Selecting Second-Line Treatment for EGFR-Mutated Advanced NSCLC


Focusing on second-line treatment options for EGFR-mutated advanced NSCLC, panelists review the use of mobocertinib and amivantamab, respectively.


Gregory J. Riely, MD, PhD: Now, we can talk briefly about some of the data for EGFR exon 20 insertion treatments. Mobocertinib is a small-molecule kinase inhibitor analogous to drugs like osimertinib or erlotinib. It's a pill that you take daily. It has a side-effect profile that is similar to EGFR inhibitors that we know and love, such as erlotinib. The data that we have for mobocertinib is from a single-arm trial that was published in JAMA Oncology last year. In that single-arm trial, they identified patients with an EGFR exon 20 insertion who had had prior platinum-doublet chemotherapy, and they enrolled them and treated them with 160 milligrams of mobocertinib. The primary end point of the trial was response rate; the overall response rate for patients with prior platinum treatment was 28%. This is a significant improvement on what we saw with other EGFR tyrosine- and kinase inhibitors in this context, where response was typically around 5% for other TKIs [tyrosine kinase inhibitors]. It really established that mobocertinib had efficacy, and then, when we looked at median progression-free survival, we were able to identify with a median follow-up of 13 months that the median progression-free survival was about 7.3 months. This really gave something to these patients who didn't have prior targeted therapy available to them using mobocertinib. Then, another drug that's recently become approved is amivantamab. Amivantamab is a drug that we've been evaluating for several years. It's an antibody; if mobocertinib is like osimertinib or erlotinib, this is more like cetuximab. It's an antibody that targets EGFR, but this is a little different because it targets both EGFR and MET. It's what's called a bispecific antibody. Amivantamab has been studied in the classical EGFR mutations, and we're waiting for some more data on how that works out. But in the meantime, it's been studied in patients with EGFR exon 20 insertions, and probably the best data for that is from what's called the CHRYSALIS trial [NCT02609776] and was published in JCO [Journal of Clinical Oncology] recently. In that group of 81 patients with EGFR exon 20 insertions, they saw a response rate of 40% and a median progression-free survival of a similar number of about 8.3 months. These were both single-arm trials without a randomized comparator arm. Ultimately, the efficacy of these agents is relatively similar. They were both studied in the same type of patient population who've had prior platinum-based chemotherapy. They are reasonable second-line agents, and they've both been approved as second-line therapies for patients with EGFR exon 20 insertion non–small cell lung cancer. When we think about any of these drugs—mobocertinib, amivantamab—they have an adverse-event profile, for sure. Lauren, can you talk a little bit about how you talk to patients about the adverse events they might expect with mobocertinib and amivantamab?

Lauren Welch, MSN, NP-C, AOCNP: Although there are obviously differences that you highlighted, mechanistically, they both have EGFR-directed effects. I'll start by talking about those—the mutual things, if you will—such as the rash, nausea, diarrhea, paronychia, mucositis. I'll make sure I mention the potential for ILD [interstitial lung disease], pneumonitis, the cardiac toxicity, although these are much less common than the GI [gastrointestinal] issues that we see. The diarrhea can be quite significant, especially with mobocertinib. The median time to onset is within 5 days. So, I'll instruct patients to have loperamide at home in advance of starting mobocertinib and to begin loperamide immediately after the first loose stool. When talking about diarrhea with patients, I make sure I inquire about what their baseline is. Everyone is quite variable here, so it's important to understand what's normal for them so you can really figure out the grade of the toxicity. We'll spend some time talking about gentle skin cleansing and frequent skin moisturization, nail care, vinegar soaks, etcetera. With amivantamab, there's the unique issue of infusion reactions. These reactions tend to occur with the first dose, which is why we divide the first dose into 2 infusions. Normally, that reaction is better with subsequent doses, but infusion reactions can be really scary for patients, their caregivers—even the clinic staff. These EGFR exon 20 insertions are still rare, and the clinic staff is not going to have a lot of experience giving amivantamab. Make sure that you prepare the patient as well as the staff for the high likelihood of the infusion reaction so that people aren't caught off-guard.

Gregory J. Riely, MD, PhD: It is worthwhile to let everybody know that this is going to happen because we're used to taxanes and things like that where it happens at a relatively low frequency, but with this one, it's a high frequency, although it has that unique feature you described where it happens the first time and doesn't happen again. It’s an unusual sort of thing. This is a good introduction to the EGFR exon 20 insertion drugs. What do we think a little bit about when we have this patient? Let's say we put this patient on mobocertinib and the patient presents back to us a few months later, after experiencing several instances per day of watery diarrhea. What would be your first steps for this situation?

Lauren Welch, MSN, NP-C, AOCNP: Almost the exact thing happened when we were conducting the trial with mobocertinib at my institution. I had a patient who had been on the drug for several months. The first question was, how are you taking the loperamide? She wasn't an excellent historian, but [we were] making sure that the patient was optimally using the loperamide, which is up to 8 tablets a day, and also utilizing other antidiarrheals like Lomotil [diphenoxylate/atropine]. If the patient continues to have grade 2 diarrhea despite those interventions, then you're having conversations about holding the mobocertinib until the diarrhea resolves, and normally that takes 3 days or so of holding the drug in order for the diarrhea to get better. Then you're having conversations about dose reduction vs resuming at the same dose. Sometimes we'll use prophylactic antidiarrheals. That can be really helpful with mobocertinib, when you know it's going to happen, trying to get ahead of it prophylactically, and then that single-dose reduction can really be a game changer for tolerance. Don’t be shy to do that. The only other thing we don't always talk enough about is the pill fatigue for these patients. The recommended dose of mobocertinib is 160 milligrams a day, which is 4 pills. If you're having them max out loperamide, that’s 8 additional pills, and then they're taking potassium supplements and magnesium supplements for the diarrhea. It can be overwhelming, and sometimes that is just simply too much, and you really have to embrace the dose reduction.

Gregory J. Riely, MD, PhD: You're spot-on there. I emphasize to patients that there's a recommended dose and then there's a dose that's right for them. Clearly, we don't want to underdose these drugs because with EGFR exon 20 insertion it's a relatively narrow therapeutic window. But at the same time, we don't want to make these patients truly miserable with these treatments, as well. I like some of your strategies you describe, Lauren, to help patients stay at an appropriate dose but otherwise get them to the right dose for them.

Transcript edited for clarity.

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