In silico molecular modeling of the EGFR exon 20 A763_Y764 insertion mutation. Mutations in this region are predicted to cause significant rearrangement of the C helix (yellow) but do not affect the erlotinib binding pocket directly (erlotinib shown in green). Insertions in EGFR exon 20 that are more distal (3′) are expected to result in a greater obstructive effect on erlotinib binding. These predictions suggest a basis for the observed variability of response to EGFR inhibition in patients with different types of EGFR exon 20 insertions. For details, see article by Arcila and colleagues on page 220.