by Dr. C.H.Weaver M.D. updated 6/2019
As individualized treatment approaches continue to gain momentum in the treatment of lung cancer, several specific gene mutations have been identified that contribute to the growth and spread of certain cancers. Once these mutations are identified, researchers can develop medications that specifically target the effects caused by the mutations.
Tagrisso (osimertinib) is a 3rd generation, EGFR- tyrosine kinase inhibitor (TKI) medication that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. EGFR mutations occur in 30–40% of NSCLC in Asian populations and to 10–15% in Western populations.
Tagrisso is approved by the United States Food and Drug Administration (FDA) for the treatment of advanced EGFR + NSCLC that that has the T790M because clinical trials have demonstrated that Tagrisso significantly delays cancer progression, and is associated with fewer side effects, than standard chemotherapy for patients with advanced non-small cell lung cancer (NSCLC).
The epidermal growth factor receptor (EGFR) is part of a pathway involved in normal cellular growth. However, mutations within the EGFR gene can result in the production of too many EGFR proteins, and can result in unregulated spread of cancer cells. Standard treatment for patients who have too many EGFR proteins, referred to as EGFR+ cancer, includes EGFR tyrosine kinase inhibitors (EGFR TKIs). These drugs block the growth stimulatory effects of the mutations within the EGFR pathway, and reduce the spread of cancer. Tagrisso specifically targets the EGFR T790M mutation, reducing the growth and spread of the cancer cells.
Tagrisso has demonstrated activity against central nervous system (CNS) lesions - 57% of Tagrisso treated patients experienced a response.
The most common side effects of Tagrisso treatment are diarrhea, rash, dry skin, nail toxicity, and fatigue.
Although EGFR TKIs are an effective treatment option for patients with EGFR + NSCLC, the cancer stops responding to these agents after approximately 9-13 months of treatment. Often, the cancers will develop additional mutations that allow that cancer cells to begin growing again, despite treatment with EGFR TKIs. One such common mutation that can develop during EGFR TKI therapy is the T790 mutation (T790M).
Tagrisso as Initial Treatment of NSCLC
Tagrisso improves progression-free survival compared to standard first line therapy in patients with EGFR -mutated NSCLC. (1,2)
A large clinical trail compared treatment with Tagrisso to standard EGFR treatment with Tarceva (erlotinib) or Iressa (gefitinib) 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. In sum, Tagrisso provided a significant progression-free survival benefit in Asian patients with EGFR-mutated NSCLC.
Tagrisso in TKI Resistant NSCLC
The clinical trial included 419 patients with EGFR+ T790M-positive advanced NSCLC that has stopped responding to prior EGFR TKI therapy. One group of patients was treated with Tagrisso, and the other group of patients was treated with the standard chemotherapy agents, pemetrexed plus carboplatin or cisplatin.(3)
- The median duration of time on treatment in which the cancer did not progress was 10.1 months for patients treated with Tagrisso, compared with only 4.4 months for those treated with chemotherapy.
- Among patients whose cancer had spread to the central nervous system (brain and spinal column), a difficult-to-treat population, the median duration of time on treatment in which the cancer did not progress was 8.5 months for patients treated with Tagrisso, compared with only 4.2 months for those treated with chemotherapy.
- Serious side effects were experienced in 23% of patients treated with Tagrisso, compared with 47% of patients treated with chemotherapy.
- At 6 months following initiation of therapy, approximately 69% of patients treated with Tagrisso were alive with no progression of cancer, compared with only 37% of patients treated with chemotherapy.
The researchers concluded that Tagrisso had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced NSCLC (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy.”
- 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
- ‘Tagrisso in treatment-naïve EGFR mutation-positive advanced NSCLC (FLAURA)’ S Ramalingam et al, The New England Journal of Medicine (NEJM), 10.1056/NEJMoa1713137, http://www.nejm.org/doi/full/10.1056/NEJMoa1713137
- Mok T, Yi-Long W, Ahn M-J, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. New England Journal of Medicine. 2016. DOI: 10.1056/NEJMoa1612674. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1612674?query=featured_home#t=articleBackground. Accessed December 7, 2016.
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