Managing EGFR, ALK and ROS1 resistance post 3rd generation TKI

S1A – Lung Cancer
MANAGING EGFR, ALK AND ROS1 RESISTANCE POST 3rd GENERATION TKI

Liam Chong Kin
University Malaya Medical Centre, Kuala Lumpur, Malaysia

Osimertinib, a third-generation EGFR-TKI, initially approved for the treatment of patients with EGFR T790M-mediated acquired resistance to first- and second-generation EGFR-TKIs, has become the standard of care for patients with advanced, treatment-naive EGFR-mutant NSCLC. Despite osimertinib’s efficacy, acquired resistance to osimertinib almost invariably develops. On-target resistance occurs via acquisition of additional tertiary mutations in the EGFR kinase domain. Fourth-generation EGFR-TKIs have been specifically designed to overcome the resistance caused by the EGFR C797S mutation. Off-target resistance mechanisms include MET or HER2 amplification, BRAF mutation, activation of the RAS-MAPK or RAS-PI3K pathways, cell-cycle gene alterations, and secondary oncogenic RET, NTRK or ALK fusions. Amivantamab (a bispecific antibody targeting EGFR and MET) plus chemotherapy +/- lazertinib has been shown to improve PFS and intracranial PFS versus chemotherapy in patients with disease progression on osimertinib. Another promising approach is the use of antibody-drug conjugates that target HER3 and TROP2. Phenotypic transformation to squamous or SCLC histology can occur in up to 15% of patients whose disease progresses on first- or later-line osimertinib.

For ALK-rearranged advanced NSCLC, secondary single ALK point mutations are the most common resistance mechanism after first- or second-generation ALK-TKIs while compound ALK mutations are most common after sequential use of earlier generation followed by the third-generation ALK-TKI, lorlatinib. Fourth-generation ALK-TKIs are designed to target this stepwise accumulation of compound mutations. First-line lorlatinib use does not result in compound ALK mutations. 

In ROS1-rearranged NSCLC, G2032R is the most common on-target resistance mutations which confers resistance to not only crizotinib but also to entrectinib and lorlatinib. Promising preclinical activity (repotrectinib and taletrectinib) and clinical efficacy (repotrectinib) against G2032R have been observed with these next-generation ROS1/TRK/ALK-TKIs.