GRACE :: Lung Cancer

Search cancerGRACE.org

CO-1686

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?

Share

 

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

Are There Clinically Significant Differences Among the Third Generation EGFR Inhibitors?

Share

WCLC_2015_16_Clinically_Significant_Differences_Third_Generation_EGFR_Inhibitors

 

Drs. Ben Solomon, Leora Horn, & Jack West compare the clinical data with the third generation EGFR TKIs so active in acquired resistance and consider whether there are significant differences between them.

Download Transcript

How Did You Like This Video?

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

 

Transcript

Dr. West:  We now have two, hopefully very soon, commercially available third-generation EGFR inhibitors, osimertinib, and also rociletinib. These agents really seem pretty comparable in efficacy — some differences in toxicity. What do you see as potentially clinically significant differences? If you had both available, how would you approach a patient with T790m mutation-positive acquired resistance?

Dr. Horn:  So yeah, I was going to say their similarities are in the T790m-positive patents — there are some differences in the negative patients.

Dr. West:  We’ll cover that too.

Dr. Horn:  But, I do think that — I’m going to use their numbers because they’re easier to remember than names, 9291 (osimertinib) is a little better tolerated, in my experience, than 1686 (rociletinib), the Clovis drug. I think that, for patients who are going to be on the Clovis drug, we’re going to have to be very diligent about monitoring their blood sugars because the hyperglycemia is a real toxicity that can be quite significant. Now, 9291 did have more rash, but, for these patents, they’re used to be dealing with a rash, they’ve had rashes for years because they’re been on erlotinib, gefitinib, afatinib, and even the rash of 9291 is less severe than the first and second generation agents.

Dr. West:  Clearly, these agents will do well with their marketed names, given how hard they are to differentiate based on their names now! Ben, what do you think here?

Dr. Solomon:  Yeah, look, I agree. I think they’re both very active, they both have response rates of about 50-60% in patients that have progressed on Iressa or Tarceva, but they are different in their toxicities, and rash and diarrhea with the AZD9291 compound, which we believe to be called osimertinib, today, is generally manageable and, for patients, quite similar to the rash they might have experienced, and diarrhea they might have experienced before, or even milder; whereas, hyperglycemia is a completely new toxicity and I think, again, patients need to be vigilant about this toxicity, and doctors need to know how to manage this toxicity with the use of Metformin and monitoring of blood glucose, so it can be a little bit trickier.

Dr. West:  I must say that, about a year and a half ago, when these data were first presented, I thought that managing hyperglycemia with some Metformin seemed pretty trivial for cancer patients who have an effective treatment against cancer — but when there’s an alternative that doesn’t have that, and, in some of my patents I’ve had challenging nausea and anorexia, you know, just diminished appetite, weight loss, fatigue — my experience has been that it’s not a trivial challenge, at least in a subset of patients. That said, they’re both a real advance.


GRACE Video

Are There Clinically Significant Differences Among the First and Second Generation EGFR TKIs (Iressa, Tarceva, Gilotrif)?

Share

WCLC_2015_13_Clinically_Significant_Differences_First_Second_Generation_EGFR_TKIs

 

Drs. Ben Solomon, Leora Horn, & Jack West review whether the data and clinical experience suggest any clinically significant differences among the first and second generation EGFR TKIs (Iressa, Tarceva, Gilotrif/Giotrif).

Download Transcript

How Did You Like This Video?

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

 

Transcript

Dr. West:  What’s your sense of whether there are clinically significant differences among the first or second generation EGFR tyrosine-kinase inhibitors — that is, Iressa, Tarceva, Gilotrif. Are these agents that you consider to be really interchangeable, does it matter what actual mutation the patient has, or do you think it’s really completely a dealer’s choice? Ben, why don’t I start with you?

Dr. Solomon:  Yeah sure, so there’s certainly differences at the clinical level — the second generation inhibitors, afatinib and dacomitinib, do have a lot more toxicity. They’re very potent inhibitors of both mutant and wild type, or normal, EGF Receptors — so skin, nail toxicities, diarrhea, are more common with those drugs than with Iressa or Tarceva. In terms of the question of efficacy, I think we’re all waiting to hear the results of a head to head study; it’s very difficult to compare different phase three studies, but there is some interesting data that has been presented with afatinib from, actually, a couple of different studies, which, admittedly, was a subgroup analysis, which suggested that in the subgroup of patients that had exon 19 deletions, as opposed to the group that had LA58r mutations, there was a survival benefit. But, it’s not clear whether that same difference might have been seen in the other studies with the other drugs, as well, if it was looked for in sufficient numbers. So, to my mind, it’s an open question about whether there’s increased efficacy. I guess the other point Leora alluded to — occasionally, you do see responses to afatinib in patients who have progressed on Iressa or Tarceva, which may suggest some differences in efficacy.

Dr. West:  What are your thoughts on whether there are clinically meaningful differences between them, and whether there is a significant difference between the main activating mutations for all EGFR TKIs, or for afatinib.

Dr. Horn:  So, I completely agree with Ben that the toxicities are clinically meaningful and different between the different agents. LUX-Lung 7 is close to accrual, and so, hopefully —

Dr. West:  That’s a trial directly comparing afatinib to gefitinib (Iressa) in EGFR mutation-positive patients, first-line.

Dr. Horn:  And it’s primarily in Asia because gefitinib, up until a few weeks ago, was not available here.

Dr. West:  I just learned that it’s actually half Asian and half European, which will be helpful to know because we do struggle with the question of whether the results out of Asia are completely generalizable to non-Asian populations. So, I think we’re going to be getting the results of that in the first half, hopefully, of 2016, at least some of the results, and, so, that will hopefully, provide — shed some light on this controversial question.


GRACE Video

Should Third Generation EGFR Inhibitors Be Used Before First Generation EGFR TKIs or After Progression?

Share

WCLC_2015_19_Third_Generation_EGFR_Inhibitors_Before_First_Generation_EGFR_TKIs

 

Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.

Download Transcript

How Did You Like This Video?

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

 

Transcript

Dr. West:  So let’s turn to the question of — you have agents like these third-generation EGFR inhibitors that have impressive activity in patients with acquired resistance after a prior, say, first-generation EGFR inhibitor like Iressa (gefitinib), Tarceva (erlotinib), or the second-generation inhibitor Gilotrif (afatinib). Those agents really have activity that seems limited to the first line setting, not much activity in acquired resistance. There’s going to be a temptation to move these later agents into the first line setting with the thought that maybe you can postpone, for much longer, acquired resistance — there’s certainly trials looking at this, but before we have the result of those trials, is that going to be something that you’re going to be tempted to do or recommend?

Dr. Horn:  Not unless I have a patient who maybe has a germline T790m mutation, so T790m at the time of diagnosis. I think that those trials need to come out and we need to see what the combined progression-free survival is, just of third-generation on its own, compared to progression-free survival with a first, followed by a third, and without that data, I’m not tempted to change my practice at this time.

Dr. West:  Ben, what do you think?

Dr. Solomon:  Yeah, I’m with Leora. I think they’re really important trials, the trials with both compounds in the first line, compared with first-generation inhibitors — and I guess the rationale is that you might be able to prevent and delay the emergence of resistance by targeting T790 right from the beginning, but we know resistance develops to these third-generation inhibitors. As well, they’re new mutations that prevent the third-generation inhibitors from binding to the EGFR, and it might be that you may not be able to rescue and make the tumor re-respond to another EGFR inhibitor later on down the track, so I don’t think we can presuppose the answer to these trials, but I think they’re important, and certainly, if the time that you can control the disease by using a third-generation inhibitor first is longer than you can by using a first-generation inhibitor, followed by a third-generation inhibitor, it’s going to change the way we all practice.

Dr. West:  Well, that’s a good point though, that these are all looking at progression-free survival as the primary endpoint, but that’s not really the key issue — it’s not whether a first-generation agent is less than a third-generation agent, as much as first-generation, followed by the third-generation, versus starting with the third-generation, because your goal isn’t just to get them to this coming Christmas, but have patients live many Christmases in the future, and, so, I think that, to me, seeing if it changes overall survival, or really, looking further beyond just one line of therapy is an important issue.


GRACE Video

Should EGFR TKI Therapy be Continued Beyond Progression?

Share
GRACE Cancer Video Library - Lung

GCVL_LU_EGFR_TKI_Therapy_Continued_Beyond_Progression

 

Dr. Greg Riely, medical oncologist from MSKCC, discusses the controversial question of whether patients should continue on an oral EGFR tyrosine kinase inhibitor after progression.

Download Transcript

How Did You Like This Video?

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

 

Transcript

After patents develop resistance to EGFR tyrosine-kinase inhibitors, such as erlotinib, gefitinib or afatinib, we eventually have to make a change in systemic therapy, and if we’ve gone through our first generation or second generation of EGFR tyrosine-kinase inhibitors, and even potentially after third generation EGFR tyrosine-kinase inhibitors, we have the option of using chemotherapy. Chemotherapy is very effective for patients with EGFR mutant lung cancer, and I think it’s definitely something that patients shouldn’t fear because it does have great activity and we can make it quite tolerable for patients to receive these chemotherapies. 

One critical question comes up, as to whether we should continue EGFR tyrosine-kinase inhibitors after development of resistance when we’re starting chemotherapy. Kind of an obvious statement is that, if the patient has developed resistance, and many of my patients ask me this question — “if I develop resistance, why should I continue an EGFR tyrosine-kinase inhibitor?” I think it’s a good question. When we started thinking about this with our patients, long ago, we did what the standard thing was, which is we stop EGFR tyrosine-kinase inhibitors and move on to chemotherapy. When we look back at some data where we had patients stop EGFR tyrosine-kinase inhibitor, prior to enrolling in a clinical trial, the general washout, this period of the time off-drug, that we call it, was about two weeks, and in that time, we saw about 20% of patients have a significant worsening of their disease course — and when I say significant worsening of their disease course, their symptoms got so bad that they were hospitalized, and some of them even died after stopping EGFR tyrosine-kinase inhibitors.

Now, I say that not to frighten people, but to point out that, often, in patients with EGFR mutant lung cancer, there is still some benefit for continuation of EGFR TKI, and there may be a role for continuing with chemotherapy. Importantly, this has been studied in a randomized fashion, so patients with EGFR mutant lung cancer with resistance to first-generation EGFR tyrosine-kinase inhibitors, were randomized to chemotherapy with an EGFR tyrosine-kinase inhibitor, and there wasn’t a difference in the outcome. So, it wasn’t clear in an overall patient population that it mattered if you continued. So, this data really indicates that it’s okay not to continue EGFR tyrosine-kinase inhibitors. I think the one area that I might disagree is maybe in the initial switch from an EGFR tyrosine-kinase inhibitor to the chemotherapy — it would be reasonable to overlap those so that you’re getting the benefits of the chemotherapy and we’re seeing shrinkage of the chemotherapy before you pull back on the EGFR tyrosine-kinase inhibitor.


Ask Us, Q&A
Lung/Thoracic Cancer Expert Content

Archives

Share

GRACE Cancer Video Library - Lung Cancer Videos

 

2015_Immunotherapy_Forum_Videos

 

2015 Acquired Resistance in Lung Cancer Patient Forum Videos

Share

Join the GRACE Faculty

Breast Cancer Blog
Pancreatic Cancer Blog
Kidney Cancer Blog
Bladder Cancer Blog
Head/Neck Cancer Blog
Share

Subscribe to the GRACEcast Podcast on iTunes

Share

Email Newsletter icon, E-mail Newsletter icon, Email List icon, E-mail List icon

Subscribe to
GRACE Notes
   (Free Newsletter)

Other Resources

Share

ClinicalTrials.gov


Biomedical Learning Institute

peerview_institute_logo_243