Raez discusses the Role for Immunotherapy for Patients with Driver Mutations.


 

 

 

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 Dr. Luis Raez, MD FACP FCCP

Chief of Hematology/Oncology and Medical Director, Memorial Cancer Institute
Clinical Associate Professor of Medicine, Florida International University
 

 

 


  


GRACE Video

Platinum-Based Chemo Doublets: Backbone for NSCLC Treatment

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Dr. Jack West, Swedish Cancer Institute, identifies the platinum-based chemotherapy doublet as the backbone of first-line treatment for the majority of NSCLC patients.

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The most common subtype of lung cancer is known as non-small cell lung cancer which comprises about 87% or 88% of all of the lung cancers out there. One of the big challenges in managing lung cancer and non-small cell lung cancer specifically is that about half of patients are diagnosed at a time when they already have stage IV or metastatic disease. At that time, this is not a cancer that we can treat to cure it, but our goal is to prolong survival as much as possible and also to minimize the cancer-related symptoms, as well as the treatment-related side effects.

Over the last 10 to 15 years we’ve really clarified the best approach in terms of chemotherapy for the majority of people with advanced non-small cell lung cancer. Now, chemotherapy is the optimal approach for patients who do not have a so-called driver mutation, which is an uncommon mutation such as EGFR or ALK or ROS1 that you may hear about which are present in a minority of patients with advanced non-small cell lung cancer, but the majority of patients don’t have one of these driver mutations.

For that majority who don’t have a driver mutation, the optimal treatment approach is standard two-drug chemotherapy. This is specifically called a platinum-based doublet and it’s called that because the main component or the first component is a drug called cisplatin or carboplatin that has been studied for many years and is paired with another drug such as Taxol, also known as paclitaxel, or Taxotere, known as docetaxel as well, Gemzar, also known as gemcitabine, Alimta, also known as pemetrexed, or occasionally other agents.

These two-drug combinations have been compared in many trials and really shown to be essentially remarkably similar if not identical in efficacy. Because of that, we usually choose the treatment, the two-drug combination, to recommend based on issues such as convenience to the patient — some of them are every week administration, others are every three weeks; for some patients coming in a long distance, three-week treatment is much more convenient. Some have hair loss, some do not, and also some of these agents may be particularly a little more effective in some subtypes of non-small cell lung cancer — known as the particular histology, and others might be a better choice for a different histology.

We’re going to talk about that specific difference and which regimens we might exactly recommend for one subtype or another in other videos, but right now it’s important just to note that the mainstay of treatment for the patients who don’t have a driver mutation, in the first line setting, is a two-drug platinum-based combination — cisplatin or carboplatin, with a partner drug, and they really do seem to produce very comparable results.

We’ll talk about some potential specific differences in other videos.

Thanks.


GRACE Video

Can Patients Benefit from Broad vs. Focal Genetic Testing?

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Drs. Ben Solomon, Leora Horn, & Jack West evaluate the merits of broad genetic testing with a “next generation sequencing” platform compared to selective, limited testing for the most proven driver mutations in patients with advanced NSCLC.

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Dr. West:  One of the bigger questions in the whole management of lung cancer is now whether and how often to do broad genomic testing, or really focal testing for a few clearly actionable mutations like EGFR, ALK rearrangement, ROS1, perhaps others that may emerge. What’s your approach — where do you think that your rank and file community oncologist should be, in terms of using broad genomic testing to find, not only the more common ones, but the rarer ones? Do we have enough rare mutations now to widen the scope of our looking, or are there barriers, whether it’s the turnaround time, or others interpreting the results of various rare rabbit holes to go down, that it make it not ready for prime time? Leora, what do you think?

Dr. Horn:  A lot of academic sites are doing it because we have clinical trials. If we’re talking about practical, you know, what day-to-day, I think that it’s important, at minimum, to do EGFR, ALK, ROS, RET, and even BRAF, because there’s been some promising data. If you can get that all done, and maybe it’s through multiplex testing, or next generation sequencing — the problem is, sometimes these test results come back and you get mutations, you don’t know what to do with them, or there’s nothing available for those patients. So, for a day-to-day, practical, we should do those minimal, actionable mutations. I think it’s always nice to know the additional information, but I don’t think it’s essential in making treatment decisions.

Dr. West:  Ben, what do you think?

Dr. Solomon:  So, I agree — I think what’s essential is that a patient gets the best available treatment. Now, the best available treatment will vary from place to place, and country to country, but currently, in most places around the world, EGFR inhibitors and ALK inhibitors are available, and guidelines from professional societies, such as the College of Pathologists, and ASCO, and IASLC, recommend at a minimum testing for EGFR and ALK, and I think that’s a minimum. Now, I think there’s a good case for adding things like ROS1, because of availability of crizotinib, and with the availability of trials at different molecular targets, I think there is a good reason, in most academic centers at least, to expand the panel to include a larger number of actionable mutations, and I think the eventual place that we’ll get to is where all of these tests get done in one test, and we get a report analogous to a Foundation Medicine report that sums up the actionable mutation.

Dr. West:  Yeah, I think once get beyond three of four, it starts to tip the scale toward just get everything at once. I mean, if we’re moving to a time when HER2 mutations, and MET over amplification, as well as, as you said, BRAF, and others, I mean, there’s RET — the list is getting long enough, and it seems that we’re adding maybe one or two every year or so, that hopefully it will be worth doing a broad panel approach for the majority of patients. But, as you say, it depends on where you are and what your access is.


GRACE Video

Do Clinical Characteristics Alter Your Enthusiasm for Immune Checkpoint inhibitors?

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Drs. Leora Horn, Ben Solomon, & Jack West assess whether clinical factors such as being a never-smoker or having a driver mutation (EGFR, ALK, etc.) reliably predict minimal benefit from immunotherapy agents.

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Dr. West:  We’re starting to see some early results suggesting that never-smokers and patient with driver mutations, like EGFR, or an ALK rearrangement, or ROS1, are particularly unlikely to have very good responses to these agents, the immune checkpoint inhibitors. Even if PD-L1 testing isn’t required, do these clinical characteristics matter to you, in terms of whether you’re less likely to recommend an immune checkpoint inhibitor as an early therapy in patients with no smoking history, or a driver mutation, are you thinking that this is really not likely to work, or are patients or clinicians so eager to use them that it’s really the first opportunity, no matter what the patient characteristics are?

Dr. Solomon: Yes, so I think the data so far haven’t been that exciting in patients, certainly with EGFR mutations, and probably also patients with ALK rearrangements, and why that is, I think, remains to be sorted out. Like you were suggesting, maybe it has to do with the mutational load, within tumors. So, I think — we want patients to receive the most effective treatments early on, and certainly, I don’t think there’s a role outside of clinical trial of using these inhibitors before therapy with an ALK or an EGFR inhibitor. I think there are some really interesting studies that look at using concurrent EGFR or ALK inhibitors with a PD-1 inhibitor, and I think it will be really interesting to see whether that increases response rates in these populations.

Dr. West:  What are your thoughts about the role for immune checkpoint inhibitors in never-smokers, and patients with driver mutations?

Dr. Horn:  I completely agree with what Ben said, you know, and many of those patients have been excluded from the first line trials, if you’re EGFR or ALK positive, because there are such great options for those patients. There was a little hint of — maybe we’re going to see some responses with the community study that was presented with nivolumab, where they showed around a 10-11% response rate in those patient populations — very small numbers, so maybe there are a group of patients that will respond, but I agree that the combination therapies look really, really interesting. The difference is that EGFR inhibitors — they’re incredibly effective, but at some point, they’re failing the patients, whereas, if a PD or PD-L1 inhibitor is working, they really have these long, durable responses that are often measured beyond just one year of therapy.


GRACE Video

What is the Value of Testing for Molecular Markers in Advanced NSCLC?

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Memorial Sloan-Kettering Cancer Center medical oncologist Dr. Greg Riely explains how testing for specific mutations in patients with advanced NSCLC can guide prognosis and treatment recommendations.

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When we’re evaluating a patient with lung cancer, the first question we start to ask is, what’s going on with this patient’s cancer? Where is the disease, so has it spread to other sites, and what does it look like under the microscope? So, what’s the tumor histology, is it an adenocarcinoma, squamous cell carcinoma. And then, importantly, molecular testing has become a critical part of our understanding of a patient with lung cancer.

Now, by doing molecular testing, we’re able to better refine the prognostic and predictive value of a variety of drugs and treatments that we have going forward, for designing an overall treatment plan for a patient. Some of the most common testing that should be done are EGFR and ALK — now, these are important because these both have FDA approved drugs that are indicated for abnormalities in EGFR and ALK. If you go beyond those two things, there are actually a long list of drugs that can target individual molecular aberrations and molecular abnormalities, but they’re uncommon, and we don’t have FDA approved drugs for those things, but I think if we go beyond those EGFR and ALK tests, we can learn a lot more and sometimes help patients a great deal.


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