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08-08-2018 | Article

Expert comment

H Jack West

Comment on: Molecular mechanisms of acquired osimertinib resistance explored

The Oxnard study provides a few important insights in a setting that has continued to evolve. The patients in this report had all received osimertinib for T790M-positive acquired resistance, and of course osimertinib is now a new standard of care as first-line treatment for EGFR mutation-positive non-small-cell lung cancer, nearly all of whom will not yet have EGFR T790M mutation at that time. We cannot presume that the mechanisms of acquired resistance on osimertinib will be the same in patients who receive it in the first line for T790M-negative disease with an activating EGFR mutation only.

The paper by Oxnard and colleagues primarily highlights that the mechanisms of acquired resistance to osimertinib are very diverse and are associated with marked differences in the duration of benefit on osimertinib. We may also learn in the future that these mechanisms are associated with different outcomes after progression on osimertinib.

For now, I would consider this work as a significant contribution that will need to be repeated in patients who develop acquired resistance on first-line osimertinib.  Though the median progression-free survival in this setting is about 19 months, we certainly see a lot of variability here, and I have had a few patients in the last several months who have either had primarily refractory disease or a very transient response to osimertinib that lasted less than 3-4 months.  It would be extremely valuable to gain an understanding of why that occurs and whether there are new treatment options that may emerge for these patients.