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Third-line therapy and beyond

Treatment standards and emerging options for significantly pre-treated advanced NSCLC

GRACE Video

Platinum-Based Doublets As the Cornerstone of First Line Treatment

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Dr. Benjamin Levy, Mount Sinai Health Systems, discusses platinum-based chemotherapy as the standard of care for advanced NSCLC patients without targetable genetic mutations.

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I’m going to be talking about the role of platinum chemotherapy for patients with advanced stage non-small cell lung cancer. No doubt, there have been significant advances in the past ten years with the development of targeted drugs for those patients who have a particular genetic makeup of their tumor. Many of these drugs have shown to be quite effective for those patients that are susceptible to such treatments. I think what we know though is unfortunately many patients will not have the genetic alterations that make them eligible for targeted treatments, and we have to default to chemotherapy.

I think ‘default’ is a bit of a misnomer because platinum chemotherapy or platinum doublet chemotherapy remains a standard of care for patients with advanced stage lung cancer who don’t harbor particular genetic alterations in their lung cancer and that’s okay. I think what we know about chemotherapy, platinum chemotherapy specifically, is that this type of approach improves survival for patients and it also can have the potential to improve quality of life as well as control symptoms as they relate to the lung cancer. So all three of those measures can be achieved with platinum chemotherapy.

Now chemotherapy comes in a variety of different shapes and sizes — the chemotherapy that we tend to use sometimes is called histology-directed chemotherapy, so patients with a particular type of lung cancer called adenocarcinoma may get one type of platinum chemotherapy, whereas patients with a particular type of lung cancer called squamous cell may get a different type of chemotherapy.

I just want to speak briefly about maintenance chemotherapy for adenocarcinoma patients. This is the most common type of lung cancer we see, and again for those patients that don’t harbor genetic alterations that make them eligible for targeted drugs, we can offer a very effective chemotherapy that’s also very tolerable and that can also be given as a maintenance strategy. What I mean by that is that patients generally get four cycles of chemotherapy and for those patients that at least achieve stable disease after their four cycles and are tolerating treatment, I think that we have good data now that we can drop the platinum and continue one of the drugs called pemetrexed and provide a survival advantage for those patients. There are certain maintenance strategies that are also being looked at in the squamous cell population and there are studies ongoing for that.

I think, in some, that the chemotherapies we have now work very well, they can extend life, they can improve quality of life and they’re well tolerated, and I also think specifically for the subset of patients that come in with adenocarcinoma or non-squamous, that there should be a consideration for patients who are tolerating chemotherapy to be offered a maintenance approach.


GRACE Video

What are the Goals of Treating Advanced NSCLC?

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Dr. Benjamin Levy, Mount Sinai Health Systems, lists the goals of treating advanced NSCLC and the methods used to achieve those goals.

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I think there are several goals when treating a patient with advanced non-small cell lung cancer. For one I think we want to extend life, two is I think we want to palliate symptoms, and three is I think we want to improve quality of life. So all three of those goals are achievable, I think, with the therapies that we have right now.

Now, some of these therapies are targeted drugs, so for patients that have genetic alterations or a genetic makeup that makes them eligible for targeted drugs, then clearly we can offer these drugs and I think we can achieve all three of those goals. But even for patients without genetic alterations, and patients who will not be receiving targeted drugs, I think we can extend life, improve quality of life and palliate symptoms by delivering chemotherapy. I think we know now that chemotherapy is not the chemotherapy of the days of old — these drugs are given in combination, are tolerable and can improve outcomes. We also have now immunotherapy, and so all three types of systemic approaches can help achieve these three goals.

In addition to these three goals, I think it’s important that we also have goals of care discussions with patients from the being of treatment. I think what that means is that we really come up with what the shared expectations are for treatment. Patients may ask specific questions like “how many months will additional chemotherapy give me versus no chemotherapy?” I think these questions are fair game. I think we can certainly talk about averages but also tell patients that they’re not an average and I would sway doctors or patients receiving information not to stick to exact numbers, but I do think that a goals of care discussion upfront is very important.

That brings into the realm the role of palliative approaches or palliative care. Many patients feel that palliative care is hospice or end of life care, but this is not the case. I think what we know now is that patients who have early palliative care referrals to palliative care specialists in conjunction with their treatment, specifically for lung cancer patients, these patients actually live longer.

So I bring up this whole concept of discussing goals of care very early on so we can make sure that our patients are referred to palliative care specialists who can treat patents alongside us and work in conjunction to help improve outcomes for our patients.


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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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

Panel Q&A Session on Acquired Resistance with Drs. Reckamp & Owonikoko

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Dr. West moderates a question & answer session with Drs. Karen Reckamp and Taofeek Owonikoko on issues of acquired resistance to targeted therapies for patients with advanced NSCLC that harbors a driver mutation.

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