Afatinib: Dose Modifications and Adverse Events

Corey J. Langer, MD:This patient was started on the standard dose of afatinib, 40 mg daily, and did experience quite a bit of diarrhea, which we generally will manage, almost immediately, at the first hint, with antimotility agents like Imodium, diphenoxylate, or what I call the BRAT diet—bananas, rice, applesauce (not juice), toast, cheese, etc. Sometimes the diarrhea persists despite these interventions. This may necessitate a dose reduction or even a brief hold on the dose and then a resumption at a lower dose. This patient required a dose reduction of 30 mg daily.

The 2 most common side effects for the first- and second-generation TKIs [tyrosine kinase inhibitors] are diarrhea and rash. This is really no surprise. All 3 agents—gefitinib, erlotinib, and afatinib—in addition to hittingEGFRmutation, will also hit wild-typeEGFR. Wild-typeEGFRmutations are found in both the skin—again, epidermal growth factor receptor—and the gut.

How do we best manage this? Conservative measures usually do the trick. Occasionally, patients have diarrhea that’s severe enough that it requires intravenous fluid. It may require other parenteral approaches.

It’s quite interesting that the side effects generally manifest fairly early. And then, often, over time, patients will develop a tachyphylaxis. The side effects, despite continuation of the therapy, will begin to recede.

Some individuals, my own group included, will start afatinib at a slightly lower dose. This is not a standard. It’s not in the package insert, but my group frequently starts at 20 mg daily. And then, in the absence of toxicity, they build the dose up, within a week or two, to 30 mg daily, and then ultimately to 40 mg daily, if the agent is well tolerated. Intriguingly, if you go back to the LUX-Lung 3 data and look at outcomes in patients who have managed to continue at 40 mg daily, or those who did require dose reduction, there was very little difference. I have equipoise regarding dosages and dose reductions with this agent.

Transcript edited for clarity.

June 2017

• A 61-year-old Caucasian woman presented with persistent cough and shortness of breath
• Patient history:
  • Never smoked
  • Mild hypertension, controlled on diuretic
  • No major cardiovascular disease or diabetes
  • Worked at local jazz club until symptoms forced her to resign
• Physical exam and imaging:
  • No palpable masses
  • CT reveals multiple tumors in right lung and brain metastases
  • ECOG PS: 1
• Biopsy and mutation analysis:
  • Adenocarcinoma
  • EGFRexon 19 deletion
  • No ALK rearrangement
• Started treatment with afatinib 40 mg once daily
  • Developed diarrhea that necessitated dose interruption
  • Recovered and resumed treatment at 30 mg once daily

March 2018

• Patient remains on afatinib, with no apparent progression