Figure 4: EGFR L798I mediates rociletinib resistance.

(a) An acquired EGFR L798I mutation was observed in cis with T790M in progression plasma from CO34. The allele fraction of each mutation in pre-treatment and progression plasma is shown. (b) Serial tumour and ctDNA measurements from CO34. Representative CT scans at the time points indicated are provided; the largest target lesion is outlined, and the emergence of a new lesion is indicated with an arrow. The upper panel displays the tumour volume represented by the sum of longest diameters (SLD) of target lesions. The lower panel displays alterations in EGFR detected in plasma. ND, not detected. (c,d) Structural modelling of rociletinib binding to (c) EGFR^T790M and (d) EGFR^T790M/L798I. The EGFR kinase is shown in a ribbon representation (green) with rociletinib in orange. Hydrogen bonding (yellow dashed lines) between the Asp800 residue in EGFR^T790M and the quaternary piperazine NH+ of rociletinib is disrupted in the EGFR^T790M/L798I mutant as a result of increased separation (average distance of 2.8A versus 6.2A in EGFR^T790M and EGFR^T790M/L798I, respectively; red brackets). In the EGFR^T790M/L798I mutant the orientation of Cys797 for reactivity with rociletinib is less optimal due to the loss of stabilizing interactions and other subtle angle changes.