Suresh Ramalingam, MD: We know that for patients with an exon 19 or exon 21 EGFR mutation, EGFR TKI [tyrosine kinase inhibitor] is the preferred frontline therapy. Multiple studies have shown that EGFR TKI is superior to chemotherapy. With that development, the next question becomes, what is the most effective frontline EGFR inhibitor?
The first-generation drugs, erlotinib and gefitinib, have been around for a while, and we also have the second-generation irreversible EGFR inhibitors in the form of afatinib and dacomitinib. And all of these drugs have demonstrated efficacy and are FDA approved as frontline therapy. Osimertinib is the third-generation EGFR inhibitor that not only inhibits exon 19 and exon 21 mutations, but it also inhibits the T790M mutation, which is the most common escape resistance mechanism when patients get first- or second-generation EGFR inhibitors.
We know that osimertinib works in patients who have developed acquired resistance based on T790M. But the next question was, what would osimertinib’s role be if it’s moved up to the frontline setting? And that was addressed by the FLAURA study. We conducted this randomized trial in a global setting comparing osimertinib to either erlotinib or gefitinib; 556 patients were enrolled in this trial and the primary endpoint was progression-free survival [PFS].
What we have already reported is that the median PFS was improved with osimertinib to 18.9 months from 10.2 months in the control group. This represented a 54% reduction in the risk of hazard with a highly significant P value. We also showed that osimertinib had better CNS [central nervous system] activity in the FLAURA trial compared to the first-generation drugs. In addition, there was a good tolerability profile more favorable to osimertinib. So based on all of these indices, osimertinib is now approved in the United States for frontline treatment, and other parts of the world, for EGFR exon 19 or 21 deletion mutation.
The NCCN [National Comprehensive Cancer Network] guidelines note that osimertinib is the preferred frontline option. The question that has not been answered yet in the FLAURA study is, what is the impact of osimertinib versus erlotinib or gefitinib on overall survival? The overall survival endpoint was not mature at the time of the initial FLAURA report. But now we know that FLAURA has met the overall survival endpoint showing superiority for osimertinib versus gefitinib or erlotinib. And the full results will be unveiled at an upcoming meeting.
What would be answered by this is that not only are we seeing improvement in progression-free survival but overall survival with osimertinib, which will further firm up the frontline options for patients with EGFR-mutated disease. This allows us to then start looking into, what are the potential resistance mechanisms when patients get first-line osimertinib and how do we overcome that resistance and potentially even delay the resistance by developing novel combination approaches?
There are already studies being initiated to combine osimertinib with bevacizumab since that combination approach has been shown to be beneficial in randomized trials with earlier generations of TKIs. There is also a study to combine osimertinib with chemotherapy for patients with EGFR-mutated disease. So I think the overall survival results of the FLAURA study will have unveiled the next strategies to take the outcome for patients with EGFR-mutated disease to the next higher level.
I’m very optimistic, particularly since we already know from the press release from AstraZeneca that the study has met its survival endpoint. That has been the open question. We saw at a relatively early phase of maturity of the data that the trend for overall survival was more favorable with osimertinib. Now it’ll be good to see the full results with the median survival numbers for osimertinib and the comparators, the final safety data, and also the hazard ratio for overall survival.
Transcript Edited for Clarity