GRACE :: Lung Cancer
Dr West

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

 

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

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.


GRACE Video

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.


GRACE Video

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.


GRACE Video

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.


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