Using Osimertinib in the Clinic
“These are very impressive data,” said Justin Gainor, MD, clinical director of the cancer immunotherapy program at Massachusetts General Cancer Center in Boston. As therapies have gotten better and patients respond to systemic therapies, the CNS is a sanctuary site of disease, and disease progression is often seen in the brain, he explained.
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Dr Gainor indicated that across most cancers and specifically with targeted therapies for lung cancer, clinicians need therapies that are highly CNS-penetrable. “An intracranial response rate of 91% is very impressive,” he said.
He also explained that osimertinib was initially approved to treat EGFRm NSCLC with the T790M gatekeeper mutation. “Data from FLAURA and now this analysis in patients with CNS metastases at baseline provide another reason why osimertinib should be used first-line across all patients with EFGRm advanced NSCLC,” he said.
Dr Gainor argued against those who believe osimertinib should be used in sequence after other EGFR-TKIs. The gatekeeper mutation develops in approximately 60% of patients, he said. In addition, data from other registration studies for EGFR-TKIs have showed that the approximately 30% to 40% of patients who discontinue their initial EGFR-TKI therapy do not go on to receive additional therapy, he added.
“The sequencing argument assumes that when patients relapse with the first EGFR-TKI, all go on to receive the next one. This is not the case,” he said.
“My view is that the most potent, best EGFR-TKI should be given first,” added Dr Gainor. After the results of FLAURA were first shared at the 2017 European Society for Medical Oncology meeting, he said he has been providing osimertinib in the first-line setting for appropriate EGFRm advanced NSCLC.
Resistance mechanisms seen with other EGFR-TKIs may not emerge with osimertinib, Dr Gainor noted. He highlighted mechanisms for on-target and off-target resistance with osimertinib, although he cautioned that much of our knowledge about osimertinib resistance is based upon patients receiving osimertinib after other EGFR-TKIs (ie, in T790M-mutation-positive populations). On-target resistance with osimertinib has been reported by way of an acquired EGFR codon 797 (C797S) mutation, and off-target mutations develop in bypass signaling pathways via the mechanism of MET amplification.
“This study is an important contribution to [the] literature and reaffirms the success of brain-penetrable drugs,” Dr Gainor said.
Based on data from the FLAURA study, the National Comprehensive Cancer Network guidelines recommend osimertinib for the treatment of NSCLC in patients with EGFR-sensitizing mutations.4 A consensus statement has also been issued by the AME Lung Cancer Collaborative Group on the use of osimertinib and includes a review of resistance mechanisms that can emerge as a result of treatment with osimertinib.5
References
- Reungwetwattana T, Nakagawa K, Chul B, et al. CNS response to osimertinib versus standard of epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer [published online August 28, 2018]. J Clin Oncol. doi: 10.1200/JCO.2018.78.3118
- United States Food and Drug Administration. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm605113.htm. Updated April 19, 2018. Accessed September 5, 2018.
- Soria J-C, Ohe Y, Vansteenkiste J, et al. for the FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125.
- National Comprehensive Cancer Network. Non-small cell lung cancer. Version 6.2018, August 2018. http://nccn.org. Accessed September 5, 2018.
- Jiang T, Su C, Ren S, et al, for the AME Lung Cancer Collaborative Group. A consensus on the role of osimertinib in non-small cell lung cancer from the AME Lung Cancer Collaborative Group. J Thorac Dis. 2018;10(7):3909-3921.
