GRACE :: Lung Cancer

non-small cell lung cancer

Dr. Goldman

Why Carboplatin, Pemetrexed and Pembrolizumab Have Become My New Go-to Regimen for First-Line Non-Squamous NSCLC Treatment

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Why carboplatin, pemetrexed and pembrolizumab have become my new go-to regimen for first-line non-squamous NSCLC treatment.

By Jonathan W. Goldman, MD


Metastatic non-small cell lung cancer (NSCLC) treatment has generally improved by optimizing care for “slices of the pie”—pieces of a pie chart representing all of lung cancer patients. Initially, mutation-based treatment led the way; 10% of lung cancers were identified as EGFR-mutant and treated with appropriate tyrosine kinase inhibitors. Subsequently, thinner and thinner slices of the population, each 1-7% of NSCLC patients, have been described and their cancers targeted. More recently, immunotherapy entered the picture, but again the greatest benefit of this therapy was limited to the 20-25% of patients that were PD-L1 positive. Despite all of these advances, we still had at least half of patients receiving more than 10-year-old chemotherapy as their initial treatment.

We now have preliminary evidence that this may be changing. Langer, et al reported in November 2016 (Lancet Oncology) the phase 2 KEYNOTE-021-G1 cohort of non-squamous NSCLC patients treated with the standard, carboplatin and Alimta (pemetrexed), alone or with the PD-1 inhibitor, Keytruda (pembrolizumab). Previous attempts to add to a platinum-doublet had generally provided marginal benefits at best (for example, with Avastin [bevacizumab] or Erbitux [cetuximab]). In contrast, the 021G trial suggested massive benefits, at least as far as response rate (RR) and progression free survival (PFS).

The 021G trial was a moderate-sized phase 2 trial with 123 patients split between the two arms. With Keytruda added to chemotherapy, the response rate increased from 29 to 55%, and importantly this benefit was irrespective of PD-L1 status (above or below a 1% PD-L1 cutoff). PFS was also significantly improved from 8.9 to 13.0 months with a hazard ratio of 0.53, which represents a decrease in the risk of cancer progression by almost half. Many of the trials leading to new drug approvals especially in an unselected cohort report hazard ratios of 0.75 or 0.80, so the benefit in 021G is staggering. The overall survival curves were overlapping at the time of the initial report, and if they suggested a possible survival benefit when updated at the 2017 ASCO Annual Meeting, there was still no statistically significant difference. This lack of a clear survival benefit is certainly at least in part due to crossover at the time of progression from the chemotherapy alone arm to get Keytruda or another immunotherapy (32% within the study and 74% if you count receiving an immunotherapy agent at any point, on or off the trial).

Furthermore, the toxicity associated with the addition of Keytruda was generally manageable, although moderate to severe toxicity (grade 3 or higher) was increased from 28 to 41%. Primarily, these were hematologic toxicities, including anemia and low blood counts, which oncologists are very comfortable managing. Stereotypical immunotherapy toxicities (such as pneumonitis, colitis or hepatitis) were reported at rates similar to previous experience with single-agent PD1 or PDL1 inhibitor therapy. Nevertheless, Keytruda was discontinued due to toxicities in 10% of patients, including in 1 patient with grade 3 pneumonitis, and doctors and patients will need to be on the lookout for such complications.

Many investigators and thought leaders were surprised when the FDA granted priority review for the front-line Keytruda-chemotherapy combination in January 2017. While lung cancer drug approvals had come from phase 2 or even phase 1 data before, that had consistently been for targeted therapy in areas of unmet need. However, just a few months later, on May 10, 2017 the FDA provided accelerated approval based on the RR and PFS benefits reported from KEYNOTE-021-G1. This does require verification in confirmatory trials including the KEYNOTE-189 trial, which mirrors the 021G trial but in a larger, phase 3 format.

This approval further shocked the lung cancer community. It certainly put standard treatment pathways and clinical trials, both open and in planning, in to disarray. However, from the FDA standpoint, how could you say no to a doubling in the response rate and a 50% decrease in the risk of progression? From the patient standpoint, there is now a novel treatment option that applies to the majority of patients. This is an event to celebrate.

There have been several lines of criticism of this combined treatment modality. The clearest is that if the overall survival curves remain overlapping, it may be advantageous to use chemotherapy and immunotherapy sequentially instead of concurrently. However, it seems likely that if the impressive RR and PFS advantages of concurrent therapy are real, they will translate into a survival advantage. It is also important to remember that patients can worsen rapidly during front-line therapy and never have the opportunity to benefit from a second-line treatment. If a survival advantage is not seen in the small phase 2 trial, it seems likely to be demonstrated in the larger phase 3 trial.

Another criticism of the concurrent approach is the associated medical and financial toxicity. Some presume that most patients will be benefiting from either the chemotherapy or the immunotherapy, and that by giving everything together, we are exposing patients to needless drug toxicity and society to unsustainable costs. One could respond, firstly, we do not know exactly how chemotherapy and immunotherapy may be interacting and there may be synergism beyond the efficacy of the individual parts. (Some hypothesize that tumor cell death via chemotherapy releases antigens that prime an immune response, which is then amplified into an immune effector response by immunotherapy.) Secondly, the toxicity profile as seen in the 021G trial shows that concurrent administration of chemotherapy and PD-1 blockade is tolerable for most patients. Thirdly, we have used expensive triplet regimens before (the best example being carboplatin, Alimta and Avastin) but at least with the 021G triplet there is evidence for major benefit.

In the end, we are all awaiting the confirmatory phase 3 trials of chemoimmunotherapy across many of the PD1 and PDL1 inhibitor drug-development pipelines. In the meantime, I applaud the FDA’s provisional approval and I am happy to be able to provide this as an option for my patients. I have heard some doctors state that they will reserve the triplet for patients that “need a response.” I have never met a patient who did not feel that he or she needed a response, and therefore the 021G triplet is my new go-to first-line regimen for non-squamous NSCLC patients without targetable mutations.


Dr. Goldman joins GRACE from UCLA Medical Center in Santa Monica, where he specializes in Hematology and Oncology.  He serves as Assistant Professor of UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology.  


 

 

 

 


Denise Brock

Lung Cancer Video Library – Evolving Options in First Line Treatment of ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

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GRACE Cancer Video Library - Lung

 

 

We 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 with 2017 updates to our Lung Cancer Video Library.  In this recent video for GRACE, Dr. Raez discusses Evolving Options in First Line Treatment of ALK-Positive Non-Small Cell Lung Cancer (NSCLC).


 

 

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TRANSCRIPTS 
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 Dr. Luis Raez, MD FACP FCCP

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

 

 


  


Denise Brock

Lung Cancer Video Library – First Line Immunotherapy for Advanced Non Small Cell Lung Cancer NSCLC

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GRACE Cancer Video Library - Lung

 

 

We 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 with 2017 updates to our Lung Cancer Video Library.  In this recent video for GRACE, Dr. Raez discusses First Line Immunotherapy for Advanced Non-Small Cell Lung Cancer NSCLC.


 

 

 

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 Dr. Luis Raez, MD FACP FCCP

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

These are very exciting times because we have recently moved immunotherapy to first line, meaning new patients with stage IV non-small cell lung cancer or metastatic patients.   Until recently immunotherapy was approved first for second line and based on some studies – very important – but immunotherapy, after that moved to the front line, so that new patients can have an opportunity to be treated.  Specifically, the Pembrolizumab was moved to the front line based on a study in which the Pembrolizumab was compared against chemotherapy, Carboplatin combination that are the standard of care so far and Pembrolizumab was able to give better outcomes than the combination or amalgamation of chemotherapy but the most important thing in this news is that we are developing markers to try to discover which patients will respond to immunotherapy and which ones will not.  The specific marker that probably everyone knows or cares about is PD-L1.  In this specific study, the patients will benefit from immunotherapy for new patients if the PD-L1 expression in the tumor, we are checking in the tumor, is more than 50%.  Immunotherapy front line was not approved for everybody, it was approved for this specific niche of patient that they will benefit.  The rest of the patients will still need to get chemotherapy or target therapy based on molecular markers if they have any of these genetic alterations that we reference all the time, EGFR, ALK, ROS1.  We only had one drug approved because unfortunately the other drug, Nivolumab, is already approved for second line.  In a similar study, Nivolumab was much against chemotherapy and Nivolumab was unable to get a better progression free survival than the patients on chemotherapy.  For that reason, we only have as a single agent so far, Pembrolizumab, approved in first line.  Of course, there will be changes because we have other immunotherapy agents coming to the market soon and new studies coming soon but so far Pembrolizumab is only approved as a single agent in the front line.  

 


  


Denise Brock

Lung Cancer Video Library – Spanish Language: Video #45 ALK Marker Testing

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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 45th video for the Spanish lung cancer video library, Dr. Santana-Davila joined GRACE to discuss ALK marker testing. 


 

 

 

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TRANSCRIPTS – Spanish and English
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Prueba de Marcadores Tumorales: Cinasa de Linfoma Anaplásico

ALK Marker Testing

 

Rafael Santana-Davila, MD
Assistant Professor of Medicine
University of Washington Seattle Cancer Care Alliance
Seattle, Washington

 

Spanish TRANSCRIPT

Uno de los principales logros que ha habido en la última década en el tratamiento del cancer de pulmón, es el descubrimiento de que en algunos casos de los casos (alrededor del 10% de los casos en general), se puede descubrir que hay una mutación que es lo que lo ha llevado a que el cáncer se reproduzca fácilmente.

En la mayoría de los casos, esto es una mutación en el gen de crecimiento epidermoide o EGFR. Esto ocurre en alrededor del 10% de los casos de cancer de pulmón general, pero puede llegar a ocurrir en el 50% de los casos de no fumadores.

Hacemos un test en el espécimen de patología y cuando es positivo, el paciente es candidato a tratarse con un medicamento que en la mayoría de los casos es una píldora. Ha habido muchos avances en el tratamiento de este tipo de cancer.

El otro marcador tumoral que buscamos es ALK (cinasa de linfoma anaplásico) que es una translocación en donde lo que pasa es que dos cromosomas intercambiaron información en dos células tumorales llevando a la formación de una nueva proteína. Cuando esto ocurre, el tratamiento está diseñado a atacar esta translocación e inhibir a esta proteína en particular.

Cuando se tiene cualquiera de estos marcadores tumorales, el tratamiento es más específico, por lo que es muy importante saber si el paciente tiene alguno de estos marcadores.


  

English TRANSCRIPT

One of the biggest accomplishments made in the last decade on lung cancer treatment is the discovery that in about 10% of all the patients there is a mutation that is related to the progression of the cancer.

In most cases, it’s a mutation in the epidermal growth factor receptor or EGFR. In general, this appears in about 10% of lung cancer cases, but there can be in 50% of the non-smokers patients. We do a pathology test of the specimen and when it’s positive, the patient is a candidate to receive a special treatment, that is usually a pill. There have been many advances in the treatment of this kind of cancer.

The other tumoral marker we look for is ALK (anaplastic lymphoma kinase), which is a translocation where two chromosomes change information in two tumoral cells and create a new protein. When this happens, the treatment is designed to attack this translocation and inhibit this particular protein.

When the patient has either one of those markers, the treatment becomes more specific. There’s the importance of knowing if the patient has one of them.

 


Denise Brock

Lung Cancer Video Library – Spanish Language: Video #44 Treatment of Stage III Unresectable Non-Small Cell Lung Cancer

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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 44th video for the Spanish lung cancer video library, Dr. Santana-Davila joined GRACE to discuss the treatment of stage 3 unresectable non-small cell lung cancer.


 

 

 

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
 

Tratamiento de Cancer de Pulmón de Células no Pequeñas en Estadio Tres no Resecable

Treatment of Stage III Nonresectable Non-Small Cell Lung Cancer

 

Rafael Santana-Davila, MD
Assistant Professor of Medicine
University of Washington Seattle Cancer Care Alliance
Seattle, Washington

 

Spanish TRANSCRIPT

Cuando el paciente se encuentra en estadio tres y no es candidato a cirugía porque el cancer está en varios ganglios del mediastino o por otras razones, lo que hacemos es quimioterapia con radiación al mismo tiempo. La radiación se da todos los días por cuatro a seis semanas y la quimioterapia dependiendo de qué régimen se escoge puede ser una vez por semana o dos ciclos de quimioterapia durante la radiación.

Para saber cuál quimioterapia es mejor es un poco controversial, pero depende mucho de la plática que se tiene con el paciente para conocer el tiempo que se tiene, los beneficios y riesgos. Los regímenes que son más comunes en Estados Unidos son carboplatino con paclitaxel una vez por semana. Una vez que se acaban las cuatro a seis semanas de radiación, se dan otros dos ciclos que se llaman ciclos de consolidación. El otro régimen que es muy común es cisplatino con etopósido y esto se da dos ciclos de quimioterapia durante la radiación sin hacer quimioterapias adicionales.


  

English TRANSCRIPT

When the patient is in stage three and is not a candidate to surgery because the cancer is in some lymph nodes of the mediastinum or other reasons, the best option is chemotherapy with radiation at the same time. The radiation is given every day for four to six weeks and the chemotherapy, depending on the regimen chosen, can be once per week or two cycles of chemotherapy during the entire treatment of radiation.

The types of chemotherapies are controversial because to choose which one is better depends on the discussion you have with your doctor to know the time they have, the risks and benefits. The most common regimens in United States are carboplatin and paclitaxel once per week. Once the four to six weeks are over, two more cycles of radiation are given to consolidate. The other common regimen is cisplatin with etoposide, they are given in two cycles of chemotherapy during the radiation with no additional chemotherapies.


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