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GRACE Video

Immunotherapy Combinations

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GRACEcast-526_Lung_West_Immunotherapy_Combinations

 

Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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The class of agents known as immune checkpoint inhibitors have really invigorated our study of lung cancer, and many other cancers over the last few years. Agents like Opdivo, also known as nivolumab, and Keytruda, known as pembrolizumab, are now commercially available, FDA approved as a second line therapy for patients who have progressed on first line standard chemotherapy. We are now actively asking the question of whether we might be able to move these immunotherapies into the first line setting and also asking whether we might do well by giving a combination of immune therapies, rather then just one treatment at a time.

So these agents, immune checkpoint inhibitors, are largely categorized into PD-1 or PD-L1 inhibitors, and those are just targeting two separate sides of an interaction between two receptors. The PD-L1 is on the tumor cells, PD-1 is on the immune T cells, and so blocking either side of this can lead to a beneficial effect because this effect leads to a braking mechanism on the immune system — you take away that braking system and you turn off the brakes and lead things to move forward, and that’s what we often see.

There are other agents that can also lead to braking mechanisms and that have been studied in other cancers. An agent such as Yervoy, which is known as ipilimumab is a CTLA-4 inhibitor and this is an agent that’s been approved in melanoma. In fact, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), as two different ways of blocking the immune system, have been shown to be beneficial as a combination in melanoma compared with either one on its own. Because of that, we’re looking at combinations of immunotherapies compared with single immunotherapy approaches, or standard chemotherapies.

One interesting study being done right now is called CheckMate 227 and it is looking at first line treatment of patients with advanced lung cancer that is either squamous or non-squamous histology. It does not require any level of PD-L1 expression on the tumors, the protein associated with tendency toward better efficacy of immunotherapies, partly with the thought that the combination of two immunotherapies may make even the cancers that don’t express PD-L1 respond well. This trial is looking at first line therapy with either standard chemotherapy of cisplatin or carboplatin with Alimta for non-squamous cancers, or Gemzar (gemcitabine) for squamous cancers, compared with either Opdivo alone or a combination of Opdivo and Yervoy — Opdivo being a PD-1 inhibitor, Yervoy being a CTLA-4 inhibitor — and asking the question of whether immunotherapy is as good, better, or worse than standard chemotherapy as a first line treatment, and whether the combination of two immunotherapies is better than first line therapy. 

I should mention that there are other trials looking at very similar versions of this question using different combinations of immunotherapies. There are many companies looking at several different immunotherapies in development and they are overall really very comparable and all quite exciting.

You can learn more about this specific trial from the link on the screen,

CheckMate 227 Clinical Trial

but I would encourage you, if you talk to your doctor and they recommend a trial with an immunotherapy in the first line setting, potentially comparing it to chemotherapy, to carefully consider it — it does not have to be this specific trial to be of interest.

We’re going to learn more about this in the coming years and we’re going to figure out the best way to integrate immunotherapies with our standard treatment approaches today.


GRACE Video

Histology-Specific Regimens – Squamous

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GCVL_LU-F06_Histology_Specific_Regimens_Squamous

 

Dr. Jack West, Swedish Cancer Institute, reviews the choices for a first-line chemotherapy regimen based on a squamous histology.

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There are a few common subtypes of non-small cell lung cancer. These are broken down by histology — the appearance of it under the microscope. The most common is called adenocarcinoma; the second most common is known as squamous histology and this accounts for somewhere in the range of 20% to 25% of the non-small cell lung cancers out there.

There are many standard chemotherapy regimens that are commonly used for patients with advanced non-small cell lung cancer, and overall they tend to produce very comparable results, making it very reasonable to choose one or another without a lot of difference, but there are certain regimens that might be more or less favored. For instance, in the setting of squamous lung cancer, there are a couple that we really choose to avoid in these patients because they are either unsafe or less effective.

So in terms of safety, one of the agents that we really prefer to not give is called Avastin and it is not a standard chemotherapy, but sometimes added to chemotherapy as a third agent that blocks the tumor blood supply. This can be helpful in some patients with non-squamous histology, but it has led to an unacceptably high risk of bleeding complications in patients with squamous histology. Because of that we do not give it in that setting — it is not considered safe.

Another agent that is really not favored is known as Alimta or pemetrexed, and that is because it does not seem to have good efficacy — it doesn’t do better than giving a placebo drug in that setting.

There are certainly other good choices. A cisplatin or carboplatin drug combined with an agent like Taxol, also known as paclitaxel, is a fine choice. There is also a related drug called Abraxane, which is also known as albumin-bound paclitaxel or NAB paclitaxel. This agent was added to carboplatin and compared to carboplatin and Taxol in a large group of patients with advanced lung cancer of a few different types, and the patients with squamous histology had a higher rate of tumor shrinkage if they received the carboplatin and Abraxane combination, than carboplatin and Taxol. It’s not an overwhelming difference and there wasn’t a clear difference in survival, but because of this some people might favor carboplatin and Abraxane.

Another choice that might be considered and favored in patients with squamous lung cancer is a platinum with Gemzar, also known as gemcitabine, and that’s because there was a randomized trial that gave cisplatin and Gemzar, or cisplatin and Alimta to patients with different types of lung cancer, and that study showed that the patients who got cisplatin and Gemzar did better overall than the patients who got cisplatin and Alimta. That might have been in large part because Alimta is not very effective in squamous lung cancer, but in fact we do tend to favor giving Gemzar as a leading partner with a platinum drug, if not a taxane. The taxane drugs: Taxol, Abraxane, or Taxotere, all seem to have efficacy that is every bit as good in the patients who have a squamous or non-squamous lung cancer.

So there are certainly several options, but some may be particularly better for patients with squamous histology.


GRACE Video

Histology-Specific Regimens – Adenocarcinoma

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GCVL_LU-F05_Histology_Specific_Regimens_Adenocarcinoma

 

Dr. Jack West, Swedish Cancer Institute, addresses the issue of choosing a first-line chemotherapy regimen based on an adenocarcinoma histology.

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There are several different subtypes of non-small cell lung cancer and these are broken down by what is called histology — how they appear under the microscope. The most common subtype of non-small cell lung cancer is known as adenocarcinoma and there may be specific recommendations about what chemotherapy to recommend for patients with an adenocarcinoma.

In general, we favor a two-drug so-called platinum-based doublet for the vast majority of patients with an advanced or stage IV lung cancer, but the exact chemotherapy combination we might favor can differ depending on whether a patient has one subtype, one histology, or another. So for patients with a lung adenocarcinoma it’s fair to say that any of the chemotherapy doublets widely used is an acceptable choice — cisplatin or carboplatin with a taxane such as Taxol, also known as paclitaxel, or docetaxel which is also known as Taxotere, you could consider Gemzar, also known as gemcitabine, but one that is often favored is called Alimta, or pemetrexed.

Why is that? Well, there was a study that was published years ago that looked at the combination of cisplatin and gemcitabine, or Gemzar, versus cisplatin and Alimta, and there were no major differences between the large groups of patients overall, but when they looked specifically at the subgroups based on whether they had a squamous or a non-squamous cancer, the patients who had a squamous cancer did better with cisplatin and gemcitabine, and the opposite was true for the patients with a non-squamous cancer — those patients did particularly well with cisplatin and Alimta. Since then there have been several other studies that have shown particularly favorable results with Alimta in patients with adenocarcinoma histology.

It’s fair to say that there are not great differences, but the tendency toward a more favorable efficacy in patients with adenocarcinoma and the good tolerability, lead many lung cancer specialists and general oncologists alike, to favor a combination of a platinum drug with Alimta for patients with a non-squamous, and especially, an adenocarcinoma histology.


GRACE Video

Platinum-Based Chemo Doublets: Backbone for NSCLC Treatment

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GRACEcast-515_Lung_West_Platinum_Based_Chemo_Doublets_Backbone_NSCLC_Treatment

 

Dr. Jack West, Swedish Cancer Institute, identifies the platinum-based chemotherapy doublet as the backbone of first-line treatment for the majority of NSCLC patients.

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The most common subtype of lung cancer is known as non-small cell lung cancer which comprises about 87% or 88% of all of the lung cancers out there. One of the big challenges in managing lung cancer and non-small cell lung cancer specifically is that about half of patients are diagnosed at a time when they already have stage IV or metastatic disease. At that time, this is not a cancer that we can treat to cure it, but our goal is to prolong survival as much as possible and also to minimize the cancer-related symptoms, as well as the treatment-related side effects.

Over the last 10 to 15 years we’ve really clarified the best approach in terms of chemotherapy for the majority of people with advanced non-small cell lung cancer. Now, chemotherapy is the optimal approach for patients who do not have a so-called driver mutation, which is an uncommon mutation such as EGFR or ALK or ROS1 that you may hear about which are present in a minority of patients with advanced non-small cell lung cancer, but the majority of patients don’t have one of these driver mutations.

For that majority who don’t have a driver mutation, the optimal treatment approach is standard two-drug chemotherapy. This is specifically called a platinum-based doublet and it’s called that because the main component or the first component is a drug called cisplatin or carboplatin that has been studied for many years and is paired with another drug such as Taxol, also known as paclitaxel, or Taxotere, known as docetaxel as well, Gemzar, also known as gemcitabine, Alimta, also known as pemetrexed, or occasionally other agents.

These two-drug combinations have been compared in many trials and really shown to be essentially remarkably similar if not identical in efficacy. Because of that, we usually choose the treatment, the two-drug combination, to recommend based on issues such as convenience to the patient — some of them are every week administration, others are every three weeks; for some patients coming in a long distance, three-week treatment is much more convenient. Some have hair loss, some do not, and also some of these agents may be particularly a little more effective in some subtypes of non-small cell lung cancer — known as the particular histology, and others might be a better choice for a different histology.

We’re going to talk about that specific difference and which regimens we might exactly recommend for one subtype or another in other videos, but right now it’s important just to note that the mainstay of treatment for the patients who don’t have a driver mutation, in the first line setting, is a two-drug platinum-based combination — cisplatin or carboplatin, with a partner drug, and they really do seem to produce very comparable results.

We’ll talk about some potential specific differences in other videos.

Thanks.


GRACE Video

Predictive Testing for Chemotherapy Responsiveness

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GCVL_LU-B12_Predictive_Testing_Chemotherapy_Responsiveness

 

Dr. Nathan Pennell, Cleveland Clinic, evaluates chemotherapy sensitivity assays, describing the difficulties inherent in predicting response to chemotherapy agents.

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I’d like to talk to you now about assays for testing for sensitivity to chemotherapy, or chemotherapy sensitivity assays. These are very simple and make perfect sense — you take a biopsy of a patient’s cancer, and do a test on it to determine what the best available personalized treatment would be, and then you tailor the patient’s treatment to that biopsy. This has been the gold standard in what we’ve been trying to do for decades, in all types of cancer, and we are already doing that in lung cancer where we’re looking for driver mutations such as EGFR mutations or ALK gene fusions, and then tailoring treatment based upon the presence of those mutations.

But what about chemotherapy? It’s still the backbone for most lung cancer patients — can we use an assay to tell which is the best chemotherapy that a patient might respond to? Well, the short answer is probably not, but let me explain why: there are two different ways to do this. One is to do specific tests or stains on the biopsy material for different markers that might predict whether chemotherapy would work or would not work, and the ones that are best known are called ERCC1 for platinum drug sensitivity, RRM1 for Gemzar sensitivity, or thymidylate synthase or TS for Alimta sensitivity. Studies have shown that different levels of these markers do tend to correlate with whether patients respond to these drugs. The problem with using these is, they’ve actually tried this in clinical trials, where some patients are treated with chemotherapy tailored to their different pattern of stains, and some people just get standard chemotherapy, and in the end, people all did about the same — chemotherapy worked just as well whether you did it based on these predictive markers, or whether you just picked it based upon the best available evidence for chemotherapy for that type of cancer.

So right now I would not recommend using that type of assay to determine a particular chemotherapy agent, despite the fact that companies right now will do this test and can send you a report with recommendations.

The other type of assay that’s done, which I think is more interesting, is they take a living bit of cancer out of the patient’s tumor, and actually grow it in a dish to treat those living cells with chemotherapy and see whether it works or not. The other way is to take living cancer and put it in a mouse and create a tumor in a mouse, what’s known as a xenograft, where we essentially create a little living model of your tumor, and you can treat the mouse with chemotherapy and see which ones work best. It’s very elegant, it’s very exciting.

The problem is, it’s expensive, it’s technically difficult, and it can take a long time and not work for a lot of people. The other problem is, the minute that you remove a cancer from a patient and put it in a dish, that cancer changes dramatically. It really doesn’t behave the same anymore, the way it did when it was in a person. It might be a little more accurate in a mouse, but even then, you can’t really trust that it’s going to behave the same way, and so as of right now, we really don’t have enough evidence that using these types of assays really will predict what’s going to happen in a real patient, and practically speaking it’s not going to be something that’s likely to be helpful in time for a patient who needs a choice right then.

The other thing to keep in mind is, lung cancer really doesn’t have a lot of differential sensitivity to different chemotherapies. What we tend to find in the clinic is that, tumors that are sensitive to chemotherapy often respond to many different types of chemotherapy; tumors that are resistant to chemotherapy are often resistant to all types of chemotherapy. You really don’t see that much differential activity from one agent to the next, so even if you get a report that predicts one better than the other, the likelihood is that it’s not going to do much better than just picking the best available proven chemotherapy.

So, in 2015, I would say don’t waste your money on these assays, but hopefully we will continue to investigate it and eventually that will change.


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