Emergence of a RET V804M Gatekeeper Mutation During Treatment With Vandetanib in RET-Rearranged NSCLC

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

“… 15 , 16 Although rare, RET mutation-mediated resistance to MKIs has been previously reported in single patients (e.g., RET V804M gatekeeper mutations and RET S904F), mechanisms underlying resistance to selective RET TKIs remain unknown. 17 - 20 Understanding these mechanisms is critical to enable the design of next-generation therapies that can overcome resistance.…”

Emergence and Targeting of Acquired and Hereditary Resistance to Multikinase RET Inhibition in Patients With RET-Altered Cancer

“…To our knowledge, case 1 is the second patient with NSCLC to be described as having an acquired RET gatekeeper mutation after prior anti-RET MKI treatment and the first to be treated successfully with RET-targeted therapy. 14 To our knowledge, this is also the first published report of a patient with hereditary RET V804M-mutant MTC treated successfully with RET-targeted therapy. For both patients, integration of preclinical RET target inhibitory activity with the actual exposures safely achieved at the recommended phase II dose of 160 mg twice a day allowed more than IC 90 calculated target coverage of both wild-type and gatekeeper-mutated RET in patients ( Figs 1B and 2B ).…”

“… 13 Two other reports described the emergence of RET kinase domain mutations (RET V804M and RET S904F) each in a single patient with RET fusion-positive NSCLC during treatment with the anti-RET MKI vandetanib. 14 , 15 Their overall frequency and clinical actionability are not clear.…”

Therapeutic strategies in RET gene rearranged non-small cell lung cancer

“…Perhaps even more impactful is the ability for liquid biopsy to detect acquired RET mutations that are acquired as resistance alterations to targeted therapy. These mutations include RET V804 gatekeeper mutation, solvent front mutations G810S/R/C, and acquired alterations in other genes such as EGFR, BRAF, PIK3CA, and others [ 21 , 24 , 25 ].…”