What is the EGFR gene mutation in lung cancer?

Lung adenocarcinoma

The EGFR mutation is present in about 20% of non-small cell lung cancers. The search for an EGFR mutation is performed on the biopsy at the time of diagnosis. The most frequent mutations are a deletion in exon 19 or point mutations in exon 21 of the EGFR gene. They are generally found in patients with adenocarcinoma, non-smokers and more frequently in women than men.

First-line therapy for lung cancer with EGFR mutation

Gefitinib, erlotinib and afatinib are the standard of therapy in treatment of EGFR mutation positive patients. Osimeritinib was also introduced from January 2019. Gefitinib and erlotinib are considered first-generation, afatinib is second-generation, and osimertinib is a third-generation EGFR inhibitor. These are drugs taken orally every day, and they are able to block and counteract the growth of cancer cells.

First- and Second-generation EGFR inhibitors

Gefitinib and erlotinib are approved in any treatment line and may be prescribed in both first and subsequent lines. Afatinib, on the other hand, can only be prescribed as a first-line treatments (for certain patients, as described below).

Eight clinical trials, conducted in Europe, Asia and the United States, compared erlotinib, gefitinib and afatinib with standard platinum-based chemotherapy in terms of objective response (reduction of size and number of lesions) and progression free survival (time between beginning of first-line and possible disease progression). The results demonstrated a 60-70% objective response for gefitinib, erlotinib and afatinib, while chemotherapy had a 35-40% objective response.

Gefitinib was the first to be used clinically. It is associated with a low probability of skin rash, diarrhea and other side effects known for this category of drugs. It also carries a risk of liver toxicity.

Erlotinib and afatinib, on the other hand, have a higher risk of rash and diarrhea (probability and severity-wise) but a lower risk of liver toxicity compared to gefitinib. In case of toxicity, the initial dose of erlotinib can be reduced (from 150 mg to 100 mg). The standard dosage that afatinib is started with is 40 mg. In the absence of toxicity, the dose may be increased to 50 mg or continued with 40 mg. In case of toxicity, it may be reduced to 30 mg to mitigate the side effects.

A comparative study between gefitinib and afatinib in first line showed better objective responses, better disease-free survival and overall survival for afatinib. The study was however not statistically significant; thus, it is difficult to draw definitive conclusions regarding which drug is superior.

Development of Osimertinib

Osimertinib was developed with the aim to overcome the resistance mechanisms that occur after treatment with first- and second-generation EGFR inhibitors as well as to obtain better control over brain metastases.

Osimertinib inhibits the EGFR receptor when it carries sensitizing mutations (exon 19 deletion or exon 21 L858R mutation) as well as in the presence of the exon 20 resistance mutation (T790M). Furthermore, osimertinib does not bind to the unmutated form of the EGFR receptor, which is present in other tissues of the body (such as the skin and gastrointestinal tract), creating a safer drug toxicity profile. The drug’s physio-chemical properties allow it to penetrate the blood-brain-barrier, reaching optimal concentrations within the central nervous system.

The recommended dose of 80 mg was established based on the results of the phase I study, AURA, where osimertinib was found to be well-tolerated given its good toxicity profile. In the AURA study, enrolled patients included those progressing after treatment with first- and second-generation EGFR inhibitors but not selected based on the presence of the T790M resistance mutation that often develops following treatment with gefitinib, erlotinib and afatinib. Osimertinib demonstrated an objective response rate of 51%. Patients may develop other resistance mechanisms, such as MET gene amplification, however in these cases, it is clear that osimertinib is not as effective.

For this reason, the phase II study, AURA 2, enrolled patients who at the time of progression after gefitinib, erlotinib or afatinib carried the exon 20 T790M mutation. The study reported a 70% objective response rate associated with a progression-free survival of 10 months. These results allowed osimertinib to be registered as a treatment for patients with EGFR T790M mutation progressing after first- or second-generation EGFR inhibitors. Recent data show that the median survival rates of patients enrolled in the AURA2 study is over 26 months, with survival rates of 80%, 55% and 37% at 12, 24 and 36 months respectively. These results are excellent taking into consideration the population was previously treated. This speaks volumes about precision medicine and how its introduction has significantly impacted the survival of non-small cell lung cancer patients. Just 10 years ago, the median survival of EGFR mutant patients was less than 12 months. Today, thanks to effective and well-tolerated treatments, the median survival of these patients can exceed 4 years.

Osimertinib’s effectiveness and relatively safe profile led to its development also in non-pretreated patients. The phase III FLAURA study was designed to demonstrate osimertinib’s superiority over gefitinib and erlotinib in patients with an EGFR mutations who have not undergone previous treatment. 156 patients were randomized to receive osimertinib, gefitinib or erlotinib. Cross-over to osimertinib was allowed for those patients who were randomized into either the gefitinib or erlotinib arms if they develop the T790M mutation at time of progression. The results demonstrated that under osimertinib: progression-free-survival was doubled, overall survival significantly improved, better control and prevention of brain metastases was achieved and finally a significant reduction in adverse drug events was observed.

Based on these results, starting from November 29th, 2019, osimertinib has also been indicated for patients carrying an EGFR mutations who have not undergone previous therapy.

Gefitinib, erlotinib, afatinib and osimertinib all represent valid therapeutic options for treatment of patients with EGFR gene mutation in first line. However, given osimertinib’s effectiveness on brain lesion control and its impact on overall survival, it is considered the first choice today.

To find out about the side effects regarding gefitinib, erlotinib, afatinib and osimertinib, go to the section dedicated to side effects.

Second-line therapy for lung cancer with EGFR mutation

If the patient has taken gefitinib, erlotinib or afatinib in first line:

When patients develop disease progression, after a median of about 10-12 months, the first thing to assess is whether the progression involves a single (unifocal) lesion or multiple (multifocal) ones. In the case of a unifocal progression, it is possible to continue with the drug in progress and subject the single site of progression to local treatment (radiotherapy or surgery).

In the case of a multifocal progression instead, the molecular mechanisms behind the development of resistance need to be explored to decide the new pharmacologic strategy.

To define the disease’s molecular characterization at time of disease progression after a first-line treatment with EGFR-TK inhibitors, the patient may perform a liquid biopsy (searching for T790M mutation on peripheral blood) or new tissue biopsy of the tumor.

In some cases, although less frequent, there are changes in histology (adenocarcinoma to small-cell lung cancer).

In other cases, new genetic alterations may appear such as the T790M mutation in exon 20 of the EGFR gene or amplification of MET gene.

In the presence of the T790M mutation, which is the most frequent resistance mechanism (55-60%), the patient is a candidate for second-line osimertinib. The phase III study AURA3 demonstrated osimertinib’s superiority compared to chemotherapy with platinum-pemetrexed in patients progressing after first- and second-generation EGFR inhibitors carrying the EGFR T790M mutation.

If the patient has taken osimertinib as first-line or does not carry T790M mutation after gefitinib, erlotinib or afatinib:

In all these cases, the treatment of choice remains platinum-based chemotherapy. The Impower 150* study demonstrated the effectiveness of combination chemotherapy with carboplatin + paclitaxel along with an antivascular drug (bevacizumab) and a PD-L1 inhibitor (atezolizumab) in patients with EGFR mutation following targeted therapy. This combination therapy is not registered in Italy yet, but may be requested on a personal basis allowing patients to receive the treatment for free.

Osimertinib: How does the therapeutic strategy change in patients with EGFR gene mutation?

Interview with Dr. Elisa Roca, Spedali Civili of Brescia

Why is Osimertinib considered an innovation in non-small cell lung cancer (NSCLC) therapy?

In the context of neoplastic lung disease, it is important to stress that there are patients with biological characteristics that allow them to benefit from targeted treatments. An example of targeted therapy is represented by 1st- and 2nd-generation EGFR inhibitors (gefitinib, erlotinib and afatinib), administered to patients with the EGFR gene mutation.

These therapeutic innovations have changed the natural history of these patients, leading to increased survival and significant quality of life improvements. Unfortunately, however, these patients are destined to develop disease progression, often due to the tumor’s ability to get resistant to these drugs.

Among the resistance mechanisms by these therapies, the T790M mutation of the EGFR gene is the most frequent and is found in 50-60% of patients in disease progression following therapy by 1st or 2nd line EGFR inhibitors.

Because of this, Osimertinib was designed; an irreversible tyrosine kinase inhibitor with high inhibitory activity against T790M mutation. This drug, compared to the previous ones, maintains the same activity against EGFR mutated genes but a lower affinity for non-mutated ones. Osimertinib thus represents an innovation in advanced NSCLC therapy as it allows patients who have developed resistance to first line targeted therapy to continue with another biological treatment (oral administration) and delay the need for chemotherapy.

Which patients can benefit from treatment with Osimertinib?

Osimertinib is a targeted biological therapy. Patients with lung adenocarcinoma, presenting with the T790M mutation and are progressing after previous therapy with a 1st or 2nd generation EGFR inhibitor may benefit from it.

Currently, the treatment is approved for 2nd-line. Studies are underway however to evaluate its effectiveness as a first-line therapy as well.

What are the data regarding Osimertinib efficacy in patients with NSCLC T790M mutation showing disease progression after a previous therapy with an EGFR-TKI?

The data on osimertinib’s efficacy derives from two phase II clinical studies, conducted on 411 patients with lung adenocarcinoma presenting with disease progression during a previous EGFR-TKI systemic therapy. Osimertinib showed an objective response rate of 66& and disease-free progression of 11 months.

The open-label, randomized, phase III AURA3 study compared platinum-based chemotherapy conducted on 419 patients with advanced lung adenocarcinoma and T790M mutation (found at time of progression after previous therapy with EGFR-TKI) showed a statistically significant improvement in progression-free survival for patients treated with Osimertinib compared to those with chemotherapy (10.1 months vs 4.4 months). An objective response rate of 71% (197/219) was found with osimertinib compared to 31% (44/140) with chemotherapy.

How is Osimertinib tolerated in patients?

In the AURA3 study, the main adverse events reported in the Osimertinib-treated arm were diarrhea, skin rash, dry skin and nailbed changes. Most side effects were mild and easily managed. Chemotherapy resulted in a higher percentage of serious side effects compared to osimertinib.

It is therefore a more effective drug and produces fewer side effects.

What are tools available in clinical practice for finding the T790M mutation?

As emphasized by the recent ESMO guidelines, patients who progress after an EGFR-TKI therapy are strongly recommended to perform a new biopsy to search for the resistance mutation as it is very relevant to the subsequent therapeutic strategy.

The T790M mutation may be found on a tissue sample or a plasma sample (liquid biopsy). If a plasma sample is used and results negative, it is recommended to also perform a tissue sample, where possible, due to the potential false-negatives obtained with the plasma-based test.

Oral inhibitors of EGFR (gefitinib, erlotinib, afatinib)
– ADJUVANT study: Gefitinib, the first molecular-target drug used in adjuvant therapy