Tolerability-Guided Dose Adjustment of Afatinib in NSCLC

Transcript:Benjamin P. Levy, MD: Afatinib certainly has demonstrated robust response rates, progression-free survival, and overall survival for EGFR-mutant lung cancer patients. I think we always have to be mindful, however, of the toxicities of this drug. It tends to be the TKI with the most adverse events. At least in the data and the meta-analysis, it does show, potentially, the most adverse events, and we just have to be mindful of these and comfortable managing them. For afatinib, I certainly will make dose reductions and be ready to do that, and often times I’ll start at 30 mg rather than 40 mg. It’s not uncommon that I have to hold the dose, as well. I educate my patients up front about the potential side effects that they may experience like rash, diarrhea, and fatigue. I tell my patients to be proactive and get Imodium to manage the diarrhea. I tell my patients about the rash that they may experience. And, I think, importantly, we bring our patients back frequently when they start this drug. So, if we’re starting afatinib on the patient, they are certainly coming back to the office perhaps 2 to 3 weeks later just to check in, and then probably every 2 weeks for at least the first couple of months just to make sure that the AEs have been managed appropriately. I tell my patients to call when they experience these side effects, and I tell them they will be expecting it. There are lots of different ways to manage this. I think being proactive is certainly one, giving your patients the heads-up, being ready to manage these appropriately and being educated about how to manage these, and being comfortable with dose reductions. And, also, being comfortable holding the dose to allow patients to recover from these side effects is important.

So, LUX-Lung 3 and LUX-Lung 6 were key phase III trials comparing afatinib to platinum-based chemotherapy for patients with advanced stage EGFR-mutant lung cancer. This trial showed, not surprisingly, an improvement in response rate, an improvement in progression-free survival, and an improvement in quality of life when afatinib was compared to chemotherapy. Afatinib was superior in all of those measures. It did not show an improvement in overall survival in the intention-to-treat analysis, and that may have been due to the high rate of crossover. However, in a subset analysis, those patients with del19 mutations—and this was pre-planned—there was a survival advantage with afatinib over chemotherapy in both trials and in the pooled analysis. I think that’s important.

We’ve never seen a survival advantage in any a subset analysis in a large phase III trial like this. I think there are some people who believe that this is not necessarily an afatinib effect, it’s more of a del19 effect. The del19 is an exquisitely sensitive mutation to any TKI you give, and I think we’ve seen this with both erlotinib and gefitinib data. But, nevertheless, it did show a survival advantage. I think we have to think about that when we’re looking at our patients who are coming in who are fit, who we think we can manage the AEs for these patients. I think afatinib, if they have the del19, should be a consideration based on that survival advantage, but being mindful of the toxicities that may come with the drug. And so, these 2 studies did change my treatment approach slightly. For those patients who are younger, fitter, who you’re comfortable managing these adverse events that may come with this drug and they have a del19, I think there should be consideration for afatinib.

There were some dose reductions in the trial with LUX-Lung 3 and LUX-Lung 6. I believe those dose reductions generally occurred within the first 6 to 8 weeks of therapy, but, importantly, that did not sacrifice efficacy when we looked at the intention-to-treat overall survival, as well as the del19 patient population. I think what we know from some data is that dose reductions with this drug don’t generally sacrifice efficacy and still lower the adverse event profile. And that’s why, in my practice, I generally am not hesitant to make a dose reduction or even start at 30 mg for patients who are eligible for afatinib.

The data suggest that drug efficacy with afatinib is not sacrificed, generally, with dose reductions and that you could perhaps mitigate some of these toxicities. That said, patients even at 30 mg can experience significant adverse events and we have to be mindful. LUX-Lung 3 and LUX-Lung 6 did change the approach for me for my patients. I think afatinib probably has a little bit of an edge in terms of its efficacy. We just have to be proactive in a way we manage the toxicity, and that does mean potentially starting at a lower dose or making dose reductions for these patients who are on therapy.

Transcript Edited for Clarity