EGFR-Mutated NSCLC: Are Frontline Combinations the Future? - Episode 6
Edgardo S. Santos Castillero, MD, FACP: You did a beautiful review of the first-generation, second-generation, and third-generation agents. You remember when afatinib, a second-generation drug, was developing. Afatinib was also studied in a real-world study called GioTag, and from that we may get some information that may be useful in clinic. Can you take us through your take-home message from the GioTag study using afatinib in the real world?
John V. Heymach, MD, PhD: For afatinib in the real world, there are a couple of key points. Afatinib is clearly active. It has some CNS [central nervous system] activity. The CNS activity does not tend to be quite as high as osimertinib, but it does have CNS activity. Afatinib also has activity against atypical mutations. It’s the only TKI [tyrosine kinase inhibitor] that’s approved for 3 atypical mutations: the S768I, the 719 mutation, and the L861 mutations. Afatinib is a drug that has a broader spectrum of activity than osimertinib does, and it has CNS activity. In common use, people will often dose reduce it because at 40 mg, the starting dose, it is often found that patients have a lot of acne and diarrhea, and they often end up tolerating 30 mg better. I start everybody at the full dose and then can go to the lower dose if they need to, but I try to keep people at the higher dose and work them through for at least a couple of months before I dose reduce, unless they really need it.
It is worth saying that afatinib does have a place. It does have some activities that the others don’t. You know the approvals, and the activity has been better than the first-generation drugs in general. It does still have a place in the real world as an EGFR inhibitor.
Edgardo S. Santos Castillero, MD, FACP: You mentioned something important. This is important for the audience and our colleagues who listen to you and me today: the issue with afatinib. When I usually go around and talk to colleagues, they sometimes believe that starting afatinib at a lower dose of 30 mg, for example, is the best way to do it because there was also a study, a retrospective analysis, that showed that that dose, the efficacy has no drop. I feel that the intensity of the treatment, which you described well, is the way to go. Try to control the disease, try to eliminate as much as we can, because at the end of the day, we know that resistance is coming. By starting on a lower dose, there is a gap that means that the resistance may go quicker than by starting at a higher dose.
John V. Heymach, MD, PhD: It’s an important point. It’s key for the EGFR inhibitors in my case, and we [at The University of Texas MD Anderson Cancer Center] have done a lot of testing of other drugs that also have a lot of skin toxicity and diarrhea, like poziotinib as well, where we need to manage it carefully. It is manageable, but it needs to be managed carefully. The key is education of the patient up front and setting expectations. The way I always explain it to patients is the following. I explain how, for these EGFR inhibitors like afatinib, dacomitinib, and erlotinib, you are going to develop a rash and acne. I sometimes have pictures to show them so they know what’s coming. Personally, I give them clindamycin gel, and I give them an antibiotic like doxycycline or minocycline up front. I tell them to buy some topical hydrocortisone as well and to buy Imodium [loperamide hydrochloride], so that they have all that in their house and they’re not wondering in the middle of the night what they’re going to do.
I tell them to expect that it’s going to get worse for the 3 to 4 weeks, but then it’s going to eventually level off and start getting better. The adverse effects won’t go away by 2 months, but they will get better. If they understand that it’s going to get worse and then it’s going to slowly get better and level off, then they’re not so quick to dose reduce at the first sign of trouble. For doctors, if you set that expectation, patients are willing to tolerate it if they know it’s going to be a month. If they’re afraid it’s going to be like this for years, then anybody would want a dose reduction. That’s why I try to get patients through 2 months of therapy. I say, “Listen, it’s going to get worse, then it’s going to get a little better. Let’s try to get to 2 months before we start thinking about dose reducing” to try to make sure patients get that full dose.
Transcript edited for clarity.