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Are There Distinctions Among Currently Available Oral EGFR Inhibitors for EGFR Mutation-Positive NSCLC?

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GRACE Cancer Video Library - Lung

GCVL_LU_Distinctions_Oral_EGFR_Inhibitors_Mutation-Positive_NSCLC

 

Dr. Greg Riely, medical oncologist from MSKCC, considers the evidence on whether there are clinically significant differences among the currently available first and second generation oral EGFR inhibitors for patients with an EGFR mutation.

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For patients who are diagnosed with EGFR mutant lung cancer, there’s a choice of initial therapies. There are three FDA approved EGFR tyrosine-kinase inhibitors — these are gefitinib (with the trade name Iressa), erlotinib (with the trade name Tarceva), or afatinib (with the trade name Gilotrif). These three drugs have been developed over the course of the past 15 years or so, and they have a great deal of similarity in that all of them target wild-type, or regular EGFR, the EGFR protein that’s found throughout your body, and they all have different doses — I think that’s probably the difference that we see among them, is largely related to dose. If we look at clinical trial data, and to talk with physicians who have given all three drugs, I think the general consensus is that, at their recommended dose, the FDA approved dose, that the side effect profile, particularly with regard to rash and diarrhea, is probably the lowest with gefitinib, rash and diarrhea is a bit higher with erlotinib, and finally, with afatinib, it’s the highest.

Now, for a given patient, this is largely irrelevant, given that we adjust doses to make it so the patient has a tolerable side effect profile, so that if we’ve given erlotinib at the FDA approved dose and found that it causes too much rash, we generally back down the dose. Similarly for afatinib, we will reduce the dose of afatinib to make the rash and diarrhea more tolerable. 

So, when taken together, picking the right EGFR tyrosine-kinase inhibitor, or picking the one that works for a given patient, is a lot about what the physician is comfortable with, and finding the right dose for that patient. 

Now, importantly, I’ll contrast these first or second-generation EGFR tyrosine-kinase inhibitors like gefitinib, erlotinib, and afatinib, with the newer tyrosine-kinase inhibitors like rociletinib, or mereletinib, the so-called third-generation, or T790M specific drugs — these have a very different profile of activity, and we still have yet to learn as much as we need to know about their side effect profile.


Differences Among Specific EGFR Mutations

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GCVL_LU_Differences_Among_Specific_EGFR_Mutations

 

Medical oncologist Dr. Greg Riely, MSKCC, discusses evidence for whether there are clinically significant differences among specific EGFR mutations that should lead to differences in management.

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Within the overview of EGFR mutations, there’s several different types — the two most common are EGFR exon 19 deletion and EGFR L858r; together, these represent more than 80% of EGFR mutations. In addition to these two common types, there are some uncommon types, but some of these are related to responsiveness to EGFR tyrosine-kinase inhibitors, so rarer ones like G719A, L861, these are rare, but we have pretty good evidence that they lead to response to drugs, just as those patients who have L858r or exon 19 deletion.

There are patients who have exon 20 insertions — in general, EGFR exon 20 insertions are associated with resistance to EGFR tyrosine-kinase inhibitors like erlotinib, gefitinib and afatinib, and so, as a consequence, that’s not our first line therapy for those patients with EGFR exon 20 insertions.

Going back to the two most common EGFR mutations, exon 19 deletion and EGFR L858r, since these are the most common ones, we have more data on patient outcomes for these two mutations. When we look at a broad variety of data, typically with afatinib, we see that afatinib may actually be more effective for those patients with EGFR exon 19 deletions than it is for patients with EGFR L858r.

There has been similar data reported for patients treated with gefitinib and erlotinib as well. Though the data is not quite as clear cut, it does seem that those drugs also work a bit better for patients with EGFR exon 19 deletions.

Now what the consequence of those differences is, is quite controversial. I think that, in general, I still recommend treatment with an EGFR tyrosine-kinase inhibitor — and I don’t prefer one or the other, for patients with EGFR exon 19 deletions, EGFR L858r, as well as the rarer ones like G719A or L861Q.


Should Avastin be Added to EGFR TKI Therapy for EGFR Mutation-Positive NSCLC?

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GRACE Cancer Video Library - Lung

GCVL_LU-FB04_Avastin_EGFR_TKI_NSCLC

 

Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

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The historical standard of care over the last several years for patients with advanced non-small cell lung cancer, whose tumor has an activating EGFR mutation, has been single-agent oral EGFR tyrosine-kinase inhibitor therapy. That is a pill like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), and these agents are associated with long responses that typically will last 9, or 12, or sometimes more months, but unfortunately, in almost every case, will demonstrate progression after some period of time — and we would always like that to be longer.

One of the big questions that we’ve wanted to know is, if we could add something to this therapy and do better than that — and one of the key questions has been about adding an anti-angiogenic agent, something that blocks the tumor’s blood supply, which is a drug like Avastin (bevacizumab), which is used in other cancer settings, and in some cases, for lung cancer, in combination with chemotherapy. In lab-based studies there is evidence that adding a blood supply blocker, an anti-angiogenic agent, to one of these EGFR inhibitors can more effectively suppress cancer cells, and for longer, but we haven’t seen clear evidence that this is beneficial for patients in the real world. In fact, there have been a couple of large studies that have asked the question about adding Avastin to a drug like Tarceva — these trials, however, have only been in broad populations that are called molecularly unselected, not looking specifically at patients with an EGFR mutation or any other feature, but just really taking all comers.

One of the key studies is called BeTa, and this was a study where all the patients had receive first-line chemotherapy, and were getting, now, a second-line treatment, after progression, and they were either getting Tarceva alone, or the combination of Tarceva with Avastin.

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The study, overall, did not show a significant improvement in survival, but when they looked at the different subgroups of patients, based on various clinical characteristics, you can see that a couple of subgroups of patients did particularly well with the combination.

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Specifically, when they looked at patients who were Asian or Pacific Islander, or never-smokers — those patients really seemed to skew more toward greater benefit with the combination of Avastin and Tarceva.

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They also looked at a small subgroup of patients, whom they had tumor tissue on and were known to have an EGFR mutation, and those patients also trended clearly toward a better effect with the combination of Avastin and Tarceva.

So, that’s provocative, but that’s just one study. What’s interesting as well, though, is that a remarkably similar study was done where patients received either Tarceva alone, or Tarceva and Avastin, as a maintenance therapy. So, they had not progressed, but they had already received first-line therapy, and then went on to get Tarceva, or Tarceva and Avastin.

GCVL_LU-FB04_Avastin_EGFR_TKI_NSCLC.004

This study also showed no significant improvement in the overall population — this was, again, a molecularly unselected population, but when they looked at the different subgroups, based on their clinical characteristics, it was the same subgroups who got the benefit, in terms of overall survival, from the combination.

GCVL_LU-FB04_Avastin_EGFR_TKI_NSCLC.005

So, again, it is the Asian and Pacific Islander patients, and the never-smokers — the two groups who we know are most enriched for having an EGFR mutation. So, this is really a bit more compelling evidence that, maybe, there’s really something there.

The question was asked more directly in a study done in Japan and just published in Lancet Oncology not too long ago.

GCVL_LU-FB04_Avastin_EGFR_TKI_NSCLC.006

This trial had about 150 patients, all with an activating EGFR mutation, who were randomized to receive Tarceva, or Tarceva and Avastin, as a first-line therapy. The study was designed to look for a significant improvement in progression-free survival, the time before at least half the patients had demonstrated significant progression of their cancer, on this combination that they started with, or the single agent.

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What they found was a significant improvement in progression-free survival in the patients who received the combination. In fact, the difference in median time to progression, the time when half the patients in each group had progressed, was over six months longer in the patients who got the combination.

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When we look at overall survival — most of the patients are still alive, so it’s too early to really say much, but the trend is in the direction of favoring the patients who received the combination.

The other side of the coin, beyond efficacy, is tolerability, and the combination was associated with more side effects, as you’d expect — although, there were no treatment-related deaths with the combination. In the Japanese experience, there were more patients who had significant problems and needed to come off of the drugs, specifically Avastin, than we’ve typically seen with this combination in other studies. 40% or so of the patients had to discontinue the Avastin because of side effects, usually high blood pressure, or leaking protein into the urine, something called proteinuria; whether that is because these patients just had been on these agents for longer than they usually are in other studies, or there is something about the Japanese patients, or EGFR patients, who were more susceptible, we don’t know. But, at the end of the day, it was still a tolerable regimen, and more of the patients did well and did not progress for much longer when they received the combination.

So where does this leave us? We have a more than six month improvement in the median time to progression with the combination, but this is only one study, done in Japan, and sometimes we see differences in studies done in one part of the world, versus another. Overall, I would say that, to me, these data are quite compelling, and it’s enough to lead me to favor the combination for my patients if an insurer will cover the Avastin, which is not, at this point, a clear standard of care. To many investigators and general oncologists, the combination is not yet their preferred regimen — they would like to see more evidence, larger studies, and ideally, work from other parts of the world to corroborate what we saw out of Japan. In fact, there are studies being done, one in Europe and one in North America, that are asking the same question, so we’ll hope to get more information soon, but this is certainly a very promising lead, and enough to lead me to favor the combination for my patients who have an EGFR mutation.


What is Maintenance Therapy for Advanced NSCLC?

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GCVL_LU-F11_Maintenance_Therapy_Advanced_NSCLC

 

The concept of maintenance therapy for advanced lung cancer has emerged over the past few years. Dr. Jack West, medical oncologist, reviews the concepts behind it and treatment options for patients.

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One of the core ideas in treating advanced non-small cell lung cancer is that we try to treat is aggressively, early on, to induce the greatest shrinkage we can, which tends to be associated with a longer survival for patients. This specifically means that we typically treat with a two, or sometimes three-drug combination as first-line therapy, and most of the time, when we see tumor shrinkage, it tends to be front-loaded, and we see that early on, in the first one or two scans done. Most commonly, we’ll give four to six cycles of treatment for patients with this multi-drug combination, and then think about stopping treatment or downshifting. This idea of downshifting to a less intensive therapy, but still keeping something going, is the idea of maintenance therapy.

GCVL_LU-F11_Maintenance_Therapy_Advanced_NSCLC.001

So what is maintenance? It is essentially to maintain the tumor shrinkage that we achieved early on, with first-line therapy, but by using a more tolerable, less intensive regimen after that, that can be continued longitudinally, without too many cumulative side effects.

There are two main ways of approaching this — one is by doing what’s called continuation maintenance. You start with a two-drug or three-drug combination, and then you drop one or two of the agents off, and keep some of the first-line therapy going, but not all of it, and this makes it less intensive, and potentially able to be given for a much longer period of time to maintain the response that was achieved early on. An alternative approach is called switch maintenance, and that is starting with four to six cycles of a combination, then stopping all of those agents and switching to one or more agents after that, that have not been given before. Again, the idea is to come up with a regimen that is not too intensive, but that can maintain the momentum that was already achieved — basically keeping the tumor shrunk for longer.

Now, what do we hope to achieve by maintenance therapy? Several studies have demonstrated that there is a very consistent improvement in progression-free survival, the time before the cancer will progress, in patients who receive effective maintenance therapy. In just about all of the cases of what we call effective maintenance therapy, this is a treatment that is essentially a standard second-line treatment, but we give it earlier than second-line, which is when the patient has actually demonstrated progression of their cancer; instead, we’re giving it more proactively — immediately after first-line, and these agents that have been shown to improve survival when given second-line, after progression, are also associated with improvement in progression-free survival, and in some cases, significant improvement in overall survival when given earlier on, as a maintenance therapy.

However, there are some potential issues and questions about how necessary maintenance therapy really is, and although it is certainly a widely practiced approach and a standard of care, it is not a mandate at this point. This is because — the fact is that, the studies that give maintenance therapy do have an imbalance, where more of the patients on randomized maintenance therapy received more intensive therapy than the patients who are randomized to receive supportive care, or no treatment, just placebo perhaps, instead, at the time of completing first-line therapy. So, what we actually see is, sometimes it may just be that more treatment is associated with better outcomes, and longer survival, than less treatment. But, one thing we can say is that maintenance therapy assures us that the patients who have achieved tumor shrinkage, or at least stable disease, and are therefore the patients most likely to benefit from later treatment, definitely get that later therapy that can help them.

One of the challenges and issues about taking breaks from treatment is that some patients will decline and not be well enough to receive additional treatment that would have otherwise helped them if they had just gotten it earlier. So, with some patients potentially falling off the curve, missing that opportunity, there is a tendency to try to push effective treatment to earlier, and minimize time off of therapy where we might have patients miss that opportunity if they decline quickly.

So, that is the general approach to maintenance therapy — it is not a mandate, but it is something that we tend to individualize for our patients, and discuss whether they feel up to tolerating more treatment after going through four to six cycles of a combination first-line therapy, and whether they need to have a break, whether they want to go on a family vacation, etc.; there’s always room for individualizing, but for many patients, continuing with maintenance therapy — either continuation, or sometimes switch maintenance to a new therapy, may be a very appropriate approach.


Join GRACE at the 2015 ALK, ROS1 & EGFR Lung Cancer Patient Forum

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WHAT: Acquired Resistance in Lung Cancer Patient Forum
WHEN: Saturday, Oct. 3, 2015
WHERE: Marriott Waterfront San Francisco, 1800 Old Bayshore Hwy, Burlingame, CA 94010
WHO: ALK, ROS1 & EGFR lung cancer patients and their caregivers

REGISTER HERE

Researchers are making advances in molecularly-driven lung cancer seemingly every day. The need for patient education is on-going and ALK+, ROS1, and EGFR lung cancer patients actively seek it.

ROS1 patients at the 2014 forum

ROS1 patients at the 2014 forum

They will find it at GRACE’s 2015 Acquired Resistance in Lung Cancer Patient Forum. The event will take place Saturday, Oct. 3, 2015, at the Marriott Waterfront San Francisco.

Patients and their caregivers who attend will hear directly from leaders in targeted therapy research. In addition to presentations and question and answer sessions, attendees will have many opportunities to approach the faculty to speak with them directly. An evening reception after the event will enable additional face time and give attendees – many of whom know each other from online support groups – a chance to meet in real life.

Scheduled presentations:

- Acquired Resistance & Why It Occurs
- Brain as a Sanctuary Site
- Repeat Biopsies and Serum-Based Testing
- Selecting Patients for Immunotherapy
- Quality of Life vs Progression Free Survival – What Are the Most Relevant Endpoints?
- Patient Assistance Programs
- Lung Cancer Survivorship

Additionally, breakouts for ALK/ROS1 patients and EGFR patients will cover issues specific to those patients:

- New Ideas and Treatment Options
- Individual Treatments for Individual Mutations
- Combinations to Prevent & Treat Acquired Resistance
- Drug Sequencing

Registration is $25 per person. GRACE has negotiated a group rate for rooms at the Marriott Waterfront San Francisco of $179 per night (request the “GRACE Patient Forum” room rate).

View the agenda for additional details and a list of confirmed faculty.

Register now button

 

 

 

 


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