Understanding Tyrosine Kinase Inhibitor Treatment of EGFR + Lung Cancer

Overview and review of Tyrosine Kinase Inhibitor therapy for EGFR + non small cell lung cancer.

by Dr. C.H. Weaver M.D. updated 2/2019

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.

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 EGFR mutation testing at initial diagnosis of all lung cancer patients.

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 selected patients with non-small cell lung cancer (NSCLC) belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within.

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.[2] 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.

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)
  • 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.

  • Gilotrif (afatinib)
  • Vizimpro (dacomitinib)

Third generation EGFR TKIs

Most patients treated with 1st or 2nd generation TKI's will eventually devleope resistance to treatment. Third generation TKI's offer new hopes for patients with progressive NSCLC.

  • Tagrisso (osimertinib)
  • CO1686 (rociletinib)
  • HM61713 (olmutinib)
  • AC0010

Tagrisso

Most patients with NSCLC that has an EGFR mutation respond well to EGFR inhibitors, however, some patients with the EGFR T790M mutation do not or become quickly resistant to treatment. Tagrisso is a 3rd generation, EGFR- TKI medication that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations.

The results demonstrating the effectiveness of Tagrisso included 2 clinical trials that involved 411 patients with advanced NSCLC who had the EGFR T790M mutation. Their cancer had progressed following treatment with a standard 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 (objective responses).
  • 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 compared to 75% with standard of care treatment. The 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.”​

Iressa®

The targeted agent Iressa 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.

Gilotrif

Afatinib 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.

Afatinib 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.

Lung cancer remains the leading cause of cancer-related deaths worldwide. In the United States, NSCLC accounts for 75–80% of all lung cancers. Although progress has been made in recent years, the majority of patients with advanced-stage lung cancer still die from their disease. New treatments are sorely needed.

There are several types of lung cancer, depending upon the type of cell within the lung from which the cancer develops. In addition, different genetic mutations and protein sequences affect characteristics of cancer cells, including their responses to certain therapies.

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.

Now, healthcare providers are able to test cancer cells to determine if they are EGFR-positive. This is important information because effective agents that specifically target the EGFR pathway are available for treatment for patients with EGFR-positive lung cancer.

Furthermore, additional genetic mutations and/or expressions of proteins have been identified that help guide optimal treatment options for those with EGFR-positive cancers.

Researchers recently 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.

References:

  1. Yang JCH, Schuler MH, Yamamoto N, et al. LUX-lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract LBA7500.
  2. Soria J-C, Enriqueta F, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. TheLancet Oncology;16(8):897-907. Available at: [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00006-6/abstract](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15%2900006-6/abstract)
  3. Keedy VL, Temin S, Somerfield MR et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. Journal of Clinical Oncology. 2011;29:2121-2127
  4. Fukuoka M, Wu Y-L, Thongprasert S et al. Biomarker analysis and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). Journal of Clinical Oncology. Early online publication June 11, 2011.
  5. Marchetti A, Martella C, Felicioni L et al. EGFR mutations in non-small cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications for pharmacologic treatment. Journal of Clinical Oncology. 2005;23:857-865.
  6. Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of Clinical Oncology. 2005;23:5900-5909.
  7. Spicer J, Tischer B, Peters M. EGFR Mutation Testing and Oncologist Treatment Choice in Advanced NSCLC: Global Trends and Differences. Presented at ELCC 2015, abstract number LBA2 PR.
  8. United States Food and Drug Administration (FDA). News release. FDA approves new pill to treat certain patients with non-small cell lung cancer. Available at: . Accessed November 13, 2015.
  9. 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
  10. ‘Tagrisso in treatment-naïve EGFR mutation-positive advanced NSCLC (FLAURA)’ S Ramalingam et al, The New England Journal of Medicine (NEJM), 10.1056/NEJMoa1713137.
  11. United States Food and Drug Administration. FDA approves targeted therapy for first-line treatment of patients with a type of metastatic lung cancer. Companion test also approved to identify appropriate patients. Available at: . Accessed July 14, 2015.
Comments

Stories