The Story of Osimertinib

NSCLC is the most common subtype of lung cancer in the world, accounting for 84% of all lung cancers (1). Over a third of NSCLC cases are due to activating mutations in the EGFR gene (2), either a small nucleotide deletion in exon 19 (ex19del) or a point mutation in exon 21 (L858R). However, as we saw in the last post, due to tumour heterogeneity, patients tend to grow resistant to targeted therapies. NSCLC tumours are no different, with ~60% of patients developing resistance to the therapy prescribed within a year of treatment (3).

In response, targeted therapy recommendations have evolved rapidly over the last several years. Keeping up with these recommendations is an important aspect in creating a strategic treatment plan.

When, and how, does the pace of change matter? Let’s see what happens to a patient with EGFR positive lung cancer, with time of first diagnosis 2014, 2015, and 2018 respectively.

The 2014 patient is recommended erlotinib. Oncologists consulting Strand IRIS may have noted the presence of osimertinib, another small molecule with good response in refractory patients. Not much changes in the 2015 patient — — erlotinib, or any one of the other small molecules, is a likely recommendation. However, osimertinib is likely to loom larger in the oncologist’s mind, and not just because of its recent accelerated approval, but because it does not appear to develop one of the dreaded resistance mutations that renders immunity to therapies such as erlotinib. Things are very simple for the 2018 patient — — osimertinib is right up there in the guidelines as a first-line therapy for EGFR positive lung cancer, along with erlotinib, and due to its better data and apparent lack of resistance mutations, is a more straightforward recommendation.

Osimertinib went from approval as a third-line treatment to first-line in a relatively short span of 4 years — — its success has been exceptional. Most drugs, however, tend to take a little longer to climb this ladder of approvals to a first-line treatment. Between September 2015 and June 2019, there have been updates to a host of NSCLC drugs including Crizotnib, Ceritinib and Loratinib.

Drug recommendations in oncology evolve very quickly — — you can almost say that they reflect the evolution of the tumor, which we spoke about in an earlier post. Using a somatic knowledge-base such as StrandIRIS can help keep you informed of all updates for hundreds of variants and of therapies recommended, as well as evidence in clinical trials — both as FDA approved treatments and for use as off-label drugs. Learn more about Strand IRIS in this brochure.

Bibliography and Further Reading

1. Lung Cancer — Non-Small Cell — Statistics. Cancer.Net https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics (2012).
2. Zhang, Y.-L. et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 7, 78985–78993 (2016).
3. Rotow, J. & Bivona, T. G. Understanding and targeting resistance mechanisms in NSCLC. Nature Reviews Cancer 17, 637–658 (2017).
4. EGFR Mutation and Lung Cancer: What is it and how is it treated? https://lcfamerica.org/lung-cancer-info/types-lung-cancer/egfr-mutation/.
5. Sherry L. Ulrich. NCCN TrendsTM Highlights: Targeted Therapy in Non-Small Cell Lung Cancer. NCCN https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=449.
6. Study of Selumetinib in Patients With Previously Treated or Untreated Advanced/Metastatic NSCLC — Full Text View — ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01783197.
7. Green, J. A. Osimertinib — first or second line for epidermal growth factor (EGFR) mutation-positive non-small cell lung cancer? J Thorac Dis 10, S3837–S3839 (2018).
8. National Taiwan University Hospital. A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment. https://clinicaltrials.gov/ct2/show/NCT02025114 (2018).
9. FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer. Drugs.com https://www.drugs.com/newdrugs/fda-approves-tagrisso-osimertinib-first-line-egfr-mutated-non-small-cell-lung-cancer-4727.html.
10. Langen, A. J. de. Combining SBRT and Immunotherapy in Early Stage NSCLC Patients Planned for Surgery: Exploring Safety and Immunological Proof of Principle. https://clinicaltrials.gov/ct2/show/NCT03446911 (2018).