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Lung Cancer Video Library – Spanish Language: Video #4 What is the role of Avastin (bevacizumab) in treating advanced NSCLC today?

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For our 4th video in the GRACE Spanish Lung Cancer Library, Antonio Calles, MD, Medical Oncologist, Thoracic Oncology Program, Hospital General Universitario, Gregorio Marraron, Madrid, Spain joined GRACE to discuss what the role of Avastin (bevacizumab) is in treating advanced NSCLC today?

 

 

 


 

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TRANSCRIPTS – Spanish and English
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¿Cuál es el rol de Avastin (bevacizumab) en el tratamiento del cáncer de pulmón de células no pequeñas en la actualidad?

Bevacizumab es un anticuerpo monoclonal dirigido contra VEGF (factor de crecimiento endotelial vascular) una proteína que secreta los tumores para aumentar la producción de vasos sanguíneos. Los tumores, como cualquier otra célula del organismo, necesitan nutrientes, glucosa, oxígeno y para eso necesita crear vasos sanguíneos para que le llegue ese suplemento a las células tumorales. Bevacizumab atrapa la proteína soluble y hace disminuir la vasculatura tumoral, normaliza esa vasculatura y permite una mejor entrada de los fármacos de quimioterapia dentro del tumor.

Bevacizumab se ha asociado a quimioterapia en primera línea de cancer de pulmón, en combinación con dobletes de platino. Los estudios demuestran que añadir Bevacizumab a la quimioterapia, aumenta la supervivencia de los pacientes que reciben este tratamiento. El ensayo clínico E4599 comparo la administración de carboplatino y taxol durante 4 ciclos cada 3 semanas vs la misma combinación en donde se añadía el antiangiogénico Bevacizumab continuado de Bevacizumab de mantenimiento. La adición de Bevacizumab a la quimioterapia, mejoraba los resultados y supervivencia de los pacientes.

Sin embargo, en el desarrollo precoz de este fármaco, se observó un aumento de sangrado y de efectos secundarios con riesgo vital. Fundamentalmente correspondía a tumores con histología epidermoide, tumores centrales, cavitados, invadían grandes vasos o había sangrados inicialmente como es la hemoptisis (expulsar sangre con la tos). En el estudio fase 3, estos pacientes fueron excluidos, por tanto, la aprobación de Bevacizumab se limitó a pacientes con histología de adenocarcinoma o histologías no escamosas en las que no hubiera invasión vascular, hemoptisis significativa o cualquier otro riesgo de sangrado relevante. De hecho, la aprobación de Bevacizumab está limitada para pacientes porque puede detener la cicatrización de las heridas y puede producir perforación intestinal y sangrados. Esto hace que la mayor parte de los pacientes con cancer de pulmón en primera línea, no pueda recibir Bevacizumab.

Aproximadamente se calcula que el 30% de los pacientes, en un practica regular, pueden llegar a recibir Bevacizumab por aquellas contraindicaciones de histología, afectación vascular y riesgo de sangrado, pero en aquellos pacientes que pueden recibir la combinación con Bevacizumab puede aumentar los resultados de la quimioterapia y se debe de recomendar a esto pacientes añadir Bevacizumab a la quimioterapia.

Recientemente se han aprobado otros fármacos en segundas líneas en combinación con quimioterapias, demostrando un beneficio de añadir anti-angiogénicos como ranibizumab y vandetanib, en segundas líneas. El concepto es que la angiogénesis en cáncer de pulmón funciona, si bien se prefiere utilizarlo en primera línea para obtener el máximo beneficio.


 

English TRANSCRIPT

Bevacizumab is a monoclonal antibody special against VEGF (vascular endothelial growth factor), a protein that is secreted by tumor to increase the productions of blood vessels. The tumors, as any other cell, need nutrients, glucose and oxygen, so it needs to create new blood vessels to get the nutrients. Bevacizumab catches the soluble protein and stops the tumoral vasculature, it normalizes it and allows a better drug entry to the tumors.

Bevacizumab has been associated to first line lung cancer chemotherapy in combinations with platinum doublets. Studies have shown that adding bevacizumab to chemotherapy increases survival of patients. The clinical trial E4599 compared the use of carboplatin and taxol for 4 cycles every 3 weeks against the addition of the anti-angiogenic bevacizumab continuing bevacizumab as maintenance. The addition of bevacizumab to chemotherapy improved the results and survival of patients.

However, in the early development of this drug it was observed an increase of bleeding and other side effects with vital risk. It fundamentally included tumors with epidermoid histology, central and cavitary tumors, they invaded big vessels or cause bleedings like hemoptysis (bleeding cough). In the phase 3 of this study, these patients were excluded, so the approval of bevacizumab was limited to patients with adenocarcinoma or non-squamous histology in which there was no vascular invasion, hemoptysis, or any other risk of bleeding. These findings made that most patients with first line lung cancer cannot use bevacizumab.

About 30% of patients in a regular practice, can receive bevacizumab for the histological conditions, vascular affectations and bleeding risk, but those who can receive bevacizumab can increase the results of chemotherapy. It should be recommended to these patients to add bevacizumab to their chemotherapy.

Recently, there has been an approval of other second line drugs in combination with chemotherapy, it proved great benefits of adding anti-angiogenic drugs like ranibizumab and vandetanib. The concept is that angiogenesis in lung cancer works, so it should be recommended as first line to obtain maximal benefits.

 


GRACE Video

Maintenance Therapy for Advanced NSCLC

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GRACEcast-522_Lung_West_Maintenance_Therapy_Advanced_NSCLC

 

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

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.


GRACE Video

Elderly Patients: Selecting Appropriate Systemic Treatment Agents

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GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents

 

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, evaluates a variety of particular systemic treatment agents for possible use in elderly patients.

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It is my privilege to speak to you today about elderly patients; consideration of which chemotherapeutic agents might be best. So we’ve seen a lot on CancerGRACE about the advent of targeted therapy and this theme that when you combine a target with a targeted therapy, like a lock and key model, you as a theme get a treatment that has less side effects, is more convenient because they’re often oral, and tend to work better.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_02

This of course has made lots of work for our medical students as we subdivide by histology, by driver mutations, and an even more complex systems view that probably starts to approach reality. But in the simplest way when thinking about targeted therapies such as erlotinib or gefitinib for EGFR mutants, or crizotinib for ALK or ROS1, and other emerging targeted therapies — as a theme these drugs are very effective and less toxic, and so to my mind, even though we don’t normally speak about them as geriatric drugs, to me they’re the epitome of geriatric drugs because of these themes.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_03

In terms of traditional chemotherapy, there’s really only one agent that I would consider to have any data for superior efficacy in the elderly. You’re looking here at the design of a randomized phase III trial that randomized patients to carboplatin and regular cremophor solvent-dissolved paclitaxel, versus carboplatin and a newer nano albumin-bound formulation called Abraxane.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_04

Patients were randomized one to one, you can see the basic results by age at the bottom of this slide. Why I’m showing this to you is that the only subgroup that had a major survival difference was the elderly. In patients of at least 70 years of age, there was a rather important improvement in survival, 19.9 versus 10.4 months — that is statistically significant. I would call that clinically meaningful but it is a retrospective subgroup analysis and so it requires confirmation in prospective studies. Two important studies are ongoing to look at this. One is looking at older patients with this regimen for their first treatment, and the other looking at such patients for their second treatment.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_05

This was a randomized trial that compared for first treatment cisplatin and pemetrexed, versus cisplatin and gemcitabine. We’ve covered this trial a number of times on GRACE before in terms of looking at histology-specific differences in drugs and we’ve seen on GRACE before that pemetrexed is a particularly effective drug for patients with non-squamous histology, which mostly means adenocarcinoma, where it’s less effective in patients with squamous histology. We’ve also seen that it tends to be one of our better tolerated chemotherapy drugs, and these results held in this definitive trial both for younger patients and for older patients. While I don’t tend to use cisplatin in older patients (we’ll get to that) I do think that pemetrexed is a particularly geriatric-friendly drug for patients with non-squamous histology.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_06

ECOG 4599, another trial we’ve covered multiple times over the years looked at the standard platinum doublet carboplatin and paclitaxel, with or without the addition of the VEGF inhibitor bevacizumab, otherwise known as Avastin.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_07

We know that trial showed a small but real survival advantage in unselected patients, but why I show it to you today is that treatment advantage really seems to slim down when we look at older patients. So in my practice I don’t tend to use bevacizumab except for my really, really most fit older patients.

All the rage these days, of course, in thoracic oncology are the immunotherapeutic agents. These drugs as a theme are more effective in the second line than chemotherapy and less toxic — these make them good geriatric drugs so bear with me a moment.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_08

Here’s the data on nivolumab in squamous cell carcinoma, second line of therapy, compared to my second least favorite geriatric drug docetaxel. We can see here a dramatic improvement in survival, and perhaps equally important, a better tail to the curve — more patients living a very long time on the nivolumab.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_09 

A similar effect shown here in non-squamous histology, and as far as to why this is making its way to a talk about geriatric oncology, here’s the toxicity.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_10 

It’s very rare in looking at thoracic oncology trials to ever have this favorable of a rate of grade 3-4 or high-grade toxicity, even for placebo. So these drugs are more effective and less toxic — these are very geriatric-friendly drugs.

Bringing it back to chemotherapy, which is what unfortunately still the majority of patients get — I think it’s worth taking a minute to talk about which of these drugs are particularly geriatric-friendly and which perhaps should be avoided for most older patients.

GCVL_LU-FA03_Elderly_Patients_Selecting_Appropriate_Systemic_Treatment_Agents_11 

So cisplatin is my least favorite drug for older patients. Why? It’s our most nausea- and vomiting-inducing drug, perhaps of any we use in oncology. It has a high rate of harming hearing and there is already age-related hearing decline, it’s one of our worst drugs on the kidneys and kidney function does tend to naturally decline with age. There are plenty of other reasons to hate cisplatin as well, making it my least favorite geriatric drug.

In contrast, its little brother carboplatin I regard as a much more geriatric-friendly drug. It has much, much less for side effects, particularly on the kidneys and for patients who already have a little bit of age-related kidney decline, the dosing formula for carboplatin, it’s called the AUC formula, inherently accounts for this, so you just don’t have to worry about it — you get the right exposure to the drug sort of automatically even if there is some preexisting decline in kidney function.

Paclitaxel I would call a middle-of-the-road geriatric drug, particularly I would call it more favorable when used on a weekly schedule. Docetaxel, as I mentioned, is my second least favorite geriatric drug — there’s a lot of count suppression, a lot of fatigue. When I do use it for older patients, I tend to reduce the dose some from the standard dose. We’ve discussed nab-paclitaxel, otherwise known as Abraxane, because of the subgroup survival data suggesting it may be more effective in older patients. Pending the confirmatory ongoing studies, I think that this is a very geriatric-friendly drug. Gemcitabine I would call on the better side of geriatric drugs, it’s mostly excreted by the kidneys so you need to pay attention if there is kidney decline, but it’s a pretty geriatric-friendly drug — an effective drug with lower side effects. Pemetrexed or Alimta we’ve already talked about as a particularly geriatric-friendly drug, I would comment though that this drug is excreted mostly by the kidneys, and so if kidney function is not ideal, it’s a drug that needs to be used with extreme caution or perhaps not at all.

I thank you for your kind attention.


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