Dr Xia on Common Resistance Mechanisms in NSCLC Following EGFR TKI Failure

“We still have [a] big challenge [with] small cell transformation. We have a lot of unknown [territory] in this area: for example, whether to continue [with] EGFR TKI, whether [an] immune checkpoint inhibitor plays a role, and whether a T-cell engager, [a] DLL3 T-cell engager, plays a role. [These] are all open questions with large unmet clinical needs.”

Yang Xia, MD, PhD, associate professor in the Department of Respiratory Medicine at the Second Affiliated Hospital of Zhejiang University School of Medicine, discussed strategies for delaying and overcoming resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non–small cell lung cancer (NSCLC), including biomarker-selected and biomarker-unselected treatment approaches and open questions around small cell lung cancer (SCLC) transformation.

According to Xia, biomarker-selected strategies for overcoming EGFR TKI resistance remain anchored in mechanisms such as the acquired C797S mutation and MET amplification, though newer, less common mechanisms are emerging. In a multicenter cohort study conducted with Xiuning Le, MD, of The University of Texas MD Anderson Cancer Center, Xia and colleagues found that adding a bypass-pathway inhibitor to the original EGFR TKI produced some activity in patients with acquired receptor tyrosine kinase (RTK) fusions or acquired BRAF V600E–mediated bypass activation, though Xia said outcomes still fall short of what is needed.

For biomarker-unselected resistance, Xia pointed to several approaches with encouraging results: the phase 3 OptiTROP-Lung04 trial (NCT05870319) of the TROP2-directed antibody-drug conjugate sacituzumab tirumotecan, which improved median progression-free survival (PFS) to 8.3 months vs 4.3 months with chemotherapy (HR, 0.49; 95% CI, 0.39-0.62); the global phase 3 HARMONi trial (NCT06396065) of the PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy, which improved PFS vs chemotherapy alone (HR, 0.52; 95% CI, 0.41-0.66); and the phase 3 MARIPOSA-2 trial (NCT04988295) of amivantamab-vmjw (Rybrevant) plus chemotherapy, which improved median PFS to 6.3 months vs 4.2 months with chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64).

Xia said small cell transformation remains a major unmet need in EGFR-mutant NSCLC, with many open questions: whether to continue EGFR TKI therapy through transformation, whether immune checkpoint inhibitors have a role, and whether DLL3-directed T-cell engagers, developed for SCLC, could be applied in this setting. Xia concluded that these represent important areas of unmet clinical need for future research.