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HER2 Mutation Positive NSCLC

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GRACE Cancer Video Library - Lung

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

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

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GRACE Cancer Video Library - Lung

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.


Dr West

Direct Comparison of 2 EGFR Inhibitors Shows There Are Clinically Significant Differences

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At ASCO 2014, I provided the commentary after a key presentation demonstrated that the second generation EGFR tyrosine kinase inhibitor (TKI) Gilotrif (or Giotrif in some parts of the world) (afatinib) as first line therapy compared to standard chemotherapy in EGFR mutation-positive patients gave a significant benefit in overall survival (OS) that hadn’t been seen when other first generation EGFR TKIs, namely Iressa (gefitinib) or Tarceva (erlotinib) were compared to chemotherapy in EGFR mutation-positive patients. The question was whether this difference meant that Gilotrif is a significantly better EGFR TKI than Iressa or Tarceva. I noted that while these results were provocative, trials with Iressa and Tarceva were far smaller and in most cases were stopped early due to early results showing that the EGFR TKI was clearly superior in short term measures like progression-free survival (PFS) and response rate.  Accordingly, we couldn’t say anything definitive about the efficacy of one EGFR TKI vs. another by making inferences of each compared with an increasingly irrelevant comparator. If trial after trial showed that the EGFR TKI was clearly better than chemotherapy, we can’t draw meaningful conclusions of one being better based on how much stronger one looked than another against an inferior option. Instead,  the only reliable way to compare two EGFR TKIs would be to directly compare two EGFR TKIs in a randomized trial with the same eligible population.  In fact, such a trial, called LUX-Lung-7, had already been not only conceived but enrolled, randomizing EGFR mutation positive patients in Asia, Europe, Canada, and Australia to either Iressa or Gilotrif. We just needed to see how it turned out. Continue reading


GRACE Video

Panel Q&A Session on Sequencing EGFR Treatments with Drs. Riely and West

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Drs. Jack West and Greg Riely field questions about which treatments should EGFR lung cancer patients consider when their cancers progress.

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GRACE Video

Treatment Options for EGFR T790M Negative Acquired Resistance

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Dr. Jack West suggests that progression in T790M-negative EGFR lung cancer patients may not require a change in therapy. In this video he details what should go into the decision to modify treatment for those patients.

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