EGFR Mutation in Lung Cancer

EGFR stands for epidermal growth factor receptor. It is a protein that sits on the surface of a cell and tells it when to grow.

Certain changes in the EGFR gene jam that switch in the "on" position. The cell keeps dividing without waiting for a signal. Those changes are called driver mutations, because the tumor depends on them to keep growing.

That dependence is a weakness. Drugs that block EGFR can shut the signal off. NCI states that EGFR variants strongly predict a better response rate and longer progression-free survival in patients who take EGFR inhibitors.

Smoking history changes the odds sharply. NCI cites an analysis of 2,142 lung adenocarcinoma samples from Memorial Sloan Kettering.

• Never-smokers: 52% had an exon 19 deletion or an L858R mutation, or 302 of 580 samples.
• Former smokers: 15%, or 181 of 1,218.
• Current smokers: 6%, or 20 of 344.

The difference between those groups was statistically significant. That is why testing is not skipped in a patient who never smoked.

This is the detail that decides your treatment, and it is easy to miss on a report.

Exon 19 deletions and exon 21 L858R are the two changes NCI calls sensitizing. Tumors carrying them respond to standard EGFR inhibitors. FDA's osimertinib approvals name these two specifically.

Exon 20 insertions behave differently. They sit in the same gene but do not respond the same way. FDA approved a separate drug for them, described further below.

So "EGFR positive" is not a complete answer. Ask which exon and which specific change.

FDA names a required companion diagnostic with each approval, and the names differ.

The cobas EGFR Mutation Test is the companion diagnostic FDA named for adjuvant osimertinib. Guardant360 CDx is the one named for amivantamab in exon 20 insertions, and it works on blood rather than tissue. FoundationOne CDx also appears on FDA's companion diagnostic list for non-small cell lung cancer, covering EGFR, ALK, and BRAF changes across several drugs.

If your report is blood-based and negative, ask whether tissue testing should follow. A blood test can miss what a tissue sample would show.

FDA approved osimertinib on December 18, 2020 as adjuvant therapy after tumor removal, for non-small cell lung cancer with EGFR exon 19 deletions or exon 21 L858R mutations. Adjuvant means treatment given after surgery to lower the chance of return.

The ADAURA trial supplied the evidence. In stage II to IIIA disease, median disease-free survival was not reached in the osimertinib group. In the placebo group it was 19.6 months, with a 95% confidence interval of 16.6 to 24.5. The hazard ratio was 0.17, with a 95% confidence interval of 0.12 to 0.23.

Dosing is 80 mg by mouth once daily, with or without food. It continues until the cancer returns, until side effects stop it, or for up to 3 years.

That is the licensed amount, printed so you can recognise your own tablets. The prescription your team wrote is the one to follow, and they can reduce it if side effects build up.

NCI's drug page lists the approved uses beyond surgery. They are worth knowing, because people often assume one setting is the whole story.

• Stage IIIA, IIIB, or IIIC disease that cannot be removed by surgery and did not worsen during or after platinum-based chemoradiation.
• First treatment for cancer that has spread to other parts of the body.
• Combined with pemetrexed and platinum-based chemotherapy as first treatment for cancer that has spread.
• Cancer that has spread and grew worse during or after another EGFR tyrosine kinase inhibitor.

That last bullet matters. Resistance to a first EGFR drug is expected over time, not a sign that testing was wrong.

FDA granted accelerated approval to amivantamab on May 21, 2021. The indication is locally advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations, after the disease progressed on platinum-based chemotherapy.

The CHRYSALIS trial enrolled 81 patients with these mutations. The overall response rate was 40%, with a 95% confidence interval of 29% to 51%. Median duration of response was 11.1 months.

Dosing is weight-based, so the infusion team calculates it for each person. It is given weekly for 4 weeks, then every 2 weeks.

EGFR is also on normal skin, nails, and gut lining. That is why the side effect list looks the way it does.

FDA lists these in more than 20% of patients on adjuvant osimertinib: lymphopenia, leukopenia, thrombocytopenia, diarrhea, anemia, rash, muscle and bone pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough. Stomatitis means mouth sores. Nail toxicity often shows as painful, inflamed skin around the nail.

For amivantamab, FDA lists rash, infusion-related reactions, paronychia, muscle and bone pain, shortness of breath, nausea, fatigue, swelling, stomatitis, cough, constipation, and vomiting in at least 20% of patients. Paronychia is that same nail-fold inflammation.

Ask for a skin plan before the rash starts. It is far easier to prevent than to reverse.

• Diarrhea. NCI grades up to six bowel movements above your normal daily number as usually manageable at home. Seven or more above normal is grade 3 or 4, which NCI describes as potentially life-threatening. Keep a count.
• Fever of 100.4 degrees F, or 38 degrees C, or higher. NCI treats this as urgent during cancer treatment. Call before taking a fever reducer.
• New or worsening cough, breathlessness, or chest tightness. Lung inflammation is a known risk with this drug class.
• A rash that blisters or peels, or that involves the eyes or mouth.
• Nail fold pain with pus or spreading redness.

• Which exact EGFR change was found, and in which exon?
• Which test was used, and was it tissue or blood?
• Is my treatment adjuvant, first-line, or after progression?
• How long is the planned course, and what marks the end?
• What is the plan for rash and nail problems before they start?
• If this drug stops working, what testing happens next?

For related reading, see Biomarker Testing and Precision Medicine, Targeted Therapy vs Chemotherapy, and Pathology Reports.

• FDA — FDA Approves Osimertinib as Adjuvant Therapy for Non-Small Cell Lung Cancer with EGFR Mutations
• FDA — FDA Grants Accelerated Approval to Amivantamab-vmjw for Metastatic Non-Small Cell Lung Cancer
• FDA — List of Cleared or Approved Companion Diagnostic Devices
• National Cancer Institute — Non-Small Cell Lung Cancer Treatment (PDQ), Health Professional Version
• National Cancer Institute — Osimertinib Mesylate
• National Cancer Institute — Diarrhea and Cancer Treatment
• National Cancer Institute — Infection and Neutropenia during Cancer Treatment