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When the newest targeted pill stops working, what happens next depends on whether the tumour kept the mutation the pill was chosen for. Two thirds lost it, and those patients relapsed much sooner and by many different routes.
Patients with advanced non-small-cell lung cancer who received osimertinib for T790M-positive acquired resistance to a prior EGFR inhibitor were identified from a multi-institutional cohort of 143 and a confirmatory trial cohort of 110, with next-generation sequencing of tumour biopsies after resistance and plasma cell-free DNA genotyping as an orthogonal approach. Of 41 patients with tumour sequencing after resistance, 13, 32%, maintained T790M, and EGFR C797S was seen in 9, 22%. Among the 28, 68%, with loss of T790M, a range of competing mechanisms was detected including acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter with T790M loss, 6.1 against 15.2 months, suggesting emergence of pre-existing resistant clones, a finding confirmed in the plasma validation cohort. In serial plasma, loss of T790M at resistance was associated with a smaller decrease in the driver EGFR mutation level after one to three weeks of therapy, 100% against 83% decrease.
It changed how resistance is investigated: the first question at progression on osimertinib is whether T790M is still there, because losing it means the tumour is no longer EGFR-driven in the growing compartment and another EGFR inhibitor will not help.
Shares EGFR C797S (and its phase with T790M), EGFR T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Resistance routes: how a blocked pathway comes back.
Shares Biopsy, Guardant360 CDx, Cell-free DNA (cfDNA), MET.
Shares Biopsy, Cell-free DNA (cfDNA), JAMA Oncology, MET.
Shares EGFR T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease.
Shares Pasi A. Jänne, EGFR T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Resistance routes: how a blocked pathway comes back.
Shares EGFR T790M, Drug-tolerant persister cells, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Pasi A. Jänne, Resistance routes: how a blocked pathway comes back, MET, Drug resistance (primary and acquired).
Shares EGFR T790M, Biopsy, Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease.