GRACE :: Lung Cancer

Immunotherapy Combinations

GRACEcast-526_Lung_West_Immunotherapy_Combinations

 

Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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The class of agents known as immune checkpoint inhibitors have really invigorated our study of lung cancer, and many other cancers over the last few years. Agents like Opdivo, also known as nivolumab, and Keytruda, known as pembrolizumab, are now commercially available, FDA approved as a second line therapy for patients who have progressed on first line standard chemotherapy. We are now actively asking the question of whether we might be able to move these immunotherapies into the first line setting and also asking whether we might do well by giving a combination of immune therapies, rather then just one treatment at a time.

So these agents, immune checkpoint inhibitors, are largely categorized into PD-1 or PD-L1 inhibitors, and those are just targeting two separate sides of an interaction between two receptors. The PD-L1 is on the tumor cells, PD-1 is on the immune T cells, and so blocking either side of this can lead to a beneficial effect because this effect leads to a braking mechanism on the immune system — you take away that braking system and you turn off the brakes and lead things to move forward, and that’s what we often see.

There are other agents that can also lead to braking mechanisms and that have been studied in other cancers. An agent such as Yervoy, which is known as ipilimumab is a CTLA-4 inhibitor and this is an agent that’s been approved in melanoma. In fact, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), as two different ways of blocking the immune system, have been shown to be beneficial as a combination in melanoma compared with either one on its own. Because of that, we’re looking at combinations of immunotherapies compared with single immunotherapy approaches, or standard chemotherapies.

One interesting study being done right now is called CheckMate 227 and it is looking at first line treatment of patients with advanced lung cancer that is either squamous or non-squamous histology. It does not require any level of PD-L1 expression on the tumors, the protein associated with tendency toward better efficacy of immunotherapies, partly with the thought that the combination of two immunotherapies may make even the cancers that don’t express PD-L1 respond well. This trial is looking at first line therapy with either standard chemotherapy of cisplatin or carboplatin with Alimta for non-squamous cancers, or Gemzar (gemcitabine) for squamous cancers, compared with either Opdivo alone or a combination of Opdivo and Yervoy — Opdivo being a PD-1 inhibitor, Yervoy being a CTLA-4 inhibitor — and asking the question of whether immunotherapy is as good, better, or worse than standard chemotherapy as a first line treatment, and whether the combination of two immunotherapies is better than first line therapy. 

I should mention that there are other trials looking at very similar versions of this question using different combinations of immunotherapies. There are many companies looking at several different immunotherapies in development and they are overall really very comparable and all quite exciting.

You can learn more about this specific trial from the link on the screen,

CheckMate 227 Clinical Trial

but I would encourage you, if you talk to your doctor and they recommend a trial with an immunotherapy in the first line setting, potentially comparing it to chemotherapy, to carefully consider it — it does not have to be this specific trial to be of interest.

We’re going to learn more about this in the coming years and we’re going to figure out the best way to integrate immunotherapies with our standard treatment approaches today.


Immunotherapy as First-Line Treatment

GRACEcast-525_Lung_West_Immunotherapy_First_Line_Treatment

 

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.


Lung Cancer Screening – Process and Potential Benefits

GRACE Cancer Video Library - Lung

GCVL_LU-A05_Lung_Cancer_Screening_Process_Potential_Benefits

 

Dr. Jed Gorden, Swedish Cancer Institute, reviews the lung cancer screening process, including low-dose CT scanning, smoking cessation, follow-up testing and counseling, and describes the potential benefits.

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Lung cancer screening is a very exciting advance in the field of lung cancer which has come about in the last several years. This is where low-dose CT scans, or “CAT” scans, very high resolution images of the lungs, are used to identify nodules and identify early cancers. The critical thing to know is that this is an advancement that has come about in the last several years due to a tremendous amount of government-funded research looking at the safety and the efficacy of using low-dose CT scans to identify high-risk patients who have lung cancer.

Let’s talk about that for a second: high-risk patients. Patients that qualify for lung cancer screening need to understand certain things, and you’re going to have to participate in a shared decision-making conversation with your team and caregivers. So who qualifies, who is high-risk? The high-risk criteria for lung cancer screening and people who should undergo low-dose CT imaging are patients who are 55 to 80 years old, who smoked for at least 30 pack-years which is one pack of cigarettes a day for 30 years, and are actively smoking or quit within the last 15 years. This is the minimum population who is at risk for lung cancer and meets the criteria to undergo low-dose CT screening.

It’s really important to understand that embarking on lung cancer screening and low-dose CT is a journey and a partnership with your team of professionals in the lung cancer screening center. The reason that I say this is because, number one: no single scan will prove that any individual doesn’t have lung cancer. It is through a partnership and continued surveillance based on specific criteria, and discussions with your team over time that will help minimize any risk of lung cancer.

Why would anyone want to embark on this journey? The data that we have and the reason we’re so excited about lung cancer screening now is that the data suggests that through low-dose CT screening of high-risk individuals that the mortality associated with lung cancer is decreased by 20% and the overall all-cause mortality is decreased by almost 7%. But it’s important to understand that this is done in the confines of a multidisciplinary team with counseling and active participation of patients who continue throughout the program and follow the guidelines that are established through screening.

So let’s talk about each one of these components. We’ve talked about the high-risk, which is the patient that’s involved — let’s talk a little bit more about high-risk. So we know that even within this risk profile are those that are at minimal risk for lung cancer, there are those that are at increased risk. We have an identified population of high-risk patients for lung cancer that we described: 55 to 80 years old, actively smoking or quit within the last 15 years, and smoked for at least 30 pack-years. We know that’s the minimum risk and it’s important for people to understand that at the minimum risk level for lung cancer, it takes almost 5,300 people screened to identify one single cancer. As the risk goes up, age goes up, increasing pack years of smoking goes up, we know that the number of people to screen goes down to about 160 to 170 people in the highest risk groups. Therefore it’s important that we adhere to these rigorous guidelines of only those patients who are at the highest risk, who meet the criteria that was described, to undergo lung cancer screening.

Number two: partnership. No single scan allows people to move forward without being continued in the program. It is a continuum that people need to engage in and a partnership with your professional team.

Number three: smoking cessation. Smoking cessation for those that are still smoking is critical to minimizing the risk for lung cancer. This is a teachable moment. This is an opportunity to partner with your team to identify the ability to quit, potential medications for helping you quit, triggers and counseling. I urge people to take advantage of this and to inquire with their team on how best to approach this process as you engage and move forward in the lung cancer screening arena.

The final thing is counseling. It is important to understand that many people who embark on the journey of lung cancer screening, both those that are in the highest risk group and those that are in the minimum risk group to qualify for lung cancer screening will oftentimes be found with an abnormality or what’s called a pulmonary nodule. A pulmonary nodule is a small abnormality seen on a CT scan. It can be described as a dot or a nodule or an abnormality, all descriptors of the same thing, but the critical thing to understand is that the overwhelming majority of the time, these are not cancer. They are benign, but we only know that through continued surveillance and strict adherence to guidelines on when to follow patients up, when to move to additional testing, and when to move on to invasive testing.

The confidence that you build with your professional team will allow you to move forward through this process with education and without fear, and allow you to move forward and minimize the risk of lung cancer in those patients who are high-risk.


Bronchoscopy and EBUS

GRACE Cancer Video Library - Lung

GCVL_LU-B05_Bronchoscopy_EBUS

 

Dr. Jed Gorden, Swedish Cancer Institute, describes the differences between bronchoscopy and endobronchial ultrasound, highlighting the advantages of EBUS in diagnosis and staging.

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Today I’m going to talk to you about bronchoscopy with endobronchial ultrasound. It’s an interesting technology — bronchoscopy in its form that we know it now, flexible bronchoscopy, has been around since about the late 1960s. This allowed us to move bronchoscopy from an operating room into outpatient settings and allow us to navigate through the airways. For those of you that have heard of colonoscopies or upper endoscopies, these are all cameras that allow us to snake through the airway or other orifices and get a much clearer picture of what’s going on inside. The challenge though with traditional bronchoscopy is it allows you to only see what’s directly in front of you — what is in the airway, and the overwhelming majority of the time the airways are normal.

A tremendous advantage to us in the field of lung cancer, lung cancer diagnosis, and lung cancer staging has been bronchoscopy coupled with ultrasound, creating what’s called endobronchial ultrasound or EBUS. This is a very small ultrasound probe coupled at the end of a bronchoscope. It enters into the airway in the exact same fashion that bronchoscopy does for traditional procedures, but what it allows us to do is look through the airway wall. This is critical because looking through the airway wall now allows us to identify lymph nodes, abnormalities that are around the trachea, the bronchi which are the divisions of the airway that go to the left lung and the right lung, and this is critically important because we know that with staging where we’re not only diagnosing those that have cancer, but where the cancer is and whether it has spread to the lymph nodes is crucial to an understanding and developing a treatment plan.

Some we now have a tool in our armamentarium to, in a very minimally invasive way, go into the airways, see what’s in the airways, and see through the airways into the lymph nodes that live in and around those airways. Once we’ve identified these very specific structures, we can sample them with small needles allowing us to puncture through the airway wall directly into a lymph node, collect a sample, have a pathologist look at it under a microscope, and tell us whether that lymph node is involved in cancer or that lymph node is not involved with cancer. Critical are the decisions that will be made for creating a treatment algorithm.

The advantage of this is that it’s minimally invasive; it’s done in the outpatient setting. It allows us to sample most of the lymph nodes that are present and are critical to decision making around lung cancer and lung cancer staging. Complications of it are very rare — sometimes after bronchoscopy and bronchoscopy with ultrasound, people can experience a fever, or maybe a sore throat, but larger complications like bleeding and infection are very rare.

The most important thing though to understand is that this is a partnership with your physician and that they explain to you what procedure you’re going to have, and how this procedure is going to benefit you, whether it’s bronchoscopy or bronchoscopy with ultrasound.

The final thing that I’m going to talk about with bronchoscopy and bronchoscopy with ultrasound is how you’ll be during the procedure. Most patients ask, “am I going to be awake; am I going to know what’s going on?” There are two ways to do bronchoscopy and bronchoscopy with ultrasound. One is what’s called conscious sedation — this is sort of a twilight phase where people are sleeping, they’re breathing on their own, responsible for their own vital signs, but a bronchoscopist is allowed to do procedures without it causing too much disturbance to the patient. This is good for procedures that last about 25 to 30 minutes and allows people to sample in the airways in a very safe fashion. Another way that bronchoscopy with ultrasound is performed is with anesthesia — this is where an anesthesiologist takes over the safety of the patient and the control of their airway. A breathing tube or a small cap over the back on the airway is placed allowing air to pass in and out and control the breathing and ensure safety during the procedure.

So when you talk with your physician about this, it’s important to understand how you will feel during the procedure, what is going to be going on in terms of your safety, sedation, and your comfort. It’s also important to know that there’s data for this; the data for this suggests that the procedures are equal. Bronchoscopy and bronchoscopy with ultrasound can be done safely in the setting of conscious sedation and in the setting of general anesthesia, and you should feel confident that you can have a safe and effective procedure.

So in summary the most important thing is that you partner with your physician in order to get the most information possible from any procedure. In this case the procedure will be bronchoscopy. Bronchoscopy is an inspection of the airway. We couple that with ultrasound which is not only inspection of the airway, but visualization through the airway wall, identifying the lymph nodes and structures. Biopsying those gets tissue which is staging and telling us how much cancer there is, and this can be done safely and effectively with you sleeping in either a conscious or twilight phase, or with general anesthesia.


Maintenance Therapy for Advanced NSCLC

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.


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