Targeting Rare EGFR Mutations in NSCLC: Afatinib and Mobocertinib


Sandip Patel, MD, highlights the use of afatinib and mobocertinib, respectively, to treat NSCLC with rare EGFR-mutation variants.

Sandip P. Patel, MD:
Another category of mutations in EGFR is atypical EGFR mutations. These are in exon 18 and exon 20. The best data set we have for those mutations is with a drug called afatinib, which is a small-molecule inhibitor that blocks EGFR and HER2 [human epidermal growth factor receptor 2]. There have been remarkable results in some of these very rare EGFR subsets, representing 5% to 10% of patients. Something to keep in mind, in addition to testing for EGFR, is making sure your test is part of a broader panel. A next-generation sequencing panel with a tissue or a liquid biopsy gives you the full swath of the EGFR gene. For appropriate patients, consider afatinib, which is FDA approved for these rare mutations.

There have been multiple clinical trials investigating afatinib, a small-molecule EGFR and HER2 inhibitor, relative to other therapeutics and traditional chemotherapies, including a study in the refractory setting and even in squamous histology. There are multiple settings. There are also some data for atypical EGFR mutations that are very robust. All these studies are randomized controlled trials, so it’s the highest level of evidence. There was demonstrated benefit with the use of afatinib compared with the other treatments available at the time for patients with durable progression-free survival and overall survival data. Arguably the strongest data we have from some of the atypical mutations are in exon 18 and exon 20.

Because afatinib is an irreversible EGFR/HER2 small-molecule inhibitor, it has adverse effects that we associate with EGFR wild-type blockade. These are typically skin and GI [gastrointestinal] toxicities—stomatitis, rash, and diarrhea are the most common. These are very treatable. I’ll typically prescribe a prophylactic topical steroid as well as loperamide when I give a prescription for a drug in this class to get ahead of the toxicities. For stomatitis, [I’ll prescribe] dexamethasone mouthwash, which is utilized with mTOR inhibitors in breast cancer. It can be very efficacious as well. The vast majority of toxicities can be controlled with supportive care medications. If these medications are insufficient, a dose reduction to afatinib 30 mg is reasonable. There are data that patients who receive 30 mg of afatinib do as well—in terms of anticancer control—as patients who receive the full dose of afatinib 40 mg.

Mobocertinib is a small-molecule inhibitor of EGFR with an approval in the EGFR exon 20 insertion setting. This mutation is in 5% to 7% of patients and can be detected by a liquid biopsy or a tissue biopsy through a broader-based panel. It has demonstrated efficacy, and it’s historically very hard to treat the exon 20 insertion subgroup. The main toxicities relate to a blockade of wild-type EGFR. These are dermatologic toxicities, which can often be managed with topical steroids; and GI toxicities, especially diarrhea, which can be managed with loperamide or Lomotil [diphenoxylate] if needed.

Early intervention and interception of these toxicities is key because it ensures that patients can continue to receive a meaningful dose. Pay careful attention to other cutaneous manifestations—perioral, oral issues, and nail issues are key as well. These can be managed with topical steroids, whether steroid mouthwashes or steroid creams that are placed adjacent to the nail bed to allow for patients to receive these effective therapies.

Transcript edited for clarity.

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