GRACE :: Lung Cancer

T790M

Denise Brock

Lung Cancer Video Library – Spanish Language: Video #37 Basics of Lung Cancer Staging

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GRACE Cancer Video Library - Lung

 

We are pleased to continue this series of informational videos for our Spanish speaking community.  GRACE is pleased to welcome Dr. Rafael Santana-Davila, Assistant Professor with the University of Washington School of Medicine and Seattle Cancer Care Alliance.  In this 37th video for the Spanish lung cancer video library, Dr. Santana-Davila joined GRACE to discuss the basics of lung cancer staging.  


 

 

 

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TRANSCRIPTS – Spanish and English
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Lo básico en los estadios de cancer de pulmón

Basics of lung cancer staging

 Dr. Luis Raez, MD FACP FCCP

Chief of Hematology/Oncology and Medical Director, Memorial Cancer Institute,
Clinical Associate Professor of Medicine, Florida International University

 

Spanish TRANSCRIPT

Lo principal que nos preguntamos nosotros cuando vemos a un paciente con cáncer es en que estadio esta, que es básicamente que tan avanzado está el cáncer. Cuando el cáncer esta solo en el pulmón, no se ha ido a ningún ganglio linfático ni a otra parte del cuerpo, le llamamos estadio uno. Cuando el cáncer ha avanzado a ganglios linfáticos cercanos pero no al mediastino es estadio dos y cuando avanza al mediastino es estadio tres. Por último cuando ha avanzado a otros órganos, a la región pleural del pulmón o a otras partes del pulmón, le llamamos estadio 4.

En cáncer de células pequeñas es relativamente fácil diagnosticar en que estadio está, ya que si está solo en un pulmón le llamamos estado limitado y cuando está en varias partes del pulmón o en el otro pulmón u otras partes del cuerpo le llamamos estadio avanzado. 


 

 

English TRANSCRIPT

The main question to have when we see a cancer patient is in what stage he is, which is basically how advanced the cancer is. When the cancer is located just in the lung, has not affected a lymph node or any other organ is called stage one. When the disease has affected lymph nodes close to the cancer but not the mediastinum is called stage two, while the affection of the mediastinum is stage three. Finally, when the cancer has spread to other organs, the pleura of the lung or other parts of the lung is called stage four.

In small lung cancer cells is relatively easy to diagnose the stage because when it’s only present in the lung it’s the limited stage and when it is located in several parts of the lung, or in the other lung or other organs is the advanced stage.


Denise Brock

Lung Cancer Video Library – Spanish Language: Video #36 Treatment Options for Acquired Resistance to EGFR TKIs: T790M-Negative Disease

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GRACE Cancer Video Library - Lung

 

We continue to provide informational videos for our Spanish speaking community and welcome Dr. Luis Raez, MD FACP FCCP, Chief of Hematology/Oncology and Medical Director at Memorial Cancer Institute, and Clinical Associate Professor of Medicine at Florida International University.  Dr. Raez joined GRACE to discuss the basics of lung cancer.  In this 36th video for the Spanish lung cancer video library, Dr. Raez discusses treatment options for acquired resistance to EGFR TKIs: T790M-negative disease.


 

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TRANSCRIPTS – Spanish and English
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Opciones de tratamiento para la resistencia adquirida a los inhibidores de tirosinas cinasa del receptor del factor de crecimiento epidérmico (EGFR): enfermedad T790M negativo.

Treatment options for acquired resistance to tyrosine kinase inhibitor in the epidermal growth factor receptor (EGFR): T790 negative disease

 Dr. Luis Raez, MD FACP FCCP

Chief of Hematology/Oncology and Medical Director, Memorial Cancer Institute,
Clinical Associate Professor of Medicine, Florida International University

 

Spanish TRANSCRIPT

También cuando hablamos de resistencia a inhibidores de la tirosina cinasa, ya hablamos que para los pacientes con 790 hay un nuevo fármaco que se llama osimertinib. El problema es ¿qué hacemos con el resto de los pacientes? Como les decía 60% de los pacientes que están en inhibidores de la tirosina cinasa, van a tener la mutación 790, que, si ustedes saben la pueden encontrar en la sangre, la orina o en una nueva biopsia, y ahí vamos a poder usar el fármaco nuevo.

Pero, ¿qué hacemos con el 40% de pacientes que no podemos documentar la mutación?

Hay esperanza para estos pacientes porque sabemos hoy en día que para muchos de estos pacientes que no tienen esta mutación, el mecanismo de resistencia está a través de la vía MET. Entonces tenemos en investigación inhibidores de MET y de su vía, que podría ser una solución para salvar a estos pacientes. La otra opción es que algunos de estos pacientes, en un grupo pequeño como del 10% hacen carcinoma de pulmón de células pequeñas. En otras palabras, el tumor original que era carcinoma de células granes se transforma en carcinoma de células pequeñas, entonces estos pacientes no van a responder a ninguna terapia blanco existente porque no tenemos terapia blanco para carcinoma de células pequeñas y entonces hay que ponerlo en quimioterapia.

Por eso es tan importante hacer una biopsia, porque si no hacemos una biopsia cuando en el paciente falla el receptor de la tirosina cinasa nunca nos vamos a enterar que el paciente transformo a carcinoma de células pequeñas y nunca le vamos a dar la quimioterapia adecuada.

Al final, mientras estos descubrimientos y otros van avanzando lo que hay que hacer es poner a los pacientes en quimioterapia. Cuando un paciente falla y no podemos documentar la mutación 790, hay que ponerlo en quimioterapia o en un estudio clínico que el paciente pueda calificar.


 

English TRANSCRIPT

When we talk about tyrosine kinase inhibitors resistance, we know that for patients with the 790 mutation, we have the drug osimertinib. The problem is, what do we do with the rest of the patients? As I told you, 60% of the patients that are in tyrosine kinase inhibitors will have the 790 mutation that if we can find them in the blood, urine or in a new biopsy, we will be able to use the new drug.

But, what do we do with the 40% of patients in which we cannot verify the mutation?

There is hope for these patients because nowadays we know that most patients without this mutation have their resistance mechanism via de MET pathway. We have MET and their pathway inhibitors that could be the solution for these patients. The other option is that some patients, in a group of around 10%, make small cell lung cancer. In other words, the original large cell lung cancer transformed into small cell lung cancer. These patients will not respond to any existing targeted therapy because we don’t have a small cell cancer treatment, so we have to put them in chemotherapy. 

That is why it is so important to make a biopsy, because if we don’t make a biopsy when the patients fails with the tyrosine kinase inhibitors, then we will never know that the patient probably transformed into a small cell lung cancer and we will never give him the right therapy.

At the end, while these findings and more research is progressing, what we have to do is put the patients in chemotherapy. When a patient fails with the treatment and we cannot verify 790 mutation, we have to put him in chemotherapy or in a suitable clinical trial.


Denise Brock

Lung Cancer Video Library – Spanish Language: Video #35 Treatment Options for Acquired Resistance to EGFR TKIs: T790M-Positive Disease

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GRACE Cancer Video Library - Lung

 

We continue to provide informational videos for our Spanish speaking community and welcome Dr. Luis Raez, MD FACP FCCP, Chief of Hematology/Oncology and Medical Director at Memorial Cancer Institute, and Clinical Associate Professor of Medicine at Florida International University.  Dr. Raez joined GRACE to discuss the basics of lung cancer.  In this 35th video for the Spanish lung cancer video library, Dr. Raez discusses treatment options for acquired resistance to EGFR TKIs: T790M-positive disease.


 

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.


 

TRANSCRIPTS – Spanish and English
download transcripts
 

Opciones de tratamiento para la resistencia adquirida a los inhibidores de tirosinas cinasa del receptor del factor de crecimiento epidérmico (EGFR): enfermedad positiva en T790M

 Treatment options for acquired resistance to tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR): T790 positive disease. 

 Dr. Luis Raez, MD FACP FCCP

Chief of Hematology/Oncology and Medical Director, Memorial Cancer Institute,
Clinical Associate Professor of Medicine, Florida International University

 

Spanish TRANSCRIPT

Hablando de resistencia en el caso de los receptores de EGFR, hay una mutación nueva que aparece llamada T790M. Es la más popular y se calcula que a veces hasta en el 60% de los pacientes que están en inhibidores de la tirosina cinasa, van a desarrollar mutaciones resistentes en T790M y hay otro 40% con otras etiologías.

Es importante documentar que el paciente tiene esta mutación nueva 790 porque ya tenemos un tratamiento específico, que es el fármaco osimertinib que ya está disponible en Estados Unidos y Europa y próximamente en todo el mundo que es otro inhibidor de la tirosina cinasa. Es un fármaco bien tolerado, no es muy tóxico, se parece a otros inhibidores de la tirosina cinasa. Incluso les diría que es menos tóxica en a lo que se refiere a piel y sistema gastrointestinal.

Lo importante es diagnosticarlo porque si uno no puede probar que el tumor ha hecho una mutación 790, no podemos darle el fármaco. Este fármaco está aprobado específicamente para pacientes que tienen esta mutación. Así que yo creo que es importante que cuando en un paciente falla un inhibidor de la tirosina cinasa, que se le haga una nueva biopsia, una biopsia líquida o una muestra de orina para documentar que el paciente haya hecho una resistencia y que se le haya encontrado la mutación 790 que usualmente no está al comienzo y así poder cambiar la terapia.


 

 

English TRANSCRIPT

Talking about resistance in the EGFR receptor, there is a new mutation called T790M. It’s by far the most popular and around 60% that are currently in tyrosine kinase inhibitor, will develop resistant mutations to T790M, the other 40% will have other etiologies.

It is of great priority to document that the patient has this new 790 mutation, because we already have a new specific treatment. This is the drug osimertinib, a tyrosine kinase inhibitor, already available in United Stated and in Europe, and in the near future worldwide. I would even say that this drug is less toxic in the skin and in the gastrointestinal tract.

The important here is the diagnosis because if one cannot prove that the tumor has made a 790 mutation, then we cannot give him the drug. This drug is approved specifically for patients with this mutation. So, I think, it’s very important that when a patient fails with the tyrosine kinase inhibitor, we should make a new biopsy, a liquid biopsy or an urine test to document that the patient has developed resistance and that he has the 790 mutation which is usually not developed in the beginning. This way, we will be able to change therapy.


Dr West

Divergent Paths for Tagrisso (Osimertinib) and Rociletinib for EGFR T790M Mutation-Positive NSCLC and Acquired Resistance: What Happened, and Where Are We Now?

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For patients with an activating EGFR mutation and who develop “acquired resistance”, the pattern of progression that occurs after a sometimes long period of good initial response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatanib), the evolving story of the treatment options has been a wild ride with several ups and a few downs. Over the last two years, several “third generation EGFR TKIs” with a strong affinity for EGFR activating mutations and, importantly, a different mutation called T790M, which is seen in 50-60% of patients with EGFR mutation-positive acquired resistance, but very low affinity for “wild type” (normal, non-mutated) EGFR molecules (which mediate the common, problematic side effects with EGFR TKIs, such as rash and diarrhea).  Given the very different paths that the two leading entrants – Astrazeneca’s Tagrisso (osimertinib, also previously known as AZD9291 and transiently as merelitinib) and Clovis’s rociletinib (also known as CO-1686) – it’s high time to review what has happened to get to where we are now.

The annual ASCO meeting in 2014 included very prominent presentations about these agents (Tagrisso and rociletinib, respectively), at that point still in early trials with several dozen patients each, that showed both agents had marked activity against the subset of patients with acquired resistance whose tumors test positive for T790M. At that time, AZD9291, which ultimately became osimertinib and then branded as Tagrisso, was a half-step ahead in terms of a slightly larger number of patients tested, but both agents were very promising for a population in which alternative treatment options other than standard chemotherapy. Though some concerns were raised about hyperglycemia (high blood sugar levels) in patients on CO-1686, my view at the time was that in people facing the threat of an advanced cancer, taking pills or even possibly insulin to manage blood sugar levels wasn’t likely to be a major issue if it worked effectively. Like many other lung cancer specialists and general oncologists alike, my perspective was that access to either agent would be a welcome opportunity for patients eligible for an accessible clinical trial. 

These two agents have been widely studied in a range of global trials as they continued their footrace over the next 12-18 months. In August, 2015, the remarkably early results with these two agents was featured in back to back articles (on Tagrisso and rociletinib, respectively in the prestigious New England Journal of Medicine.

But since that time, the paths of those two agents have diverged remarkably.  Tagrisso became FDA-approved in November, 2015 after continuing to demonstrate a response rate of significant tumor shrinkage in about 55-60% of T790M-positive recipients and up to 90% experiencing “disease control” that includes less significant shrinkage and stable disease. Importantly, these responses tend to last for many months to a year or longer, and this longitudinal treatment has been associated with a very low risk of significant side effects, with most patients experiencing either no issues or a rash and diarrhea that is so minimal that, in my experience, they haven’t felt warrants a hint of complaint.  The value of offering Tagrisso for T790M-positive acquired resistance has really changed the standard of care for EGFR mutation-positive patients with progression, making it instantly critical to seek and hope to find a T790M mutation, with a valuable subsequent treatment option to pursue before moving on to other options routinely offered for advanced NSCLC.

The path of rociletinib has been very dramatic over the past 6-7 months, but unfortunately it has been in a downward trajectory. Though provocative work over the past year has shown that this agent could work well in patients with T790M detected even in plasma, perhaps obviating the need for repeat tissue biopsies, the side effect profile with further use made it arguably a less attractive option than Tagrisso.  In my own experience, the constellation of nausea, diminished appetite, and diarrhea could create a cascade of weakness and misery that required aggressive dose reductions in a significant minority of patients and an occasional patient expressing dramatically “if this is what I need to do to have my cancer respond, I’d rather die” (though other patients certainly tolerate it better). But the biggest hit came in November, 2015, when the FDA reported that it was planning to delay a decision on potential approval of rociletinib after updated information revealed that the response rate reported to rociletinib of 59% was actually an “unconfirmed” response rate that dropped to about half that rate when looking only at confirmed responses (though the latest published update pegs response rate at 45%). The fortunes for rociletinib, along with Clovis’s stock price, dropped like a rock.

Tailspin

 Since then, clinical trials with rociletinib have continued on, and the FDA has continued its review process for the drug. The Oncology Drug Advisory Committee (ODAC) to the FDA, eviewing the evidence in April, came back with a 12-1 vote against approval until results from a randomized trial of rociletinib vs. chemotherapy be completed and demonstrate a clear benefit for rociletinib.  Then, in early May, Clovis announced very suddenly that the FDA, which almost always followed ODAC’s thoughtful recommendations, had notified the company that the FDA would not be offering an approval until further data supported its use. In that same press release, Clovis announced that it was terminating all trials with rociletinib (and was laying off 35% of its employees).

One important issue that the potential approval of rociletinib raised was the question of whether it should be compared to osimertinib or not. Technically, rociletinib didn’t need to be better than its predecessor to the market in the same space, but it is hard to determine what value there is in offering an agent with seemingly less activity and worse side effects than an agent we already have available. This issue of a strong incumbent will be a critical factor for other would-be challengers, further behind in development, which enter a world with Tagrisso as an entrenched, effective therapy in this setting, so how might other agents fit in?

A key relevant question here is how similar or dissimilar these agents truly are. One might well assume that there is a great deal of “cross-resistance” to drugs in the same family, as we see minimal activity of one first or second generation EGFR TKI after another (such as trying Tarceva after Iressa, or Gilotrif after Tarceva), just as you wouldn’t expect to have many people wildly excited about having a Pepsi after drinking a two liter bottle of Coke. But in fact, Dr. Lecia Sequist and colleagues from Massachusetts General Hospital recently reported that they have seen several cases of tumor shrinkage or prolonged stable disease on Tagrisso – including in the brain as well as other parts of the body — in patients who had demonstrated clear progression on rociletinib previously. As someone who had patients progressing on rociletinib in clinical trials, I followed this lead and have treated several of my patients with Tagrisso and also seen several very encouraging responses after progression on rociletinib. This is an important finding for patients in this setting who may benefit.

These advances are very significant, but we must still acknowledge the work that still needs to be done. Third generation EGFR TKIs may prove to offer meaningful benefits to the 40-50% of patients with T790M-negative acquired resistance, or we may need to search for better options elsewhere. It will also represent a great breakthrough if we can do repeat biopsies to check for T790M or other mutations in circulating plasma of patients rather than be required to pursue invasive biopsies at several time points over the course of treatment.  Though we probably can’t predict future developments much better than we might have predicted the drama in this space over the past two years, I can predict that it will be eventful and that we will only have a better understanding of and treatments for EGFR mutation-positive NSCLC in the future.

What do you think of these developments?


GRACE Video

Rociletinib/Osimertinib for EGFR T790M-negative NSCLC

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GRACE Cancer Video Library - Lung

GCVL_LU-F13_Rociletinib_Osimertinib_EGFR_T790M-Negative_NSCLC

 

Dr. Jack West, Swedish Cancer Institute, reviews trial evidence for the efficacy of rociletinib and osimertinib for EGFR acquired resistance not driven by a T790M mutation.

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Transcript

For patients who have an activating mutation in their cancer known as EGFR we have several very good first line treatment options to consider. There are three leading contenders as oral targeted therapies that block EGFR and tend to work very well for patients with an EGFR mutation. These agents are known as Iressa (gefitinib), Tarceva (erlotinib), and Gilotrif (afatinib). These agents have a chance of shrinking the tumor in the range of 60% to 75% which is great, but unfortunately these responses do not last forever and on average, patients will develop progression of their cancer, so-called acquired resistance to this first line therapy, after something in the range of nine to 12 months — can be less, can be more.

The question is what to do when that occurs. Well, there are a couple of agents that have shown great promise and great activity, at least in the subset of patients who have a mutation, found at the time of this acquired resistance, that is known as T790M. And so we repeat a biopsy of an area of progressing cancer while patients are on and progressing on this first line EGFR inhibitor, and 50% or 60% will have this acquired resistance mutation known as T790M. For those patients, we standardly consider drugs like osimertinib and rociletinib, and I say standardly consider as if they’re commercially available, and they’re not yet, at this moment in late 2015, FDA approved but it is expected that both will be approved by the FDA based on their very good activity in the very near future, perhaps by the time you see this.

But these agents are best studied and have their greatest activity in the patients with a T790M mutation. So what about the patients who are still 40% or 50% of that population with progressing cancer on an EGFR inhibitor who don’t have a T790M mutation? It turns out that both of these agents have good activity, or at least some degree of activity, in patients who are T790M-negative. It doesn’t tend to be as long-lasting and the response rates tend to be lower, but the activity is certainly encouraging.

GCVL_LU-XXNN_Jack_West_Swedish_15_01

When you look at what’s called a waterfall plot that’s shown here of how patients respond, the bars going downward represent patients whose cancers have shrunk, and the ones that go upward are the ones whose cancers have progressed on a therapy. You can see that when we look at patients who received osimertinib, the AstraZeneca drug AZD9291, there is good activity in the majority of patients who receive this agent, even if they have no T790M mutation.

GCVL_LU-XXNN_Jack_West_Swedish_15_02

The same is true for rociletinib, the Clovis drug CO1686 — the waterfall plot shows that most of the bars do go down, and that a lot of patients receive a substantial benefit, even if they do not have T790M detected in their rebiopsied tumor.

So there are studies that are looking specifically at these agents in patients who are T790M-negative. A trial with rociletinib known as TIGER-3 is looking at patients who have received prior EGFR inhibitors like Iressa, Tarceva or Gilotrif, and have also received prior chemotherapy. These patients are then randomized to either receive rociletinib or a standard chemotherapy as a single agent, and there are several that your doctor can choose from. This trial will be looking at which patients do better depending on whether they get the targeted therapy or standard chemotherapy.

There is another trial being done with osimertinib in combination with an EGFR monoclonal antibody known as necitumumab, so a two drug combination being looked at in patients who are T790M-negative after progressing on a first line EGFR inhibitor. So both of these agents are being studied not just in patients with a T790M-positive cancer, but a T790M-negative cancer, and if you do have acquired resistance and are found to not have a T790M mutation, you might want to look into information about these trials to see if one might be a good choice for you.


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