Optimizing Afatinib Use: Dosing Strategies and Adverse Event Management

Transcript:

Charu Aggarwal, MD, MPH: There are peculiarities when we think of afatinib use. In my experience, I don’t think everybody needs the full dose of 40 mg a day. I will certainly do a poll amongst us in terms of what dose we start at. But in my practice, I find that it’s much more tolerable to start with the lower dose, depending on the frailty of the person. I may start at 30 mg or maybe even as low as 20 mg, see how they’re doing, and assess their response. If they’re actually responding and tolerating that dose, I may not go up to 40 mg. In my practice, I have almost never started at 40 mg. Dr [Martin] Dietrich, what has your practice been when it comes to afatinib? What is your experience like?

Martin Dietrich, MD, PhD: I think the wild-type sparing component of afatinib is a little bit less favorable than we would see with osimertinib. I think dosing here is a major, major factor. If I have a patient on afatinib, I do prophylaxis for the dermatologic reactions. I think that’s a concern. I also think that we have some reassuring data that the 30-mg and 40-mg efficacies really don’t seem to differ significantly. So certainly, in patients at risk, older patients, I would feel comfortable maybe considering even an up-front dose reduction for these patients. I think it does need management for adverse effects [AEs] to a higher degree than we would see for osimertinib for sure.

Charu Aggarwal, MD, MPH: What about you, Dr [Kaushal] Parikh? What’s your strategy for afatinib?

Kaushal Parikh, MD: I routinely use 30 mg of afatinib. I don’t usually go with 40 mg unless someone is really, really robust, [and] young. There’s also now a phase 3 trial of afatinib vs chemotherapy in uncommon mutations. The ACHILLES [Japan Registry of Clinical Trials; jRCTs031180175] study, which was just presented at ESMO [the European Society for Medical Oncology Congress] again, provides some reassurance, as afatinib is better suited for these uncommon mutations. As Dr [Tarek] Mikal mentioned earlier, a large number of them will have compound mutations; 30% of these patients in the ACHILLES study had compound mutations. Afatinib had a PFS [progression-free survival] of 10 and half months compared [with] 5 and half months with chemotherapy.

This is again some more reassurance apart from the initial data that we have known from the LUX-Lung studies [NCT00949650, NCT01121393, and NCT01466660] with afatinib in uncommon mutations. Again, this study allowed patients to have either 30 mg or 40 mg of afatinib. My practice has been 30 mg. As far as osimertinib is considered in these uncommon mutations, the L861Q is an uncommon mutation where I would favor osimertinib. I think it’s sort of a classic-like mutation, which with significantly durable responses was seen both in UNICORN studies [NCT05421936] as well as other retrospective experiences. Exon-20 insertion mutation is worth mentioning; that’s the FQEA insertion or the LQEA insertion, where we still see activity with osimertinib. That’s the only exon-20 insertion mutation in my mind where I’m trying an upfront EGFR-TKI [tyrosine kinase inhibitors], particularly a third-generation TKI.

Charu Aggarwal, MD, MPH: I think this is really terrific information. I think it solidifies our current practice. Dr [Nagashree] Seetharamu, what is your practice for the dosing of afatinib? Talk to us a little bit about strategies to manage AEs.

Nagashree Seetharamu, MD: I also start low. I mean, with a lot of TKI, definitely for afatinib, 30 mg is typically what I start with. But again, if a patient is frail or elderly, maybe even lower. There have been a few occasions where I started with 40 mg and patients have done OK, but it’s really more of an initial assessment as to how the patient may tolerate it, including whether they have dysphagia, they have baseline, [gastroesophageal reflux disease]–like symptoms, their frailty score, etc. So that’s No. 1. The other thing is with regard to the management of AEs, we also have a discussion with the patient about cutaneous...like, skin care at the very beginning of the mullions and then just prepare them for any acne form or rash and timely communication, if that were to happen. Also, for the first episode of diarrhea that they have, I do know that these are patients [who] have a propensity to have GI [gastrointestinal] toxicity, so I have them take Imodium [loperamide] in the morning, even before a diarrheal episode occurs.

That has really helped with this drug and many other drugs in this class that have diarrhea as a very common AE. So that’s another strategy. Then of course, dose adjustment as time goes on, if the patient is unable to tolerate it. I think with these measures, for the most part, I’ve not really had any major issues. I used to do the same thing with mobocertinib,which is no longer there. I do still have some patients on it. This strategy works very well with any of these agents. In regards to osimertinib, which we were talking about earlier, in addition to everything else that was said, there have been other occasions where I have used it, as opposed to afatinib or those with CNS [central nervous system disease], because that’s an unmet need. Afatinib doesn’t cross the blood-brain barrier. So, we are kind of stuck in that situation. In those instances, I have used osimertinib with those patients.

Charu Aggarwal, MD, MPH: Dr [Tarek] Mekhail, what about you? What has your practice been for dosing?

Tarek Mekhail, MD, MSc, FRCSI, FRCSEd: I don’t have too much to add. You said not many patients need 40 mg, I would say nobody needs 40 mg. I start at 30 mg and I do not dose escalate it. I just stay at 30 mg and maybe go down to 20 mg. I don’t tend to give prophylactic treatments, but I see patients on day 7 and sometimes on day 14 if the need arises. But I think 30 mg as a dose is as good as 40 mg. And we know that from the clinical trial, the vast majority of patients did not continue on the 40 mg. So I’m very comfortable with that dose. I second what has been mentioned about CNS disease, but that’s a special circumstance.

Charu Aggarwal, MD, MPH: I think this echoes real-world data and real-world practice. There was a publication a few years ago by Dr Hamos and their group that looked at real-world data regarding the impact of afatinib dose modification on safety and effectiveness in patients with EGFR-mutant, non–small cell lung cancer. They found that afatinib dose adjustment reduced the frequency as well as the intensity of adverse drug reactions.

The modifications of the dose they found had actually no impact on efficacy, as many of us have seen on prospective clinical trials as well as anecdotally in all our practices. They found in the study that 18.7 months was the median duration of time on treatment, even amongst those with a poor performance status. About 12% of the patients in this real-world study had a very poor performance status. I think it just adds to our practice and confirms what we are saying, starting with a low dose may be fine.

Dr Mekhail, you are probably right. None of the patients in my practice receive 40 mg either. So potentially no one needs that higher dose.

Transcript edited for clarity.