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Approval of Third-Generation TKIs for EGFR-Targeted Therapies

Insights From:Alice T. Shaw, MD, PhD, Massachusetts General Hospital; Gregory J. Riely, MD, Memorial Sloan Kettering; Mark A. Socinski, MD, UPMC
Published: Tuesday, Feb 09, 2016


Transcript:

Gregory J. Riely, MD:
When I find a patient with an EGFR-mutant lung cancer, I’m always pretty excited because I have a first-line therapy that I know works relatively well in the shape of one of the first- or second-generation EGFR tyrosine kinase inhibitors like erlotinib, gefitinib, or afatinib. Until now, once that patient developed resistance, I moved on to chemotherapy. So we had first-line EGFR TKI, but then we moved on to chemotherapy. Now, we have options for second-line EGFR TKIs. So with those patients who develop resistance to a first-line EGFR inhibitor, we have drugs that have known activity and proven activity for patients with resistance to EGFR TKIs.

The most common mechanism of resistance to first- or second-generation TKIs is development of a second mutation in the EGFR gene called T790M. This T790M is typically identified on a tumor biopsy. Occasionally, people identify it on plasma genotyping as well. But, by far, the most common way we identify this, is on mutation testing from tumor biopsies. When we identify the T790M, we’re going to have two options available. One is rociletinib, previously referred to as the Clovis drug. Rociletinib is a drug that was specifically designed to target T790M, as well as the activated mutations: exon 19 deletion and L858R. In patients with T790M-positive non–small cell lung cancer who have acquired resistance to erlotinib or gefitinib, it has a response rate around 60%. So, 60% of patients have significant shrinkage and a significant median progression-free survival, clearly establishing this as an option for second-line.

Similarly, AZD9291, or osimertinib, is another T790M-specific EGFR tyrosine kinase inhibitor that’s been explored in very much the same patient population— those patients with T790M-positive EGFR-mutant lung cancer with acquired resistance to erlotinib, gefitinib, or afatinib. AZD9291, or osimertinib, has a response rate of about 60% in that patient population, again significant median progression-free survival. This provides us with two options in the second-line for patients with EGFR-mutant lung cancer.

I often give a talk where I emphasize that not all non–small cell lung cancer is the same, and I emphasize that EGFR-mutant lung cancer is different from the rest. But unfortunately, I’ve only had chemotherapy as my second-line option. Now, to emphasize that EGFR-mutant lung cancer is a separate disease, we can put together a first-line and second-line specific therapy for EGFR-mutant lung cancer.

Now, when I pick osimertinib or rociletinib for a patient, I have to think about the side effects that that patient is going to have. And these drugs have been designed to dial out a lot of the wild-type effect of EGFR inhibitors. So, when you think about erlotinib, gefitinib, or afatinib, a lot of the side effects we understand are related to targeting wild-type regular EGFR—so rash, diarrhea, paronychia. These are common things with these drugs because they’re hitting wild-type EGFR. Now, with the third-generation TKIs that don’t target wild-type, we have much less of that problem. The problem still exists, and so patients still have some skin side effects. There can be some mild diarrhea, but it’s much less frequent, and I think that’s a big relief for most of us. But they do bring their own sets of side effects.

Rociletinib does have some hyperglycemia that’s observed, a grade 3, so the kind of thing you have to make an intervention for in about 25% of patients. A number of patients that you give this drug to are going to have a problem that you have to sometimes pick a new drug for. I think this is something that we’re going to learn how to deal with; it’s not a challenging thing. Typically, we give metformin, and it’s manageable. But it’s going to be a new part of our care for patients with non–small cell lung cancer that hasn’t been something we thought about before.

In contrast, osimertinib, AZD9291, does not have a significant problem with hyperglycemia. It might have a somewhat higher rate of interstitial lung disease and some of the other EGFR wild-type related side effects like rash. But I think the big contrasting side effect profile is really about the hyperglycemia, which is somewhat more common in rociletinib. But either way, both these drugs are extraordinarily effective in patients with EGFR T790M non–small cell lung cancer, and it’s really exciting that we now have both a first-line and second-line targeted therapy for those patients with EGFR-mutant lung cancer.

Transcript Edited for Clarity
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Transcript:

Gregory J. Riely, MD:
When I find a patient with an EGFR-mutant lung cancer, I’m always pretty excited because I have a first-line therapy that I know works relatively well in the shape of one of the first- or second-generation EGFR tyrosine kinase inhibitors like erlotinib, gefitinib, or afatinib. Until now, once that patient developed resistance, I moved on to chemotherapy. So we had first-line EGFR TKI, but then we moved on to chemotherapy. Now, we have options for second-line EGFR TKIs. So with those patients who develop resistance to a first-line EGFR inhibitor, we have drugs that have known activity and proven activity for patients with resistance to EGFR TKIs.

The most common mechanism of resistance to first- or second-generation TKIs is development of a second mutation in the EGFR gene called T790M. This T790M is typically identified on a tumor biopsy. Occasionally, people identify it on plasma genotyping as well. But, by far, the most common way we identify this, is on mutation testing from tumor biopsies. When we identify the T790M, we’re going to have two options available. One is rociletinib, previously referred to as the Clovis drug. Rociletinib is a drug that was specifically designed to target T790M, as well as the activated mutations: exon 19 deletion and L858R. In patients with T790M-positive non–small cell lung cancer who have acquired resistance to erlotinib or gefitinib, it has a response rate around 60%. So, 60% of patients have significant shrinkage and a significant median progression-free survival, clearly establishing this as an option for second-line.

Similarly, AZD9291, or osimertinib, is another T790M-specific EGFR tyrosine kinase inhibitor that’s been explored in very much the same patient population— those patients with T790M-positive EGFR-mutant lung cancer with acquired resistance to erlotinib, gefitinib, or afatinib. AZD9291, or osimertinib, has a response rate of about 60% in that patient population, again significant median progression-free survival. This provides us with two options in the second-line for patients with EGFR-mutant lung cancer.

I often give a talk where I emphasize that not all non–small cell lung cancer is the same, and I emphasize that EGFR-mutant lung cancer is different from the rest. But unfortunately, I’ve only had chemotherapy as my second-line option. Now, to emphasize that EGFR-mutant lung cancer is a separate disease, we can put together a first-line and second-line specific therapy for EGFR-mutant lung cancer.

Now, when I pick osimertinib or rociletinib for a patient, I have to think about the side effects that that patient is going to have. And these drugs have been designed to dial out a lot of the wild-type effect of EGFR inhibitors. So, when you think about erlotinib, gefitinib, or afatinib, a lot of the side effects we understand are related to targeting wild-type regular EGFR—so rash, diarrhea, paronychia. These are common things with these drugs because they’re hitting wild-type EGFR. Now, with the third-generation TKIs that don’t target wild-type, we have much less of that problem. The problem still exists, and so patients still have some skin side effects. There can be some mild diarrhea, but it’s much less frequent, and I think that’s a big relief for most of us. But they do bring their own sets of side effects.

Rociletinib does have some hyperglycemia that’s observed, a grade 3, so the kind of thing you have to make an intervention for in about 25% of patients. A number of patients that you give this drug to are going to have a problem that you have to sometimes pick a new drug for. I think this is something that we’re going to learn how to deal with; it’s not a challenging thing. Typically, we give metformin, and it’s manageable. But it’s going to be a new part of our care for patients with non–small cell lung cancer that hasn’t been something we thought about before.

In contrast, osimertinib, AZD9291, does not have a significant problem with hyperglycemia. It might have a somewhat higher rate of interstitial lung disease and some of the other EGFR wild-type related side effects like rash. But I think the big contrasting side effect profile is really about the hyperglycemia, which is somewhat more common in rociletinib. But either way, both these drugs are extraordinarily effective in patients with EGFR T790M non–small cell lung cancer, and it’s really exciting that we now have both a first-line and second-line targeted therapy for those patients with EGFR-mutant lung cancer.

Transcript Edited for Clarity
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