GRACE :: Lung Cancer

Nathan Pennell

GRACE Video

Predictive Testing for Chemotherapy Responsiveness

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Dr. Nathan Pennell, Cleveland Clinic, evaluates chemotherapy sensitivity assays, describing the difficulties inherent in predicting response to chemotherapy agents.

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I’d like to talk to you now about assays for testing for sensitivity to chemotherapy, or chemotherapy sensitivity assays. These are very simple and make perfect sense — you take a biopsy of a patient’s cancer, and do a test on it to determine what the best available personalized treatment would be, and then you tailor the patient’s treatment to that biopsy. This has been the gold standard in what we’ve been trying to do for decades, in all types of cancer, and we are already doing that in lung cancer where we’re looking for driver mutations such as EGFR mutations or ALK gene fusions, and then tailoring treatment based upon the presence of those mutations.

But what about chemotherapy? It’s still the backbone for most lung cancer patients — can we use an assay to tell which is the best chemotherapy that a patient might respond to? Well, the short answer is probably not, but let me explain why: there are two different ways to do this. One is to do specific tests or stains on the biopsy material for different markers that might predict whether chemotherapy would work or would not work, and the ones that are best known are called ERCC1 for platinum drug sensitivity, RRM1 for Gemzar sensitivity, or thymidylate synthase or TS for Alimta sensitivity. Studies have shown that different levels of these markers do tend to correlate with whether patients respond to these drugs. The problem with using these is, they’ve actually tried this in clinical trials, where some patients are treated with chemotherapy tailored to their different pattern of stains, and some people just get standard chemotherapy, and in the end, people all did about the same — chemotherapy worked just as well whether you did it based on these predictive markers, or whether you just picked it based upon the best available evidence for chemotherapy for that type of cancer.

So right now I would not recommend using that type of assay to determine a particular chemotherapy agent, despite the fact that companies right now will do this test and can send you a report with recommendations.

The other type of assay that’s done, which I think is more interesting, is they take a living bit of cancer out of the patient’s tumor, and actually grow it in a dish to treat those living cells with chemotherapy and see whether it works or not. The other way is to take living cancer and put it in a mouse and create a tumor in a mouse, what’s known as a xenograft, where we essentially create a little living model of your tumor, and you can treat the mouse with chemotherapy and see which ones work best. It’s very elegant, it’s very exciting.

The problem is, it’s expensive, it’s technically difficult, and it can take a long time and not work for a lot of people. The other problem is, the minute that you remove a cancer from a patient and put it in a dish, that cancer changes dramatically. It really doesn’t behave the same anymore, the way it did when it was in a person. It might be a little more accurate in a mouse, but even then, you can’t really trust that it’s going to behave the same way, and so as of right now, we really don’t have enough evidence that using these types of assays really will predict what’s going to happen in a real patient, and practically speaking it’s not going to be something that’s likely to be helpful in time for a patient who needs a choice right then.

The other thing to keep in mind is, lung cancer really doesn’t have a lot of differential sensitivity to different chemotherapies. What we tend to find in the clinic is that, tumors that are sensitive to chemotherapy often respond to many different types of chemotherapy; tumors that are resistant to chemotherapy are often resistant to all types of chemotherapy. You really don’t see that much differential activity from one agent to the next, so even if you get a report that predicts one better than the other, the likelihood is that it’s not going to do much better than just picking the best available proven chemotherapy.

So, in 2015, I would say don’t waste your money on these assays, but hopefully we will continue to investigate it and eventually that will change.


GRACE Video

HER2 Mutation Positive NSCLC

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GCVL_LU-F17_HER2_Mutation_Positive_NSCLC

 

Dr. Nathan Pennell, Cleveland Clinic, describes treatment of NSCLC patients with HER2 mutations using agents such as Gilotrif or Herceptin.

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I’d like to talk now about HER2 mutation-positive non-small cell lung cancer. HER2 has actually been around for a while — most patients are familiar with this in the breast cancer field. HER2 is overexpressed, or a lot of it is expressed, in a subgroup of patients with breast cancer, and this is important because there are treatments against HER2 like Herceptin, which have improved the survival of breast cancer patients who have high levels of HER2 expression. This has also been tried in lung cancer because HER2 expression can be high in lung cancer as well. Unfortunately, the HER2 inhibitors like Herceptin have not been effective in lung cancer patients, historically.

What’s changed recently has been the understanding that a small group of lung adenocarcinoma patients, probably about 2%, will have an activating mutation in HER2, very similar to what’s seen in EGFR mutation-positive non-small cell lung cancer, but in HER2 instead. This is a real driver mutation and from other driver mutations like EGFR mutations, we know that inhibiting that driver can be very effective in treating patients.

The problem with this is it’s so new that there really haven’t been any clinical trials that tell us what the best treatment is for HER2 mutation-positive lung cancer, or how long you would expect this to last. There have been case reports of people treated with HER2 inhibitors such as Gilotrif or afatinib, which, while it’s approved for EGFR mutation-positive lung cancer, also inhibits HER2. We know that some patients have responded for some period of time to these drugs. We also have heard reports that Herceptin, usually used in combination with chemotherapy, can benefit some patients with HER2 mutation-positive non-small cell lung cancer, but there really isn’t enough evidence in 2015 to make a definitive recommendation of one or another of these drugs in this setting.

So if you have a tumor and they’ve identified an activating HER2 mutation in the cancer, the first choice I would recommend is participation in a clinical trial. One of the arms of what’s known as the National Cancer Institute’s MATCH trial includes all patients of all types of cancer that have derangements in HER2, including HER2 mutations, to treat patients specifically with a HER2 inhibitor. This would be, probably, my first choice for a HER2 positive patient, but if a trial isn’t available, or you’re not eligible for some other reason, talk to your doctor about perhaps trying off-label, either Gilotrif or Herceptin, in combination with chemotherapy. While there isn’t a recommendation about one or the other, both might be effective, and after discussion with your doctor, one might be an option for you. Although, I would reserve this for after exhausting traditional methods such as chemotherapy and immune therapy.


GRACE Video

ALK Inhibitors for Acquired Resistance: Zykadia and Alectinib

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Dr. Nathan Pennell, Cleveland Clinic, discusses acquired resistance to Xalkori in ALK-positive patients, and second generation inhibitors designed to overcome that resistance, such as Zykadia and alectinib.

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I’d like to talk now about next-generation anaplastic lymphoma kinase, or ALK, inhibitors. So, we know for patients with ALK-positive non-small cell lung cancer, that targeted treatment with ALK inhibitors like Xalkori, or crizotinib, are now the standard of care for patients with advanced disease, based on head to head trials showing that they work better than chemotherapy in inducing major tumor responses and delaying the progression of the disease, and potentially even improving survival. While responses can sometimes last a long time with Xalkori, unfortunately a majority of patients will eventually go on to develop what is known as acquired resistance where the cancer begins to grow despite continued treatment with the drug that worked so well initially. Something has changed in the cancer that’s caused the drug to no longer work to inhibit it, and when we biopsy these cancers, we find that there are a lot of different changes.

So unlike epidermal growth factor receptor mutation-positive lung cancer, there is no one dominant mutation that’s leading to resistance in ALK- positive lung cancer. There are lots of different mechanisms, but fortunately there are a wide array of new ALK inhibitors out there which have shown to be effective in this setting.

The first one that was farthest along and, in fact, is already approved for patients in this setting, is called Zykadia, or ceritinib. This was approved last year based on a large trial in patients who had progressed on the Xalkori, and about 50-70% of patients will have a major response to the Zykadia, with a duration of disease control that’s, on average, probably in the eight to ten month range. This drug is a little bit tougher than the Xalkori, so many patients have some nausea or vomiting, diarrhea or upset stomach, but these are things that oncologists are used to dealing with and with dose reductions and management of side effects, patients can tolerate this and it can work quite well.

There are also a number of other ALK inhibitors that are still in clinical trials that are likely to be approved soon. Probably the one that’s farthest along is known as alectinib. So we’ve just recently seen trials, again, showing that between 50-70% of patients with acquired resistance to the Xalkori will respond to alectinib, and the vast majority will have disease control for a fairly good period of time — again, the average is somewhere in the eight to ten month range, but many patients longer than that, and at least in published results, alectinib may be easier to tolerate than the Zykadia.

So this is just the tip of the iceberg. At last count, I think there were six or seven other next-generation ALK inhibitors in development — I don’t have time to list all of them, and none of them have been compared to one another to know which one is best, but all of them, at least preliminarily, appear to be effective in the setting of acquired resistance to crizotinib.

What I would recommend in 2015 is, if patients develop an acquired resistance to the Xalkori, that they preferentially enroll on a clinical trial of one of the new next-generation ALK inhibitors because I think this is the only way we’ll ever learn which of them is best and which one works the longest. But, if you don’t have a clinical trial available to you, or you’re not eligible for a clinical trial, your doctor can prescribe Zykadia right now and we know that’s an effective treatment.

The other thing that’s nice about these drugs is that they all seem to have some activity in brain metastases. We know that ALK-positive patients develop brain metastases at an extremely high rate, and this can be a real problem, sometimes even while the rest of the cancer remains under control. Both alectinib and Zykadia have been shown to have efficacy in brain metastases, in addition to the rest of the body — so, good news for ALK-positive lung cancer patients.


GRACE Video

Combinations and Other Options for Acquired Resistance in EGFR Mutation-Positive NSCLC

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GCVL_LU-F14_Combinations_Other_Options_EGFR_Acquired_Resistance

 

Dr. Nathan Pennell, Cleveland Clinic, describes other options for treatment of acquired resistance, including chemotherapy, ablation with SBRT and a combination of Gilotrif and Erbitux.

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On other videos in this series, we talked about next generation inhibitors for molecularly defined subgroups of patients who’ve developed acquired resistance. Now I want to talk about other options — if you don’t have a clinical trial available, or if you’ve already tried a next generation inhibitor and it stopped working.

We know that for patients with EGFR mutation-positive lung cancer, or ALK-positive lung cancer, the targeted therapies with drugs like Tarceva or Xalkori are more effective than chemotherapy and are really the standard of care for these patients. But unfortunately, most patients go on to develop what’s known as acquired resistance, where the cancer eventually begins to grow despite initially being controlled by the targeted therapy. While there are drugs being developed that are better inhibitors in that setting, they’re not always available outside of a clinical trial, or perhaps not ideally suited for a particular patient’s situation. So, what do you do in that setting?

There are a number of different options. The first thing to keep in mind is, not every patient who is developing acquired resistance needs to change what they’re doing. Sometimes, if the cancer is beginning to grow, it can grow in a very slow, asymptomatic way. In other words, it’s not causing symptoms, every time you do a scan it’s a little bit bigger, but the patient feels fine, is not having a lot of side effects from the drugs — you can continue to watch these. This can be anxiety-provoking, but I’ve watched patients for six months, nine months, sometimes longer before we really need to make a change. In the same vein, we know that about 20% of patients who develop acquired resistance don’t develop resistance everywhere in the body. Maybe only one or a couple of the tumors are growing, and if you biopsy those you can see that new mutations and mechanisms of resistance can arise in individual tumors while the rest of the cancer remains under control.

To borrow a phrase from my friend Dr. Ross Camidge at the University of Colorado: don’t overthink it — if one of the tumors is growing and all of the rest of them are the same, we can ablate the tumor that’s growing, essentially eliminate that, and patients can stay on the drug that they’re already on, sometimes, again, for six or nine months, sometimes longer, before resistance emerges elsewhere in the body.

The most commonly used mechanism for this is something called stereotactic body radiotherapy, or SBRT, which is a very effective way of using radiation to target individual tumors that tends to have very few side effects. Most patients, however, will eventually need to change the therapy that they’re on.

So, if you can’t stay on the drug any longer and you need to make a switch, one thing that many patients don’t even consider is going to chemotherapy. We know now that, since patients are being tested for EGFR mutations and ALK gene fusions upfront, many of them never receive chemotherapy and they start on a targeted therapy, but chemotherapy can be very effective for patients with EGFR mutant lung cancer or ALK-positive lung cancer, and in fact, tends to work better on average than in people who don’t have these mutations. I’ve had many patients who’ve had longer periods of disease control on chemotherapy than they had on the targeted therapies that everyone was so excited about. So, don’t despair if your doctor suggests chemotherapy because it may be a good option for you.

There are other clinical trials available, we’ve got the immune therapies that are out there — just the same treatments that are available for other types of lung cancer. There is one other thing I want to mention, for EGFR mutation-positive patients, there is a second generation inhibitor called afatinib, or Gilotrif. Gilotrif by itself is not effective for acquired resistance in EGFR, but when you add it to a second EGFR inhibitor called Erbitux, or cetuximab, in a large phase IB trial, we know that about a third of patients will have a major response to that combination, regardless of why their cancer developed acquired resistance. Sometimes this can last, on average, seven or eight months; I’ve used this and actually seen pretty good responses. It can be a little bit tough — both drugs cause diarrhea and skin rash, which can be worse when given together, but these tend to be manageable for most people.

So, in 2015, if your cancer develops acquired resistance to a targeted therapy and there isn’t a clinical trial available for one of the newer agents, don’t despair. There still are a number of things that can be tried, from remaining on the drug, to ablating the limited number of spots that are progressing, to switching to chemotherapy or participating in another clinical trial.


GRACE Video

Third Generation EGFR TKIs for Acquired Resistance

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GCVL_LU-F12_Third_Generation_EGFR_TKI_Acquired_Resistance

 

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

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So I’d like to talk now about third generation, or mutation-specific inhibitors for epidermal growth factor receptor mutation-positive lung cancer. We know that for EGFR mutation-positive lung cancer, targeted therapy with drugs like Tarceva, Iressa, or Gilotrif are the standard of care based on trials showing they’re better than chemotherapy for improving tumor responses and the time to progression of cancer for many patients, and they can be very effective and sometimes last a long time.

Unfortunately, the majority of patients will eventually go on to develop something called acquired resistance, where the cancer begins to grow despite continued treatment with the drug that worked so well, sometimes for a long time. Something has changed in the cancer that has caused it to be resistant to the drug. When we biopsy these tumors that are progressing, what we find for EGFR mutant patients is that about 50-60% of these tumors have a new mutation, something called T790m, in exon 20. The original mutation is still there, but now it has a new mutation and this has caused the cancer to no longer respond to the Tarceva or the Gilotrif.

The good news is, there’s a whole new class of drugs available that have been specifically designed for this type of cancer, the T790m-positive cancer. These are called mutation-specific inhibitors because they inhibit only the mutant EGFR, and not the normal wild type EGFR that’s spread throughout the rest of your body. So, they tend not to have the same side effects that drugs like Tarceva or Gilotrif would have. They have less of the acne-like rash, less diarrhea; they do have different side effects. For example, one of the best known drugs is called Rociletinib, formerly CO-1686, and while it doesn’t have a rash or much diarrhea, it can raise blood sugar similar to type 2 diabetes which usually can be managed in the same way with oral drugs. The other well known drug is called AZD-9291, and one or both of these drugs is likely to be approved within the next year for T790m-positive EGFR mutant lung cancer.

Both of these have had large trials that have been presented showing that between 50% and 70% of patients with the T790m mutation will have a major response, and the vast majority of patients will have disease control, with a median time, average time, somewhere in the 8-10 month range before progression — some patients significantly longer. These are really nice options for patients who have this specific type of cancer.

Unfortunately, patients will need to have a new biopsy of their cancer at the time of developing acquired resistance, although they are trying to develop blood tests which are hopefully going to eventually replace needing a new procedure to biopsy your cancer. In 2015, for patients who develop acquired resistance, I would recommend a biopsy of the progressing cancer, and if they have T790m, enroll them on one of the clinical trials with either Rociletinib, AZD-9291, or one of the many other third generation EGFR inhibitors that are farther back in development.


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