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by Dr. C.H. Weaver M.D. updated 11/2022

Advances in cancer research have highlighted the importance of understanding the specific characteristics of each person’s cancer. These characteristics—which include not only the particular type of cell involved but also gene mutations and protein expression—can have a profound effect on the behavior of the cancer and its response to particular treatments.

The EGFR—which stands for “epidermal growth factor receptor”—contributes to the growth of some lung cancers and drugs that block the activity of EGFR slow cancer growth and prolong survival.

Lung CancerConnect 490

EGFRs are small proteins that are found on the surface of all cells. EGFR binds proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote growth of a cell in a strictly controlled manner. However, in many cancer cells, EGFR is either abundantly over-expressed or the EGFR biological processes that normally stimulate cell growth are constantly active. This leads to the uncontrolled and excessive growth of the cancer cell.

Guidelines from the International Association for the Study of Lung Cancer (IASLC) have been developed and they recommend testing for EGFR and ALK mutations, and PDL-1 in all individuals with newly diagnosed lung cancer.

Among people with NSCLC, EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma. EGFR mutations occur in 30–40% of NSCLC's in Asian populations compared to 10–15% in Western populations.1

EGFR-targeted drugs that have been shown to benefit select patients with NSCLC belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within.

Tagrisso (Osimertinib) is currently the standard of care for patients with EGFR-mutated NSCLC, but the need for novel agents is underscored as disease progression on Tagrisso is inevitable. Bispecific antibodies, antibody-drug conjugates (ADCs), EGF vaccines, and fourth-generation EGFR TKIs are all under development to enrich the treatment paradigm.

First-generation EGFR TKIs

The working mechanism of first-generation EGFR-TKIs is to block the activation of downstream signaling induced by EGFR through binding to the ATP-binding sites.

  • Tarceva® (erlotinib)
  • Iressa® (gefitinib)- is approved for patients whose tumors express the most common types of EGFR mutations in NSCLC (exon 19 deletions or exon 21 L858R substitution gene mutations). The therascreen EGFR RGQ PCR Kit was approved as a companion diagnostic test to identify patients with tumors having the EGFR gene mutations in order to determine which patients would be appropriate for treatment.
  • Icotininib (only available in China)

Second-generation EGFR TKIs

The development of second-generation EGFR TKIs was necessary to overcome the acquired resistance which comes from the failure of first-generation EGFR TKIs. So the working mechanisms of second-generation EGFR TKIs are not exactly similar to first-generation EGFR TKIs and these drugs can provide benefit when first generation drugs no longer work.

Third generation EGFR TKIs

Most patients treated with 1st or 2nd generation TKI's eventually develop resistance to treatment.2 Third generation TKI's improve outcomes and Tagrisso has become the standard initial treatment for EGFR expressing NSCLC.

The most important mechanism of acquired resistance to TKI's is the EGFR T790M mutation. Occurrence of the T790M mutation is reported to be greater than 50%.3 To overcome this resistance third-generation EGFR-mutant selective TKIs were developed.4,5 These drugs are specifically designed to inhibit EGFR T790M.6,7

Third generation EGFR TKIs provide benefit in patients who progressed after treated with other EGFR TKIs especially in the T790M mutation-positive patients. Unfortunately there are resistance mechanisms to third-generation EGFR TKIs as well and the C797S mutation is considered the most challenging for Tagrisso.8,9

Lung Newsletter 490


Tagrisso is a 3rd generation, EGFR- TKI medication that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations.10,11

The results demonstrating the effectiveness of Tagrisso included 2 clinical trials that involved 411 patients with advanced NSCLC who had the EGFR T790M mutation and cancer that had progressed following treatment with a 1st or 2nd generation EGFR inhibitor. All patients were treated with Tagrisso.

  • Approximately 60% of the patients in both trials experienced a complete or partial reduction in the size of their cancer 
  • The most common side effects were diarrhea, and skin and nail conditions.

A second clinical trail compared treatment with Tagrisso to standard treatment with Tarceva or Iressa as first line therapy in 556 patients from Asia, Europe, and North America with NSCLC and EGFR mutations.

Overall treatment with Tagrisso improved progression-free survival by 54%. The overall response to treatment was 80% with Tagrisso and average duration of response was two-fold higher for patients treated with Tagrisso (17.6 months) compared to standard of care (8.7 months). The median progression-free survival was 16.5 months with Tagrisso compared to 11.0 months for the standard therapy.

Tagrisso provided a significant progression-free survival benefit in Asian patients with EGFR-mutated NSCLC. Tagrisso should be the preferred first line treatment for EGFR-mutant NSCLC in Asia.”​10-14

EGFR Exon insertions

EGFR exon insertions make up 4% to 10% of all EGFR-mutant NSCLC, These mutations typically appear in never-smokers, female patients, and those of East Asian descent. 

  • Rybrevant (amivantamab-vmjw) and Exkivity (mobocertinib) are both FDA approved. Rybrevant is a dual EGFR-MET antibody that binds to the extracellular portion of EGFR.43 Rybrevant targets the Exon 20 mutation - the third most prevalent EGFR mutation in NSCLC. Rybrevant is the first bispecific antibody to target both EGFR and MET and received FDA approval for use patients with NSCLC who harbor EGFR exon 20 insertion mutations.
  • Exkivity is a small molecule EGFR TKI that has been chemically optimized to be more selective on exon 20 mutations.44
  • CLN-081 is a novel, irreversible oral EGFR inhibitor with selectivity for EGFR exon 20 insertions that has shown promising activity. In a phase 1/2 trial of 73 patients, the agent led to a confirmed partial response (cPR) rate of 38.4% and a median DOR of 10 months.45
  • Sunvozertinib, a novel, oral EGFR exon 20 inhibitor reported to have a 52% response rate in a “pooled analyses”45

MET Exon 14 skipping mutations

MET exon 14 skipping mutations are found in approximately 3% of patients with NSCLC and are generally more common in older patients, women, and non-smokers. The FDA has approved Tepmetko (tepotinib) and Tabrecta (capmatinib).46,47

  • Capmatinib - The U.S. Food and Drug Administration initially granted Breakthrough Therapy Designation to capmatinib (INC280) as a first-line treatment for patients for non-small cell lung cancer (NSCLC) patients with the MET exon 14 skipping (METex14) mutation.
  • Tepmetko - is an oral MET kinase inhibitor that is designed to selectively inhibit the oncogenic signaling caused by MET (gene) alterations, including both MET exon 14 skipping alterations and MET amplifications, or MET protein over expression.

The EGFR M766Q mutation represents a novel Tagrisso resistance mechanism and may potentially be treated with Nerylnx (neratinib) or poziotinib.

Resistance to Tagrisso will ultimately develop in nearly all patients, and subsequent treatment options to overcome this resistance are needed.

Researchers recently published a case report of a woman undergoing third-line treatment with Tagrisso that developed progressive disease. Liquid biopsy analyses of circulating tumor cell-free DNA sequencing performed at the time of disease progression revealed the presence of a new EGFR mutation in exon 20, EGFR M766Q and TP53 V203M and EGFR S306L.

The effect of the EGFR M766Q mutation on sensitivity/resistance to different EGFR TKIs was evaluated pre-clinically and confirmed. The cancer cells however were sensitive to treatment with low concentrations of Nerlynx (neratinib) and clinically achievable doses of poziotinib, an investigational, irreversible pan-HER TKI targeting EGFR and HER2 with exon 20 insertion mutations.35

Additional analysis of large-scale clinical data needs to be performed to offer insight into how frequently the EGFR M766Q mutation is encountered. Patients developing this resistance mechanism should discuss the potential role of Nerylnx or poziotinib in the management of their EGFR-mutant lung cancer.42

Fourth-generation EGFR TKIs

In order to overcome the resistance to the C797S mutation which occurs in 32% of patients fourth-generation EGFR-TKIs are being developed.

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Recommended Articles

  • BLU-945 is a TKI that was designed to suppress activating EGFR mutations and spare wild type EGFR.37
  • EAI045 EAI045 targets both the T790M and C797S EGFR mutants. Interestingly, it is only when combined with cetuximab that EAI045 is working.15

Overcoming Met Resistance

  • Savolitinb - is a potent, selective MET TKI and has been combined with Tagrisso to determine an optimal combination dose that has demonstrated clinical responses in global expansion cohorts of the TATTON clinical trial.

Whats Next?

Antibody Drug Conjugates

Patritumab deruxtecan is an Antibody Drug Conjugate (ADC) that is comprised of 3 components: anti-HER3 monoclonal antibody, patritumab, that is covalently linked to a topoisomerase I inhibitor payload, an exatecan derivative, through a tetrapeptide-based cleavable linker.

HER3 is not a resistance mechanism for EGFR TKIs but is highly expressed in NSCLC, at 83%. Patritumab deruxtecan was evaluated in patients with locally advanced or metastatic NSCLC with EGFR mutations who had progressed on previous EGFR TKI treatment. Results indicated that the agent demonstrated durable activity following failure of EGFR TKI and platinum-based chemotherapy. At a median follow-up of 10.2 months the confirmed response rate was 39% and median response duration was approximately 7.0 months.41

EGFR TKI versus Chemotherapy

Compared with traditional platinum-based combination chemotherapy, EGFR TKI monotherapy has become the recommended treatment strategy and the cornerstone of combined therapy for NSCLC patients with an EGFR mutation*.* The oldest and most widely used and effective EGFR inhibitor is Tarceva (erlotinib). A study known as IPASS illustrates how treatment response can vary by EGFR mutation status. The study, conducted in East Asia, enrolled patients with advanced adenocarcinoma of the lung.15 Study participants were treated with either Iressa or combination chemotherapy. Among patients with an EGFR mutation, Iressa delayed cancer progression to a greater extent than chemotherapy. In contrast, among people without an EGFR mutation, Iressa resulted in worse outcomes than chemotherapy.

To compare Tarceva with chemotherapy for the initial treatment of advanced NSCLC that tests positive for an EGFR mutation, researchers conducted a study among 165 patients with Stage IIIB or Stage IV NSCLC. Half the patients were treated with Tarceva and half were treated with combination chemotherapy consisting of Gemzar® (gemcitabine) and carboplatin.

  • Treatment with Tarceva substantially delayed cancer progression. Median survival without cancer progression was 13.1 months among patients treated with Tarceva and 4.6 months among patients treated with chemotherapy.
  • Serious side effects were also less common in the Tarceva group.

Tarceva Effective as Maintenance Therapy in NSCLC

The safety and effectiveness of Tarceva maintenance therapy was evaluated in a Phase III clinical trial known as SATURN. Maintenance therapy refers to treatment that is given after initial treatment but before cancer progression. It is a relatively new approach to lung cancer treatment.

The study enrolled more than 880 patients with advanced NSCLC that had not progressed following initial, platinum-based chemotherapy. Half the patients received Tarceva maintenance therapy, and half received a placebo.

  • Compared with a placebo, overall survival was 23% better among patients treated with Tarceva, and progression-free survival was 41% better.
  • The most common side effects among patients treated with Tarceva were rash (49%) and diarrhea (20%).

Based on these results, the FDA expanded the approval of Tarceva to include maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer that has not progressed after four cycles of platinum-based first-line chemotherapy.

EGFR TKI Combined With Chemotherapy

Single agent EGFR TKI therapy is generally superior to chemotherapy and doctors have evaluated combining TKI's with chemotherapy. So far clinical trials of combined therapy in general appear to improve progression free survival by 3-4 months compared to TKI therapy alone.16,17,18

The RELAY clinical trial evaluated 449 patients with untreated metastatic NSCLC harboring EGFR exon 19 deletion or exon 21 (L858R) substitution mutations. Patients were treated with Tarceva with or without Cyramza and directly compared. Those receiving the Tarceva - Cyramza combination survived on average 19.4 months compared to 12.4 months for those treated with Tarceva alone.

Improvements were also consistently seen across all specified subgroups, including patients with tumors that had exon 19 and 21 mutations. Results of the RELAY clinical trial ultimately led to the US Food and Drug Administration approving Cyramza in combination with Tarceva for first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. Overall survival data is still and will be published in the future.36

EGFR TKI Combined with Avastin (anti-angiogenic drugs)

Outcomes appear to be better in some 19,20,30 but not all33 clinical trials when a TKI is combined with the anti-angiogenic monoclonal antibody Avastin (bevacizumab). The Avastin EGFR-TKI combinations have exhibited significant effectiveness in unselected NSCLC patients. For example Avastin combined with Tarceva improved progression free survival by 9-10 months when used as first or second line treatment for advanced EGFR + NSCLC.19,20,30 However studies looking specifically at individuals with exon 19 deletion or exon 21 L858R mutations found no benefit from the addition of Avastin.33

EGFR TKI Combined With Immunotherapy

The PD-1/PD-L1 checkpoint inhibitor precision cancer immunotherapies, Opdivo (nivolumab) and Keytruda (pembrolizumab) have become the standard of care for advanced NSCLC. Based on this reason, they are currently undergoing evaluation in combination with TKI's for EGFR + NSCLC as well.21,22,23

EGFR TKI Combined With Metformin

Combining a TKI with the diabetic medication Metformin may significantly improve survival.31,32 Learn more...


Gilotrif blocks the EGFR pathway as well as the ErbB family of receptors that are associated with the EGFR pathway, including HER2 (ErbB2) and HER4 (ErbB4). Afatinib may block the EGFR pathway more thoroughly than other targeted therapies. Initial treatment with the targeted drug afatinib also prolongs progression-free survival in patients with EGFR-positive advanced lung cancer when compared with standard chemotherapy.

In a study of 345 patients with advanced NSCLC who had EGFR mutations patients were treated with either afatinib or standard combination chemotherapy treatment. After a median follow-up of 8 months, afatinib delayed disease progression by more than 4 months over standard therapy—progression-free survival (PFS) was 11.1 months with afatinib, compared to 6.9 months with standard therapy.

Gilotrif was particularly beneficial to the 308 patients who had one of two common types of EGFR mutations (deletion 19 or L858R) that account of approximately 90 percent of all EGFR mutations. These patients experienced almost double the PFS—13.6 months in the afatinib group and 6.9 months in the standard chemotherapy group.

​Gilotrif Improves Outcomes in Lung Cancer

The targeted agent Gilotrif (afatinib) improves outcomes compared to Tarceva (erlotinib) among patients with squamous cell lung cancer. These results were recently published in TheLancet Oncology.

The epidermal growth factor receptor (EGFR) refers to a pathway in cells that is involved in cellular growth and spread. Some cancer cells have overactive EGFR pathways, causing cancer cells to replicate and spread to different sites in the body. These cancers are referred to as EGFR-positive.

Researchers conducted a clinical trial to compare two different agents that target the EGFR pathway in different ways. Patients in the trial were divided into two groups: one group was treated with Gilotrif and the other group was treated with erlotinib.

The trial included approximately 800 patients and included over 20 countries. All patients had advanced, squamous cell lung cancer, and had received prior treatment.

At the time of data analysis, median overall survival and progression-free survival was greater in the group of patients treated with afatinib than the group treated with Tarceva.

Control of disease was also greater in the group treated with Gilotrif than Tarceva.

The researchers concluded that Gilotrif appears to be an effective treatment option for patients with advanced squamous cell lung cancer.

Keep Current with Advances in Lung Cancer Treatment Here.


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  13. Abstract LBA6_PR ‘Tagrisso vs standard of care (SoC) EGFR-TKI as first-line treatment in patients with EGFR-TKI sensitising mutation (EGFRm) positive advanced non-small cell lung cancer (NSCLC): FLAURA Asian subset‘ will be presented by Byoung Chul Cho during the Mini Oral session Thoracic malignancies 2 on Sunday, 19 November 2017, 14:30 to 15:25 (SGT) in Room 310. Annals of Oncology, Volume 28, 2017 Supplement 10
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