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Denise Brock

Lung Cancer Video Library – Controlling Brain Metastases in Patients with Molecular Driven Advanced NSCLC

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GRACE Cancer Video Library - Lung

Dr. Alice Shaw, Associate Professor of Medicine at Harvard Medical School, and Attending Physician Thoracic Cancer Program at Massachusetts General Hospital joined GRACE to discuss updates to our Lung Cancer Video Library. In this video, Dr. Shaw discusses controlling brain metastases in patients with molecular driven advanced non-small cell lung cancer.

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GRACE Video

ROS-1 Rearrangements: What Are They?

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GRACE Cancer Video Library - Lung

GCVL_LU-BA03_ROS-1_Rearrangements_Defined

 

Dr. Ross Camidge, University of Colorado, describes ROS-1 rearrangements and compares them to ALK rearrangements in frequency of occurrence and response to treatment.

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ROS-1 rearrangements are like the sister to ALK gene rearrangements. They’re also a gene which is silenced in most adult tissues, which is turned on again by a gene rearrangement creating what’s called a fusion protein which can drive the cancer cell. Structurally they’re very similar to ALK rearrangements and they respond to many of the same drugs. Particularly crizotinib, the first licensed ALK inhibitor, has also clearly shown good activity in ROS-1 driven cancers.

They’re rarer, maybe one quarter as common as ALK rearrangements or less. There are subtle differences. The benefit of crizotinib in ROS-1 gene rearranged lung cancer actually seems greater than it is in ALK, so the response rate is 70% as opposed to 60%. The median progression-free survival, the time it takes for the cancer to grow, on average is about 19 months as opposed to nine or ten months with ALK.

People are wondering about why the difference is, and there are various theories. Maybe crizotinib is actually a better ROS-1 inhibitor than it is an ALK inhibitor. Maybe the frequency of progression within the brain, which we know is somewhat of an Achilles heel for crizotinib and ALK-positive lung cancer — maybe that’s not such an issue with the ROS-1 rearranged patients simply because they have a lower frequency of deposits in the brain. Increasingly on a biological level, we’ve also seen a little bit of data that ROS-1 may be a more genetically simple cancer that ALK. It occurs in a part of the genome, part of the DNA of the cell, which is more structurally stable, so its ability to mutate and evolve in the presence of the drug and then progress later may be less. Either way, it’s a good thing to have if you have it.


GRACE Video

Is There a Role for PCI in Locally Advanced NSCLC?

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Dr. Nasser Hanna, Indiana University Health, addresses the issue of prophylactic cranial irradiation (PCI) in locally advanced NSCLC.

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Unfortunately many people with stage III disease are not cured of their cancer. We’re doing better, but we’re not doing good enough for most people and for those people who are not being cured, oftentimes the cancer will recur in what we call “distant sites.” That may be bones, it may be the liver, it may be the adrenal glands, these two small glands that sit above the kidneys, and sometimes it can be the brain.

When cancer progresses and shows up in the liver or shows up in the adrenal gland, it can certainly be disconcerting, sometimes it can cause symptoms and people don’t feel well, but oftentimes it’s something we just see radiographically. That’s oftentimes not true when cancer recurs in the brain. When it recurs in the brain, oftentimes it’s very unpleasant for somebody. They may have headaches, they may have double vision, they may have unsteadiness or nausea, they may pass out, they may even have seizure activity. So the idea of trying to prevent cancer from spreading to the brain is of paramount importance.

Now in another type of lung cancer, small cell lung cancer, we have utilized a strategy of prophylactically radiating the brain because we know that so many patients with small cell lung cancer eventually develop cancer in the brain. Prophylactically radiating the brain before any signs of cancer have appeared there may do one of two things. Number one is there actually may be microscopic disease in the brain that we really can’t detect on imaging studies for which you’re radiating when you’re doing the so-called prophylactic brain radiation. Secondly, some people believe that when you radiate the brain, it forms sort of an inhospitable environment for cancer to subsequently implant and seed. Either way, we’ve demonstrated that in patients with small cell lung cancer, you can reduce the incidence of brain metastases and in some cases actually help people live longer if you prophylactically radiate the brain.

Now the incidence of brain metastases in those with stage III non-small cell lung cancer is not as high as those with small cell lung cancer. Having said that, about 30-35% of those with stage III disease do eventually develop brain metastases. So the question has come up: should we or could we prophylactically radiate the brain and achieve fewer brain recurrences and perhaps maybe even help people live longer or cure more disease? Well the answer to this question is really unknown — there was one attempt at a carefully conducted clinical trial to test this idea, and unfortunately it was very difficult to accrue to this clinical trial, and it ended up only accruing about a third of the patients that it was meant to accrue.

We got some limited information from this clinical trial and what we learned is yes, we can reduce the incidence of cancer appearing in the brain by prophylactically radiating it. We really weren’t able to demonstrate in this small group of patients an ability to cure more people or help more people live longer, and certainly prophylactically radiating the brain does come with some side effects such as hair loss, fatigue, sometimes headaches, and sometimes nausea.

As of today, it is not standard to prophylactically radiate the brain in patients with non-small cell lung cancer and I’m not sure we’re ever going to get the completion of a clinical trial that will adequately address that, so I suspect for now and probably forever that will not be a standard approach for patients with stage III disease.


GRACE Video

Detecting Lung Cancer: Presenting Symptoms

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Dr. Gerard Silvestri, Medical University of South Carolina, describes some of the typical presenting symptoms of lung cancer.

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It’s really difficult for patients with lung cancer because the presenting symptoms can look an awful lot like bronchitis — patients tend to cough, patients can cough up streaky blood, patients can have chest discomfort. The difference between a lung cancer cough and a chronic bronchitis cough in a smoker is that it usually lasts a bit longer, it’s a bit deeper, and it’s different than their usual smoker’s cough. The sighting of blood within coughing is certainly a serious sign and should not be disregarded.

Sometimes, though, lung cancer can present with symptoms outside the chest because lung cancer does spread to other parts of the body, so occasionally we’ll get patients presenting with headaches because the cancer has gone from the lung to the brain, or bone pain because the cancer has gone from the lung to the bone. Generalized weight loss is another symptom that we concern ourselves with in patients with lung cancer.


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.


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