GRACE :: Lung Cancer


Other targeted therapies

Additional targeted therapy approaches against lung cancer


Platinum-Based Doublets As the Cornerstone of First Line Treatment

GRACE Cancer Video Library - Lung



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.


Is Targeted Therapy Feasible As Consolidation in Locally Advanced NSCLC?

GRACE Cancer Video Library - Lung



Dr. Nasser Hanna, Indiana University Health, reviews efforts to utilize targeted therapies as consolidation after chemoradiation in locally advanced NSCLC.

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Because those strategies testing additional systemic therapy utilized chemotherapy and those strategies did not improve outcomes compared to concurrent chemoradiation alone, we looked to try to give other forms of systemic therapy that were not chemotherapy to see if perhaps that would improve outcomes. Beginning in the 2000s there were a number of new drugs that appeared to be active in people with lung cancer and these are what we call molecularly targeted therapies. The first of these molecularly targeted therapies targeted a certain growth receptor on the surface of cancer cells, and this is called the epidermal growth factor receptor (EGFR) and we had a drug at the time which would target cancer cells that expressed this epidermal growth factor receptor. Well we understood in the 2000s that the vast majority of people with lung cancer have tumors that overexpress these growth receptors on the surface.

So clinical trials were designed to incorporate these new molecularly targeted therapies into the backbone of therapy that we had already established. Probably the best known of these trials was conducted by one of the United States cooperative groups in which all patients with stage III unresectable non-small cell lung cancer received the standard concurrent chemotherapy and radiation therapy backbone. Now in this trial patients were allowed to receive additional chemotherapy after that but the bottom line with this trial and the importance of this trial is then at that point patients were then randomized to receive either this molecularly targeted therapy or to receive a placebo.

At the time, again, this was the most effective molecularly targeted therapy we had in lung cancer and this was our greatest hope for further advancement over just giving concurrent chemoradiation alone. This drug was called gefitinib, it is approved by the FDA today and it is commercially available for people who have metastatic disease. What this trial demonstrated was giving that drug after chemotherapy and radiation therapy did not improve outcomes. In fact more people who received placebo had long term survival compared to those who received the gefitinib. So that hypothesis was utterly rejected and clearly is not the way forward.

Since that trial was designed we’ve come to better understand which patients actually benefit from these drugs that target the epidermal growth factor receptor. In fact we have new targets including a gene called anaplastic lymphoma kinase or the ALK gene and we have molecularly targeted therapy against tumors that have that gene abnormality.

So the current state of the art clinical trials testing molecularly targeted therapy are not just indiscriminately giving everybody the drugs, but they’re testing the idea that perhaps there are subsets of patients who would preferentially benefit from these targeted therapies. So one of the United States cooperative groups right now is conducting a clinical trial for patients with stage III unresectable disease. Everyone is getting concurrent chemoradiation, but those patients who have either an abnormality in the epidermal growth factor receptor gene, or in the anaplastic lymphoma kinase gene are also being randomized to receive the molecularly targeted therapy or not.

So this is a very different idea, this is not just empirically giving everybody these molecularly targeted therapies, but it’s targeting patients for these drugs based on the molecular biology of their disease. Now these trials are ongoing right now and I think we’re optimistic and we’re hopeful because we’ve seen the activity of these targeted drugs in patients who have metastatic disease. Perhaps we’ll see some improvements in outcomes in these targeted populations — that question is probably not really going to have an answer for about two or three years. That’s the current state of the art treatment that’s being tested regarding molecularly targeted therapy in stage III cancer.


Elderly Patients: Single Agent vs. Doublet Chemotherapy

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, discusses the use of single agent vs. doublet chemotherapy in elderly patients.

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I have the privilege of speaking to you today on the topic of therapeutic intensity for older lung cancer patients. My talk is entitled “How many drugs for elderly patients — 0, 1, or 2,” because that’s one of the major controversies that plays out in the real world.

The first point to be made in discussing the appropriate intensity of treatment for older patients is that older patients have a lot more life expectancy than many people think by common sense.


A 70 year old man in good health has an average of 14 years of life expectancy — that number is 16 years for women, and so a lot of this therapeutic nihilism that comes from doctors that say, “well this person is old, they’re going to die soon anyway,” is really unfounded — there’s quite a bit of quality life to be had for many older lung cancer patients and therefore, appropriate treatment should be pursued.


The traditional view of quality of life in cancer is that chemotherapy causes all kinds of terrible side effects — lots of nausea, loss of hair, fatigue and infections. So the dominant world view to many, both patients and I think doctors even too, is that the kindest thing to do is to give no drugs to avoid these horrible side effects and that’s the best way to maximize quality of life. It is certainly true that our drugs have very real side effects that cause very real suffering. The problem is that simplistic view of quality of life ignores the suffering that the cancer causes, and lung cancer is unfortunately one of the more brutal cancers.


When lung cancer presses on a nerve, and there are nerves throughout the body, it causes pain. When it spreads within the lung, is can clip off airways, causing cough and shortness of breath. When it spreads anywhere in the body, the soluble factors it releases can cause fatigue, trouble eating, blood clots, and so on and so forth. Anywhere in the body you can imagine lung cancer spreading, it can cause suffering. So I actually view quality of life more as a balance where our considerations have to consider both the suffering caused by the side effects of our treatment, on the one hand, but also preventing the suffering that lung cancer causes. A good treatment is one that minimizes the side effects, but also minimizes the suffering from the cancer and looks globally at total quality of life.

ELVIS, beyond being the king of trials, at least in terms of trial naming, was also the first trial to show a real improvement in survival by treating older lung cancer patients. At the time of design of this study there was legitimate controversy as to whether we were doing good by treating older lung cancer patients at all.


So this trial, at that time, randomized fit older patients to single agent therapy with a drug called vinorelbine or to placebo. As you can see at the left, there was a small but significant survival advantage with the use of vinorelbine, and at least as importantly, at right, you can see there was also a  quality of life advantage to the use of this treatment.

However, our standard of care for patients unselected by age is actually two drugs, not one. One of those drugs should be a platinum drug, and the other a partner drug like vinorelbine or many others.


CALGB 9730 was a randomized trial; patients were unselected by age — half got doublet therapy, two drugs, the other half got just one drug. So you can see at left, in younger patients, there is a survival advantage to the use of two drugs over one, and as you can see at the right, this survival advantage held for older patients.

After those results there was a lot of controversy still about whether to give two drugs or one. The camp that believed that one drug was better for older patients gave gemcitabine or vinorelbine. The camp the believed in two — a lot of us were very into this regimen of carboplatin with paclitaxel broken up to be given weekly. What we liked about this regimen is that for the fit older patient who tolerates beautifully, you can plow straight ahead, maximize his or her benefit. For the older patient that starts to get into some trouble with side effects, you can dose modify or even completely bail — you’re not stuck with three or four weeks worth of drug in the patient.


So this was a very well designed French trial that took what those who believed in single agent were using for fit older patients, versus what those who believed in double agent were using for their patients, and randomized them one against the other.


As you can see here, there was an improvement in cancer control with two drugs versus one, and this did translate into a significant and meaningful improvement in survival.

But you might ask me, “are all older patients fit,” and of course they’re not. With aging comes more medical problems, more medicines, greater fatigue, loss of hearing, loss of kidney function, and a variety of other physiological changes, and so it’s important to talk not just about the fit elderly, but also about the less fit elderly. In oncology, fitness is measured in terms of performance status.

Performance status 2 are those borderline patients that we think of, how intensely should we treat and where there’s great controversy.


There actually is a recent trial that looks specifically at these PS 2 or borderline-functional patients giving them single agent therapy with pemetrexed or double agent therapy with carboplatin and pemetrexed.


Overall this trial of patients with borderline-functional status showed an improvement in survival with two drugs versus one.


A huge portion of the patients in this trial were elderly, and so when we look at our less fit elderly patients as a subgroup of this trial, you see here that there’s still an improvement in survival.

 I should mention the two drugs versus one elderly study that I had mentioned earlier did have a subgroup analysis by those patients with borderline-functional status, and there was an improvement as well in that group.


Here’s toxicity when looking at two drugs versus one — you can see of course there are more side effects with two drugs versus one, but really nothing horrible. Carboplatin really added a small but real amount of toxicity, and for the survival advantage and improvement in suffering from cancer control provided, in my opinion it’s worth it for patients with good performance status, as well as perhaps those with somewhat borderline status.


So in summary, two is better that one, and I show here for your amusement my twins Betty and Dina that we’re delighted to welcome to the family — two is better than one! I thank you for your kind attention.


ALK Inhibitors for Acquired Resistance: Zykadia and Alectinib

GRACE Cancer Video Library - Lung



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.


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

GRACE Cancer Video Library - Lung



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.

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