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Sequencing EGFR-Targeted Therapies in NSCLC

Insights From: Benjamin P. Levy, MD, Mount Sinai Hospital
Published: Thursday, Dec 29, 2016



Transcript:

Benjamin P. Levy, MD:
You have to use your best drug first. I think you have to really seize the opportunity with these patients and give them your best drug, and that best drug is based not only on its efficacy, but its toxicity. And, I think, thankfully, and fortunately, we have oral agents that work if first- or second-generation TKIs don’t work. So, for me, I try to make the best decision up front that delivers the best chance of response, but also is mindful of toxicities.

Unfortunately, we’re not curing these patients and all of the efforts that we deliver in terms of targeted therapies are still palliative. Now, we’re making strides, but patients should receive the best drug first, the one that has the best response rates but also factors in toxicity. So, I always try to use my best drug first. But, with the caveat being, if that drug doesn’t work, there are other drugs down the pike that are approved now that may work just as well once patients develop progression on first- or second-generation TKIs.

I think, any time we make decisions for our patients who are EGFR-positive up front with a TKI, we have to be ready to make dose modifications or dose reductions due to these severities or potential severities of the adverse events. Now, for many patients whom we treat, we don’t need to make dose reductions. I would say probably in 20% to 30% of our patient population in my practice, we make some dose reductions, and that can be with afatinib. If we’re starting at 40 mg, we often have to go down to 30 mg if they’re experiencing a grade 3 rash or diarrhea. And it’s the same with erlotinib, as well. If we start out with erlotinib, 150 mg is the starting dose, but I’m ready to make a dose reduction to 100 mg. And, I think, this is where care gets very nuanced and individualized. I think we have to be proactive about managing adverse events with TKIs. I think we need to be comfortable knowing what the proper management is in terms of the rash and diarrhea, but also comfortable holding the dose if the AE is very severe and reducing the dose. There are all kinds of algorithms online that I encourage people to look at. These drugs work very well, but they do have an AE profile that physicians need to be cognizant of and know how to manage moving forward.

Dose adjustments with EGFR TKIs generally does not lead to a compromise in efficacy, and there are data on this. I think even with afatinib, we know that patients who are on 30 mg, probably experience less toxicity, but do just as well as the 40 mg dose. These are not robust data, but certainly have been out there. I think we know that there’s probably therapeutic value of even 15 mg of erlotinib. I certainly don’t go that low, generally, but the dosing of these drugs sometimes need to be adjusted, and there need to be dose reductions. Generally, that doesn’t come at the cost of efficacy. That doesn’t mean I don’t start at the highest dose possible. But, certainly, be mindful that when you’re reducing the dose, you’re probably not sacrificing efficacy moving forward.

First-generation and second-generation TKIs—erlotinib, gefitinib, afatinib—of course, come with AEs that we need to be mindful of. The most common are rash and diarrhea, but certainly fatigue is out there. We see that frequently in our patients. Keratoconjunctivitis or other ocular disorders we need to be mindful of. In all of these AEs, you have to be proactive about managing them, and being proactive means being ready to make dose reductions or dose interruptions. That’s okay. Withholding the dose for a few days while the patient recovers is okay and perhaps resuming at a lower dose once you restart. But, being proactive also means knowing how to manage these AEs specifically. Now, for fatigue, there’s not a lot we can do other than hold the dose. But, I would say for patients who experience rash, certainly doxycycline orally, clindamycin, or steroid creams and gels can certainly help out. And, for diarrhea, I tell patients to go ahead and get Imodium even before they start taking the drug; going to their local pharmacy, getting the Imodium, and being proactive about that. That’s important. So, those are really 2 measures that I always tell patients. And I tell patients up front that these adverse events will probably happen and we will be proactive about managing them. You may need to go on doxycycline for your rash. You may need some creams throughout your treatment course. Of course, with the diarrhea, for as high as 60% to 70% in these patients who take TKIs, it is very important to make sure that they’re proactive about taking Imodium.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
You have to use your best drug first. I think you have to really seize the opportunity with these patients and give them your best drug, and that best drug is based not only on its efficacy, but its toxicity. And, I think, thankfully, and fortunately, we have oral agents that work if first- or second-generation TKIs don’t work. So, for me, I try to make the best decision up front that delivers the best chance of response, but also is mindful of toxicities.

Unfortunately, we’re not curing these patients and all of the efforts that we deliver in terms of targeted therapies are still palliative. Now, we’re making strides, but patients should receive the best drug first, the one that has the best response rates but also factors in toxicity. So, I always try to use my best drug first. But, with the caveat being, if that drug doesn’t work, there are other drugs down the pike that are approved now that may work just as well once patients develop progression on first- or second-generation TKIs.

I think, any time we make decisions for our patients who are EGFR-positive up front with a TKI, we have to be ready to make dose modifications or dose reductions due to these severities or potential severities of the adverse events. Now, for many patients whom we treat, we don’t need to make dose reductions. I would say probably in 20% to 30% of our patient population in my practice, we make some dose reductions, and that can be with afatinib. If we’re starting at 40 mg, we often have to go down to 30 mg if they’re experiencing a grade 3 rash or diarrhea. And it’s the same with erlotinib, as well. If we start out with erlotinib, 150 mg is the starting dose, but I’m ready to make a dose reduction to 100 mg. And, I think, this is where care gets very nuanced and individualized. I think we have to be proactive about managing adverse events with TKIs. I think we need to be comfortable knowing what the proper management is in terms of the rash and diarrhea, but also comfortable holding the dose if the AE is very severe and reducing the dose. There are all kinds of algorithms online that I encourage people to look at. These drugs work very well, but they do have an AE profile that physicians need to be cognizant of and know how to manage moving forward.

Dose adjustments with EGFR TKIs generally does not lead to a compromise in efficacy, and there are data on this. I think even with afatinib, we know that patients who are on 30 mg, probably experience less toxicity, but do just as well as the 40 mg dose. These are not robust data, but certainly have been out there. I think we know that there’s probably therapeutic value of even 15 mg of erlotinib. I certainly don’t go that low, generally, but the dosing of these drugs sometimes need to be adjusted, and there need to be dose reductions. Generally, that doesn’t come at the cost of efficacy. That doesn’t mean I don’t start at the highest dose possible. But, certainly, be mindful that when you’re reducing the dose, you’re probably not sacrificing efficacy moving forward.

First-generation and second-generation TKIs—erlotinib, gefitinib, afatinib—of course, come with AEs that we need to be mindful of. The most common are rash and diarrhea, but certainly fatigue is out there. We see that frequently in our patients. Keratoconjunctivitis or other ocular disorders we need to be mindful of. In all of these AEs, you have to be proactive about managing them, and being proactive means being ready to make dose reductions or dose interruptions. That’s okay. Withholding the dose for a few days while the patient recovers is okay and perhaps resuming at a lower dose once you restart. But, being proactive also means knowing how to manage these AEs specifically. Now, for fatigue, there’s not a lot we can do other than hold the dose. But, I would say for patients who experience rash, certainly doxycycline orally, clindamycin, or steroid creams and gels can certainly help out. And, for diarrhea, I tell patients to go ahead and get Imodium even before they start taking the drug; going to their local pharmacy, getting the Imodium, and being proactive about that. That’s important. So, those are really 2 measures that I always tell patients. And I tell patients up front that these adverse events will probably happen and we will be proactive about managing them. You may need to go on doxycycline for your rash. You may need some creams throughout your treatment course. Of course, with the diarrhea, for as high as 60% to 70% in these patients who take TKIs, it is very important to make sure that they’re proactive about taking Imodium.

Transcript Edited for Clarity
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