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What Are the Most Common EGFR Mutations? | Inciteful Med

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The most common EGFR mutations in non-small cell lung cancer are Exon 19 deletions and the Exon 21 L858R substitution, making up 85-90% of cases. Identifying these specific mutations allows doctors to treat the cancer with highly effective, targeted daily pills instead of traditional chemotherapy.

Key Takeaways

  • • Exon 19 deletions and Exon 21 L858R substitutions are the two most common EGFR mutations, accounting for 85% to 90% of cases.
  • • Classic EGFR mutations are highly sensitive to targeted therapy pills called Tyrosine Kinase Inhibitors (TKIs), like osimertinib.
  • • Exon 20 insertions are the third most common mutation and usually require specialized infusions or chemotherapy instead of standard TKIs.
  • • Cancers can eventually develop acquired resistance mutations like T790M or C797S, requiring doctors to switch to a new targeted treatment.
  • • Biomarker testing takes 1 to 3 weeks, and it is highly recommended to wait for these results before starting cancer treatment.

When doctors test lung cancer for an EGFR mutation, they are looking for specific changes in the cancer’s DNA. The two most common changes are Exon 19 deletions and the Exon 21 L858R substitution [1][2]. Together, these “classic” mutations make up about 85% to 90% of all EGFR mutations in non-small cell lung cancer (NSCLC) [3][4]. The third most common type is a group called Exon 20 insertions, accounting for up to 12% [1][5]. Knowing exactly which mutation you have is critical because it tells your treatment team exactly which targeted therapy—often a daily pill taken at home—will work best for you [6].

What is an EGFR Mutation?

The Epidermal Growth Factor Receptor (EGFR) is a protein that normally helps cells grow and divide. When the gene that creates this protein mutates (changes), the receptor can get stuck in the “on” position. This causes cells to multiply uncontrollably, leading to cancer. Finding out exactly where this gene is mutated—typically referred to by the “exon” or section of the gene—guides your treatment team in choosing medications called Tyrosine Kinase Inhibitors (TKIs) [3]. These are specialized, targeted therapies that directly block the overactive proteins and are frequently taken as a daily pill.

The “Classic” Mutations (85-90% of cases)

If you have an EGFR mutation, it is highly likely to be one of these two “classic” types [7]. Both are highly sensitive to targeted TKI pills, meaning these drugs are usually the first line of treatment instead of traditional chemotherapy. For both of these classic mutations, a newer, third-generation drug called osimertinib is generally the preferred first treatment [6].

  • Exon 19 deletions (Ex19del): This is the single most common EGFR mutation. A small piece of the DNA is missing (deleted). Patients with this mutation often respond very well to targeted therapies and tend to have slightly better long-term outcomes compared to other EGFR mutations [8][9].
  • Exon 21 L858R substitution: This is the second most common mutation. Here, one specific building block of the DNA is swapped out for another (a substitution). This mutation also responds very well to targeted TKIs [10][11].

Exon 20 Insertions and “Uncommon” Mutations (10-15% of cases)

Not all EGFR mutations behave the same way. The remaining 10% to 15% are a diverse group [12].

  • Exon 20 insertions: The third most common EGFR mutation involves extra pieces of DNA inserted into the gene [13]. Unlike the classic mutations, Exon 20 insertions are usually resistant to standard daily TKI pills [14][1]. Patients with this mutation often start with chemotherapy or newer specialized treatments delivered by infusion, such as amivantamab [5].
  • Other uncommon mutations (G719X, L861Q, S768I): These rare mutations change how the tumor responds to treatment. Certain targeted therapies, such as the second-generation TKI afatinib, have proven to be quite active against these specific changes [15][16].

Acquired Resistance Mutations

Cancers are highly adaptable. Over time, cancer cells can change to protect themselves against targeted therapies. When this happens, new mutations emerge, known as resistance mutations [17]. It is important to know that targeted therapies can often keep the cancer controlled for a long time—sometimes years—before this happens. Your doctors will constantly monitor you for these changes so they can quickly switch to a “Plan B” new treatment if needed.

  • T790M: If a patient is treated with an older (first- or second-generation) TKI, the tumor might eventually develop the T790M mutation, which occurs in about 60% of cases when the older drug stops working [18][19]. Third-generation TKIs (like osimertinib) were specifically developed to target this mutation and overcome the resistance [20].
  • C797S: For patients treated with third-generation TKIs from the start, a different resistance mutation called C797S can eventually emerge [21]. Researchers are actively developing new treatments and clinical trials to target this specific change as a next step [22][17].

Who Gets EGFR Mutations?

EGFR mutations are most commonly found in patients with non-small cell lung cancer, particularly a subtype called adenocarcinoma. They are also significantly more common in people of Asian descent (found in 30% to 50% of lung cancers) compared to people of Caucasian descent (found in 10% to 15%) [23]. Furthermore, they are frequently found in patients who have never smoked or who were light smokers [24]. However, anyone with lung adenocarcinoma can have an EGFR mutation regardless of their smoking history. This is why universal biomarker testing is recommended for all patients [24].

How We Find Them

To identify your specific mutation, doctors will test a sample of the tumor (a tissue biopsy) or a sample of your blood (a liquid biopsy) [25]. Liquid biopsies look for tiny fragments of tumor DNA floating in the blood and are especially useful for monitoring how the tumor changes over time or checking for resistance mutations through a simple blood draw [26][27].

The Wait for Results

Genomic sequencing for these biomarkers can take 1 to 3 weeks to return results. While the waiting period can be incredibly anxious, it is usually safe and highly recommended by oncologists to wait for these results before starting treatment. Finding an EGFR mutation can change your entire treatment plan from traditional intravenous chemotherapy to a highly effective targeted pill.

Frequently Asked Questions

What are the most common EGFR mutations in lung cancer?
The most common EGFR mutation is the Exon 19 deletion, followed closely by the Exon 21 L858R substitution. Together, these two classic mutations account for 85 to 90 percent of all EGFR mutations in non-small cell lung cancer.
How do doctors treat the most common EGFR mutations?
Classic EGFR mutations are highly sensitive to targeted therapies called Tyrosine Kinase Inhibitors (TKIs). These are specialized daily pills, such as osimertinib, that directly block the overactive proteins driving the cancer's growth rather than using traditional chemotherapy.
Are Exon 20 insertions treated differently than classic EGFR mutations?
Yes, Exon 20 insertions are usually resistant to standard daily TKI pills. Patients with this specific mutation often require chemotherapy or newer specialized treatments delivered by infusion, such as amivantamab.
What happens if my cancer stops responding to targeted therapy?
Cancer cells can adapt and develop new changes known as acquired resistance mutations, such as T790M or C797S. If this happens, your doctor will use blood tests or biopsies to identify the new mutation and switch your treatment to a new therapy designed to overcome that resistance.
How long does it take to get EGFR mutation test results?
Genomic sequencing for EGFR biomarkers typically takes one to three weeks to return results. Oncologists highly recommend waiting for these results before starting treatment, as finding a mutation can completely change your treatment plan to a targeted pill.

Questions for Your Doctor

  • • What specific EGFR mutation—such as an Exon 19 deletion, L858R, or an Exon 20 insertion—was identified on my biomarker report?
  • • Am I a candidate to take a daily targeted therapy pill like osimertinib, and what are its most common side effects?
  • • Are we still waiting on any other biomarker test results, and should I delay starting traditional chemotherapy until we have the complete genetic picture?
  • • How frequently will we use liquid biopsies (blood tests) to monitor whether my cancer is responding or if a resistance mutation is developing?
  • • If my cancer eventually develops resistance to my initial targeted therapy, what clinical trials or alternative treatments would become our 'Plan B'?

Questions for You

  • • Have I communicated to my care team what my biggest priorities are (e.g., maintaining daily routines, minimizing side effects) as we finalize my treatment plan?
  • • How am I managing my anxiety during the 1 to 3 week waiting period for my full biomarker results to come back?
  • • Who in my support system can I rely on to help me keep track of a strict daily pill schedule if I am prescribed a targeted therapy at home?

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This page provides educational information about EGFR mutations and targeted lung cancer therapies. Always consult your oncologist to interpret your specific biomarker testing results and determine the best treatment plan for you.

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