GRACE :: Lung Cancer

Epidermal growth factor receptor (EGFR)-based therapies

Discussion of a full range of EGFR-based treatments, including tyrosine kinases and antibodies

Dr West

Is immunotherapy the wrong choice for some lung cancer patients?

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Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy — specifically, those patients with an EGFR mutation and perhaps others with another “driver mutation” such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

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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?

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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

Rociletinib/Osimertinib for EGFR T790M-negative NSCLC

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GRACE Cancer Video Library - Lung

GCVL_LU-F13_Rociletinib_Osimertinib_EGFR_T790M-Negative_NSCLC

 

Dr. Jack West, Swedish Cancer Institute, reviews trial evidence for the efficacy of rociletinib and osimertinib for EGFR acquired resistance not driven by a T790M mutation.

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For patients who have an activating mutation in their cancer known as EGFR we have several very good first line treatment options to consider. There are three leading contenders as oral targeted therapies that block EGFR and tend to work very well for patients with an EGFR mutation. These agents are known as Iressa (gefitinib), Tarceva (erlotinib), and Gilotrif (afatinib). These agents have a chance of shrinking the tumor in the range of 60% to 75% which is great, but unfortunately these responses do not last forever and on average, patients will develop progression of their cancer, so-called acquired resistance to this first line therapy, after something in the range of nine to 12 months — can be less, can be more.

The question is what to do when that occurs. Well, there are a couple of agents that have shown great promise and great activity, at least in the subset of patients who have a mutation, found at the time of this acquired resistance, that is known as T790M. And so we repeat a biopsy of an area of progressing cancer while patients are on and progressing on this first line EGFR inhibitor, and 50% or 60% will have this acquired resistance mutation known as T790M. For those patients, we standardly consider drugs like osimertinib and rociletinib, and I say standardly consider as if they’re commercially available, and they’re not yet, at this moment in late 2015, FDA approved but it is expected that both will be approved by the FDA based on their very good activity in the very near future, perhaps by the time you see this.

But these agents are best studied and have their greatest activity in the patients with a T790M mutation. So what about the patients who are still 40% or 50% of that population with progressing cancer on an EGFR inhibitor who don’t have a T790M mutation? It turns out that both of these agents have good activity, or at least some degree of activity, in patients who are T790M-negative. It doesn’t tend to be as long-lasting and the response rates tend to be lower, but the activity is certainly encouraging.

GCVL_LU-XXNN_Jack_West_Swedish_15_01

When you look at what’s called a waterfall plot that’s shown here of how patients respond, the bars going downward represent patients whose cancers have shrunk, and the ones that go upward are the ones whose cancers have progressed on a therapy. You can see that when we look at patients who received osimertinib, the AstraZeneca drug AZD9291, there is good activity in the majority of patients who receive this agent, even if they have no T790M mutation.

GCVL_LU-XXNN_Jack_West_Swedish_15_02

The same is true for rociletinib, the Clovis drug CO1686 — the waterfall plot shows that most of the bars do go down, and that a lot of patients receive a substantial benefit, even if they do not have T790M detected in their rebiopsied tumor.

So there are studies that are looking specifically at these agents in patients who are T790M-negative. A trial with rociletinib known as TIGER-3 is looking at patients who have received prior EGFR inhibitors like Iressa, Tarceva or Gilotrif, and have also received prior chemotherapy. These patients are then randomized to either receive rociletinib or a standard chemotherapy as a single agent, and there are several that your doctor can choose from. This trial will be looking at which patients do better depending on whether they get the targeted therapy or standard chemotherapy.

There is another trial being done with osimertinib in combination with an EGFR monoclonal antibody known as necitumumab, so a two drug combination being looked at in patients who are T790M-negative after progressing on a first line EGFR inhibitor. So both of these agents are being studied not just in patients with a T790M-positive cancer, but a T790M-negative cancer, and if you do have acquired resistance and are found to not have a T790M mutation, you might want to look into information about these trials to see if one might be a good choice for you.


GRACE Video

The Role of Targeted Therapy Post-Resection

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GCVL_LU-D21_Targeted_Therapy_Post-Resection

 

Dr. Heather Wakelee, Stanford University Medical Center, evaluates the lack of evidence for the use of targeted therapies after surgery, and describes ongoing trials attempting to resolve that issue.

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Since the mid-2000s we’ve known that many patients who have non-small cell lung cancer, particularly the adenocarcinoma type, have particular gene mutations that we can identify and when we find them, treat with specific new drugs. We know this data from patients with metastatic lung cancer — the first to be discovered was EGFR or epidermal growth factor receptor, then ALK or anaplastic lymphoma kinase. Now there’s a very long list of gene mutations that we can identify when we look in patients with advanced stage lung cancer, and when we find them, offer specific targeted therapy that can have a very high likelihood of shrinking the tumor. This has really changed the way we think about and treat advanced stage lung cancer. However we haven’t figured out how to best use those treatments for patients who have earlier stages of lung cancer.

So in the setting of an early stage lung cancer that’s been removed with surgery, patients are theoretically cured at that point. Chemotherapy has been proven to lower the chance of the cancer coming back, but when you find one of these mutations in the tumor, the temptation is to give one of these targeted drugs. That strategy has been looked at in multiple clinical trials and we still don’t have a straightforward answer.

The largest trial to look at this so far was called the RADIANT trial and in that trial, after getting chemotherapy if that was the right thing for them, patients either received the EGFR drug called erlotinib, or a placebo. Now most of those patients in that trial actually did not have a specific mutation in EGFR because the study was designed before we knew about how important those mutations were. In the subset of patients who did have the EGFR mutation, those getting erlotinib seemed to have more time before the cancer came back, but if you looked at their overall survival, it wasn’t any different than the patients who had been on the placebo arm. The theory is that those who were on the placebo arm who had the cancer come back, when it came back they were then able to get erlotinib or a similar drug and have the same benefit. So it’s not clear that starting the erlotinib right at the time of surgery actually helps people live longer, though it might slow down the time to recurrence.

That’s obviously not a complete answer so there are more studies happening now trying to get a better sense of what we should do in that setting. There are a couple of trials in China, actually several trials in China, a study in Japan, and now a big study in the United States, all with the same general idea that a patient who has a tumor resected or removed by surgery, who is shown to have an EGFR mutation in that tumor, is randomized to either get an EGFR drug or to get placebo. Some of the studies have chemotherapy before or after, some compare it to chemotherapy, so there are some differences, but the general idea is whether or not giving the EGFR targeted drug will actually help people be cured or live longer versus waiting, and then for those who do have recurrence, giving it at that time. So those are really important trials that are ongoing and we’ll hope to know the answers in the next few years.

For the patients with the ALK translocation in the United States, the big trial called ALCHEMIST is open not just to EGFR but also to ALK patients. What that trial is about is asking that any patient who has a surgery at a site that’s participating in ALCHEMIST have part of their tissue from the tumor sent in to a central laboratory to be tested for EGFR or ALK. Those patients who have EGFR are then randomized to either get the EGFR drug erlotinib, or to get a placebo pill, and those who have ALK to get the ALK drug crizotinib versus a placebo pill. Over time people will be followed to see — does this change when the cancer comes back, and does it ultimately change overall survival for the patients where the cancer does come back?

So this is a really critical trial and it’s going to help us know what the best way is to use these targeted drugs for patients in this setting. Until we have those trial results back, I do not recommend that patients get the EGFR or ALK targeted drugs after surgery because we just don’t know if that’s going to help them live longer.


GRACE Video

Is Targeted Therapy Feasible As Consolidation in Locally Advanced NSCLC?

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GCVL_LU-EA01_Targeted_Therapy_Consolidation_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, reviews efforts to utilize targeted therapies as consolidation after chemoradiation in locally advanced NSCLC.

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Because those strategies testing additional systemic therapy utilized chemotherapy and those strategies did not improve outcomes compared to concurrent chemoradiation alone, we looked to try to give other forms of systemic therapy that were not chemotherapy to see if perhaps that would improve outcomes. Beginning in the 2000s there were a number of new drugs that appeared to be active in people with lung cancer and these are what we call molecularly targeted therapies. The first of these molecularly targeted therapies targeted a certain growth receptor on the surface of cancer cells, and this is called the epidermal growth factor receptor (EGFR) and we had a drug at the time which would target cancer cells that expressed this epidermal growth factor receptor. Well we understood in the 2000s that the vast majority of people with lung cancer have tumors that overexpress these growth receptors on the surface.

So clinical trials were designed to incorporate these new molecularly targeted therapies into the backbone of therapy that we had already established. Probably the best known of these trials was conducted by one of the United States cooperative groups in which all patients with stage III unresectable non-small cell lung cancer received the standard concurrent chemotherapy and radiation therapy backbone. Now in this trial patients were allowed to receive additional chemotherapy after that but the bottom line with this trial and the importance of this trial is then at that point patients were then randomized to receive either this molecularly targeted therapy or to receive a placebo.

At the time, again, this was the most effective molecularly targeted therapy we had in lung cancer and this was our greatest hope for further advancement over just giving concurrent chemoradiation alone. This drug was called gefitinib, it is approved by the FDA today and it is commercially available for people who have metastatic disease. What this trial demonstrated was giving that drug after chemotherapy and radiation therapy did not improve outcomes. In fact more people who received placebo had long term survival compared to those who received the gefitinib. So that hypothesis was utterly rejected and clearly is not the way forward.

Since that trial was designed we’ve come to better understand which patients actually benefit from these drugs that target the epidermal growth factor receptor. In fact we have new targets including a gene called anaplastic lymphoma kinase or the ALK gene and we have molecularly targeted therapy against tumors that have that gene abnormality.

So the current state of the art clinical trials testing molecularly targeted therapy are not just indiscriminately giving everybody the drugs, but they’re testing the idea that perhaps there are subsets of patients who would preferentially benefit from these targeted therapies. So one of the United States cooperative groups right now is conducting a clinical trial for patients with stage III unresectable disease. Everyone is getting concurrent chemoradiation, but those patients who have either an abnormality in the epidermal growth factor receptor gene, or in the anaplastic lymphoma kinase gene are also being randomized to receive the molecularly targeted therapy or not.

So this is a very different idea, this is not just empirically giving everybody these molecularly targeted therapies, but it’s targeting patients for these drugs based on the molecular biology of their disease. Now these trials are ongoing right now and I think we’re optimistic and we’re hopeful because we’ve seen the activity of these targeted drugs in patients who have metastatic disease. Perhaps we’ll see some improvements in outcomes in these targeted populations — that question is probably not really going to have an answer for about two or three years. That’s the current state of the art treatment that’s being tested regarding molecularly targeted therapy in stage III cancer.


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