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Luis E Raez

More Immunotherapy Agents are in Development for Lung Cancer

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Luis E. Raez, MD, FACP, FCCP

Luis E. Raez, MD, FACP, FCCP, Chief of Hematology/Oncology and Medical Director of Memorial Cancer Institute (Miami, FL) Clinical Associate Professor of Medicine, Herbert Wertheim College of Medicine, Florida International University

In the last 2 years we were very happy to have seen: nivolumab, pembrolizumab and recently atezolizumab approved for non-small cell lung cancer (NSCLC). If you remember all of them are approved for second line therapy of NSCLC and pembrolizumab has been moved and approved already for first line NSCLC therapy if the tumor expresses PDL-1 immunohistochemistry staining (IHC) more than 50%. All of these agents block the interaction between the receptor PD-1 present in T lymphocytes and the ligand PDL-1 present in tumor cells and they are called “checkpoint inhibitors”. Some of them like atezolizumab block the PDL-1 ligand and the others are PD-1 inhibitors, there are no clear differences among them other than the current FDA indications. Soon we will know if there are differences in these 2 types of inhibitors among themselves regardless effectivity or toxicity. However these are not the only agents, we have more PDL-1 inhibitors in development like: avelumab (also known as MSB0010718C) that is in priority review for urothelial cancer but results from the JAVELIN trial were recently reported in December in Vienna during the 17th International Association for the Study of Lung Cancer (IASLC) Annual Meeting showing good responses and toxicity profile similar to the other inhibitors. The same happened with another anti-PDL-1 called durvalumab that was also presented at the IASLC meeting too with similar outcomes. But not only anti PD-1/PDL-1 antibodies are considered check point inhibitors we also have to remember that we have anti-CTL4 antibodies called ipilimumab and tremelimumab; none of them are approved for lung cancer yet but the first is already commercially available for melanoma. The importance of these anti-CTL4 antibodies is in the fact that they stimulate the immune response by a different mechanism of the PD-1/PDL-1 inhibitors then the great interest from the research community in combining these 2 different type of drugs to try to enhance the immune response as already has happened successfully in melanoma where the combination of ipilimumab + nivolumab is becoming standard. Other investigators are already combining durvalumab with tremelimumab for NSCLC, the first phase I study was published in the journal “Lancet” in February 2016 where they showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status. During World Lung IASLC conference in December 2016 the combination of ipilimumab + nivolumab was presented showing good tolerance for the patients and enhancing the immune response of single agent nivolumab and the final paper was published also in “Lancet” in January 2017.

But this story even gets better: while some pharmaceutical companies are developing similar check point inhibitors to the 2 types described (anti PD-1/PDL-1 and anti-CTL4) other companies are exploring other targets and checkpoints so there is a large list of potential candidates that can be targeted with  the hope to achieve an immune response like: A2AR, B7-H3, also called CD276, B7-H4, also called VTCN1, BTLA also called CD272, IDO, short for Indoleamine 2,3-dioxygenase; KIR, short for Killer-cell Immunoglobulin-like Receptor, LAG3, short for Lymphocyte Activation Gene-3, TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, and VISTA (protein), Short for V-domain Ig suppressor of T cell activation, among others.

The future is very exciting these days for the possibilities that is bringing to our NSCLC patients.


 Luis E. Raez, MD, FACP, FCCP is the Chief of Hematology/Oncology and Medical Director at Memorial Cancer Institute. He is also the Oncology Research Director of Memorial Healthcare System and Director of the Thoracic Oncology Program, Clinical Associate Professor of Medicine at Florida International University and Visiting Professor of Medicine at Cayetano Heredia University in Peru. He is also an Affiliate Associate Professor of Clinical Biomedical Science for Florida Atlantic University.


 

 

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


 

 

 


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


 

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.


Denise Brock

Lung Cancer Video Library – Spanish Language: Video #34 Acquired Resistance to Targeted Therapies: Biology and Different Clinical Patterns

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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 34th video for the Spanish lung cancer video library, Dr. Raez discusses acquired resistance to targeted therapies: biology and different clinical patterns.


 

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
 

Resistencia adquirida a terapias dirigidas: biología y diferentes patrones clínicos

Acquired resistance to targeted therapies: biology and different clinical patterns

 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

Lamentablemente, a pesar que es muy emocionante ver como los pacientes que tienen las mutaciones de EGFR y las translocaciones ALK responden al inicio, sabemos que los tumores van a crear resistencia a estos agentes.

Usualmente es a los 10 o 12 meses que la mitad de los pacientes que están en estas terapias blanco, genera resistencia por muchas razones. Por ejemplo, en los receptores de EGFR, aparecen nuevas mutaciones como la mutación EGFRT790. En el caso de las translocaciones de ALK, también aparecen otras variantes nuevas que no están al comienzo que son variantes asociadas y documentadas para resistencia.

A pesar de que hay sensibilidad al comienzo, tenemos que estar alerta y monitorizando ya sea con radiografía o próximamente vamos a tener biopsias líquidas que vamos a poder estar monitorizando en la sangre para ver cuando empiezan la clonas resistentes a aparecer y en qué momento hay que empezar a cambiar la terapia.

Como ustedes saben felizmente, en el caso de la EGFR, cuando aparece resistencia tenemos otras terapias blanco como osimertinib. En el caso de las translocaciones ALK tenemos otras terapias blanco a parte de crisotinib que se usa al comienzo, tenemos ceritinib, alectinib y otros fármacos más que están por venir.

 


 

 

English TRANSCRIPT

Unfortunately, despite the excitement of seeing patients with EGFR mutations and ALK translocations responding great to the treatment, we know that these tumors will create resistance to the therapy.

Usually at 10 or 12 months, half targeted therapy patients create resistance for many reasons. For example, in EGFR receptors, new mutations arise like EGFRT790. In ALK translocations, new variants appear that are associated and documented to resistance.

Despite there is sensitivity at the beginning, we have to be alert and monitoring with a radiography or in the near future with a liquid biopsy where we will be able to monitor blood and see when the resistant clones start to develop, and then change the therapy.

As you know, in EGFR when resistance starts, we have other new targeted therapies like osimertinib. In the ALK translocations, we have other targeted therapies besides crisotinib that is used in the beginning. We also have ceritinib, alectinib and other drugs that are coming.

 


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