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GRACE Video

Immunotherapy as First-Line Treatment

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Dr. Jack West, Swedish Cancer Institute, raises the question of whether to use immune checkpoint inhibitors as first-line treatment of lung cancer, alone or in combination with chemotherapy.

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A class of agents known as immune checkpoint inhibitors has really incredibly invigorated the field of lung cancer and many other cancers over the last year or two. These agents are given intravenously and essentially take off a braking mechanism for the immune system and by doing that, can stimulate it to recognize and attack your own cancer. These agents, at least a couple of them, have been approved by the FDA as of now, in late 2015, and the question is whether they should be used earlier than the second line setting where they’ve already been approved.

Two agents, one known as Opdivo or nivolumab, and another known as Keytruda or pembrolizumab, are approved in patients who have already demonstrated progression after receiving a first line chemotherapy. So the question is: should these treatments be given earlier in therapy? There are two leading considerations in how we might do this. One is that we might give an immunotherapy in combination with standard chemotherapy. There are other ways to do this that might give the immunotherapy instead of standard chemotherapy. There are studies looking at various combinations being done with any of the many immune checkpoint inhibitors that are in development right now.

An interesting trial that is being done now is with pembrolizumab, or Keytruda — this is the KEYNOTE-189 trial that is looking at whether the addition of Keytruda to standard chemotherapy improves outcomes for patients when they get it first line. Specifically this trial is for patients with a non-squamous cancer and these patients can have any level of PD-L1 expression, the protein that tends to be associated with better activity of the immune checkpoint inhibitors — there’s no restriction on PD-L1 expression and patients just have to have not received prior therapy for advanced lung cancer. These patients are then randomized to receive the two drug chemotherapy combination of cisplatin or carboplatin with Alimta, or that same chemotherapy combination with Keytruda (pembrolizumab). That study is being done now and we hope to learn more about it in the next year or two, to learn whether it is beneficial to give these immunotherapy agents in combination with chemotherapy, compared to giving them sequentially.

Another very similar study, though looking at squamous lung cancer, is called EMPOWER 131 — this is with an immune checkpoint inhibitor known as atezolizumab. This agent is being looked at in combination with either carboplatin and Taxol, or carboplatin and Abraxane, a very similar agent. There are two arms of this study where a patient gets a combination of chemotherapy and the immune therapy, and the third arm is just carboplatin and Abraxane alone. We should learn more about the potential benefits of combining immune checkpoint inhibitors with chemotherapy in the first line setting from this, looking at both patients with squamous and non-squamous histology in different trials.


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

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

What is the Role of Bevacizumab in Stage IV NSCLC?

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GCVL_LU-F09_Bevacizumab_Role_Stage_IV_NSCLC

 

Dr. Jack West, Swedish Cancer Institute, discusses the anti-angiogenic agent bevacizumab (Avastin) and the trial evidence of its efficacy for non-squamous NSCLC.

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In addition to standard chemotherapy, usually a two drug combination, we sometimes add a third drug called Avastin, also known as bevacizumab. Now this is not a standard chemotherapy agent — instead Avastin acts as an anti-angiogenic therapy, that is, it blocks the tumor’s blood supply, and it is sometimes included in the treatment regimen really only for the patients who have a non-squamous cancer.

Why is that? Well, years ago when Avastin was first being studied in many different kinds of patients with lung cancer — non-small cell lung cancer, either squamous or non-squamous, we found that a significant minority of patients had problems with bleeding complications, specifically coughing up blood that reached a potentially life-threatening or fatal level. That was found to be almost always limited to the patients with squamous histology. So obviously we decided that was not the way to go, and studies after that really limited treatment with Avastin to patients with non-squamous lung cancer. After that we found that even though you could have bleeding complications in a small minority of patients, it was much less of a concern when Avastin is limited to patients with non-squamous lung cancer.

Now, it is FDA approved in combination with two-drug chemotherapy, specifically the combination of carboplatin and Taxol, also known as paclitaxel. That’s because a key trial known as ECOG 4599, which was done across many different centers in North America, compared standard chemotherapy with carboplatin and paclitaxel or Taxol, to the same chemotherapy with Avastin added to it. The study found that patients tended to live longer by an average of about two months. Because of that, and the tolerable side effect profile, it became standard of care to at least consider adding Avastin to the two-drug chemotherapy combination for patients with non-squamous histology.

Now importantly, a couple of other studies have been done since that time, also using Avastin, that didn’t clearly show a survival benefit, and because of that, Avastin is really considered an option but not an absolute mandate, and many oncologists do not routinely use it for most or all of their patients. It’s something to discuss with a patient perhaps, but for patients who have a history of brain metastases or any potential bleeding complications, it may not be advisable because the safety may be enough of a concern to minimize that, and it has not consistently shown a survival benefit after that ECOG trial that I mentioned. But, for some patients it is reasonable to do a two-drug combination of chemotherapy, whether that is carboplatin and Taxol, or perhaps a different one such as carboplatin and Alimta, also known as pemetrexed, while adding Avastin to that.


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