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GRACE Video

Clinical Trial Spotlight: Options for EGFR Mutation-Positive Patients with T790M Mutation-Negative Acquired Resistance

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LCAM 2015

 

Dr. Jack West reviews treatment options for patients with an EGFR activating mutation and acquired resistance but no T790M mutation, focusing on a clinical trial with the novel hypoxia-induced pan-HER inhibitor TH4000.

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GRACE Video

Clinical Trial Spotlight: Should a Third Generation EGFR Inhibitor be First Line Therapy for EGFR Mutation-Positive NSCLC?

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LCAM 2015

 

Dr. Jack West introduces the question of whether third generation EGFR tyrosine kinase inhibitors osimertinib and rociletinib should be used as first line therapy rather than for acquired resistance, including discussing key clinical trials on the topic.

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GRACE Video

First Line Treatment of EGFR Mutation-Positive NSCLC

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GRACE Cancer Video Library - Lung

GCVL_LU_First_Line_Treatment_EGFR_Mutation-Positive_NSCLC

 

MSKCC medical oncologist Dr. Greg Riely reviews the optimal first line treatment of patients with an EGFR mutation-positive advanced lung cancer.

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When we identify a patient with an EGFR mutant form of lung cancer, we know that there’s a mutation in their tumor. That helps us figure out the first line of treatment — the initial therapy for patients. Now, some of the initial work identifying drugs for patients with EGFR mutant lung cancer focused on patients who had had multiple prior therapies, but over the last five years we’ve had a luxury of big, randomized clinical trials where we take hundreds of patients and randomize half of them to treatment with chemotherapy, and half of them to treatment with EGFR tyrosine-kinase inhibitors — drugs like erlotinib, gefitinib and afatinib.

When we look at those trial results, we see really remarkable improvements in the chance of the tumor shrinking, so that it’s much more likely that with these oral treatments for lung cancer, like erlotinib, gefitinib, or afatinib, that the tumors will shrink — much more likely than with chemotherapy. Importantly, it’s also shown that, from these trials, that we see much longer time until the cancer grows. So, taking a pill leads to longer disease control than we see with IV chemotherapies.


GRACE Video

Should EGFR TKI Therapy be Continued Beyond Progression?

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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.

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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.


GRACE Video

The Potential Value of Repeat Biopsies in Acquired Resistance

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GRACE Cancer Video Library - Lung

GCVL_LU_Potential_Value_Repeat_Biopsies_Acquired_Resistance

 

MSKCC medical oncologist Dr. Greg Riely explains the growing value of a repeat biopsy after the development of acquired resistance in patients with an EGFR mutation.

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Transcript

So, after initial therapy with EGFR tyrosine-kinase inhibitors, patients often develop — always, really, develop progressive disease, known as resistance, where the tumor has become resistant to therapy. How we manage patients and how we treat their disease, after development of resistance, is a complicated area. One way we can learn a little bit more about a patient’s tumor, and help to refine our decision making, is to do a biopsy of a site of progressive disease.

What we learn from a biopsy really is two-fold. The first, and easiest part, is the pathologist looks at it under the microscope and says, “is this still non-small cell lung cancer, or is this changed?” A relatively rare phenomenon is transformation of non-small cell lung cancer into small cell lung cancer — it happens maybe one to three percent of the time, but it’s a relevant thing to find, and we would adjust chemotherapy as a consequence of this.

Another thing to look for when we biopsy a site of resistance is acquisition of new mutations. One of the most common new mutations identified, it happens in about two-thirds of patients, is a secondary mutation called T790M. The important thing about identifying T790M is that we can now, in clinical trials, and hopefully in the future, with FDA approved drugs, target that T790M mutation with a new drug; we have two new drugs that are being developed now, one is called rociletinib and one is called mereletinib — these are specifically designed to target T790M. Now, importantly, any given biopsy has a chance of finding a mutation that’s present, and it also has a chance of missing it — whether that’s because we biopsied a site that didn’t have that mutation or, for whatever reason, our testing didn’t identify the T790M mutation. I think it’s important to know that as a caveat before going in to re-biopsy, but I do think that biopsying tumors at the time of resistance to EGFR tyrosine-kinase inhibitors does help devise the next best therapy for a patient.


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