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GRACE Video

Maintenance Therapy for Advanced NSCLC

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Dr. Jack West, Swedish Cancer Institute, defines maintenance therapy in advanced NSCLC and discusses maintenance treatment strategies.

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For patients with advanced non-small cell lung cancer, our typical approach, if we have someone who does not have a driver mutation that we typically treat with a pill-based targeted therapy, is to give chemotherapy. That chemotherapy is typically given in a cycle of three weeks or sometimes a four week period of time where the blood counts go down and then recover. That treatment is typically given once every three weeks, sometimes once or twice on a weekly basis in that three week interval, but we typically give that therapy for about four to six cycles of therapy — that’s about three to five months of treatment. By that time, by four to six cycles in, the two drug combination that includes a drug called platinum is usually creating some cumulative side effects: fatigue, low blood counts, and other complicating issues that make it increasingly challenging to administer more of the same potentially intensive therapy, and by four to six cycles you really tend to reach a point of diminishing returns.

At that point we often favor a maintenance therapy approach. That is, dropping the carboplatin or stopping all of the agents that have been given previously and either continuing one or more of the agents from the first line setting, or using what’s called switch maintenance to give a completely different treatment. These maintenance therapies are designed to do what their name suggests — to maintain a response after we’ve seen the most shrinkage that we’re likely to get from the more intensive first line therapy.

When we do a continuous maintenance approach, it’s typically taking a drug like cisplatin or carboplatin in combination with one or two partner drugs, usually a second chemotherapy agent and sometimes Avastin which blocks a tumor’s blood supply, and then after four to six cycles we drop the platinum and we will typically continue a drug like Alimta if that’s been given in the first line setting, and if a drug like Avastin has also been given we might continue that and give Alimta and Avastin together until the cancer progresses.

If a combination like carboplatin and Taxol were given with Avastin, the maintenance therapy is often just the Avastin because Taxol tends to have some cumulative neuropathy issues — numbness and tingling that can lead to a real limitation in how much of that therapy you can give. We might also consider a switch maintenance approach — instead of continuing some of the agents, come in with Alimta as a single agent if a patient has non-squamous histology. Another agent that is approved as a switch maintenance therapy is Tarceva (erlotinib) — this doesn’t tend to be as favored as a switch maintenance because the efficacy of Tarceva in patients who don’t have an EGFR mutation tends to be on the lower side.

What do these maintenance therapies have in common? Well they’re all agents that can be given on a longitudinal basis without a lot of cumulative side effects and they tend to be the agents that have good activity in patients who have already been on prior therapy. So any of these is a reasonable choice, the most common being a continuation maintenance of dropping the platinum and continuing one or two partner drugs that were given with it, or sometimes switching to an agent like Alimta (pemetrexed) or Tarceva (erlotinib). It’s also reasonable to not pursue maintenance therapy if a patient has cumulative side effects and really needs a break from therapy. That is certainly something to discuss with the patient; it’s not as if maintenance therapy is a mandate for all patients, but it is something that is a strong consideration if a patient is motivated and can continue to tolerate ongoing therapy after four to six cycles.


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

Third Generation EGFR TKIs for Acquired Resistance

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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.


GRACE Video

Targeted Therapies in a Post-Operative/Adjuvant Setting

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Dr. Nathan Pennell, Cleveland Clinic, reviews the available trial evidence for the use of targeted therapies in the post-operative/adjuvant setting.

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I’d like to talk to you now about adjuvant treatment with molecularly targeted therapies for non-small call lung cancer. We know that early stage patients, so patients with stage I, II, or III non-small cell lung cancer — many patients are cured with surgery, but unfortunately, many patients go on to recur with metastatic disease. The reason this happens is that some of the cancer cells have escaped from the tumor before surgery and spread elsewhere in the body. This is called microscopic metastatic disease, and for this reason, we offer patients at high risk of occurrence adjuvant therapy. Adjuvant just means that we give four cycles of chemotherapy after surgery, and we know that this provides a modest, but significant improvement in cure rates after surgery alone.

Well, what about for patients who have molecularly defined subgroups of cancer, like EGFR mutation-positive cancer, or ALK-positive cancer? We know that, in the advanced setting, targeted therapies like Tarceva or Gilotrif for EGFR-positive cancer, or crizotinib or Xalkori for ALK-positive lung cancer, are better than chemotherapy in terms of inducing tumor responses, delaying the progression of cancer, and potentially even improving overall survival.

Since they work in the advanced setting, wouldn’t it make sense that they might work better in the adjuvant setting as well? Well, it’s not quite that simple. For one thing, we don’t have any evidence for any type of molecular subgroup, other than EGFR mutation-positive patients, but even in that setting, we really don’t have good evidence that adjuvant therapy improves cure rates after surgery alone. We have a little bit of evidence, so we know that the doctors at Memorial Sloan Kettering Cancer Institute in New York have treated several hundred patients with adjuvant Tarceva after surgery and they’ve reported that the patients have probably a lower than expected recurrence rate compared to what we might expect for that risk of patients, and they’ve suggested that maybe even they’re improving cure rates with adjuvant Tarceva.

Unfortunately, you can’t draw conclusions from a retrospective series and not a prospective trial. There have been at least two prospective trials that have been done, including one phase II trial that treated patients with two years of adjuvant Tarceva after surgery and then a subgroup of patients from a phase III trial called the RADIANT trial — so these were not EGFR mutation-positive patients in the overall trial, but there were 160 mutation-positive patients on the trial who were treated with two years of Tarceva, or two years of a placebo. All of these put together have suggested that adjuvant Tarceva does potentially delay the recurrence of cancers, but once the adjuvant treatment stopped, many patients went on to recur at a later time. None of the trials have suggested that patients lived longer or were cured at a higher rate than patients who were treated with standard treatment, including adjuvant chemotherapy.

What we really need is a randomized prospective phase III trial. Luckily, there is one that’s open and enrolling called the ALCHEMIST trial. Patients with stage IB, II, or III non-small cell lung cancer are tested for EGFR mutations or ALK gene fusions, and if those are found, they’re randomly assigned to two years of Tarceva for EGFR, or Xalkori for ALK-positive lung cancer patients, or two years of a placebo. Hopefully, at the end of this trial we’ll know whether patients are cured at a higher rate when treated with these adjuvant target therapies, versus just delaying the recurrence of the cancer.

For now, in 2015, I would not routinely recommend adjuvant therapy with a targeted drug like Tarceva or Xalkori outside of a clinical trial, but would strongly encourage patients to enroll in the ALCHEMIST trial.


GRACE Video

Emerging Options for T790M-Positive Acquired Resistance

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Acquired resistance in EGFR patients is often driven by the T790M mutation. T790M-positive tumors respond differently to treatments than T790M-negative tumors. Dr. Greg Riely details how each status can predict patients’ responses to current treatments.

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