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Schneider Urges Closer Review of Mechanisms of Resistance in Relapsed NSCLC

*April 2024*

Although the use of the tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) is the preferred frontline approach in patients with non-small cell lung cancer (NSCLC) with classic EGFR mutations, acquired resistance mechanisms invariably develop.

“When we think about acquired resistance to TKIs, this is not limited to EGFR and ALK—it is a universal persistent challenge,” Jamie L. Schneider, MD, PhD, said during a presentation at the 21st Annual Winter Lung Cancer Conference, which was held February 2 to 4, 2024, in Hollywood, Florida, and was sponsored by Physicians’ Education Resource, LLC (PER). Schneider is a medical oncologist and assistant in medicine at Massachusetts General Hospital and an instructor in medicine at Harvard Medical School in Boston.

Acquired resistance is characterized by on-target and off-target mechanisms. “The clearest path for overcoming on-target resistance is to leverage a persistent oncogene dependency with an eye toward next-generation TKIs,” Schneider said. For off-target resistance which is more complex given its heterogeneity, solutions lie in bypass pathways, lineage change, and cellular phenotypic changes such as epithelial-mesenchymal transition.1

Resistance mechanisms after first- and second-line osimertinib are quite diverse but similar patterns do emerge. Results of retrospective studies have provided information about the distribution of resistance mechanisms: On-target resistance mechanisms include EGFR amplification and EGFR GT245; off-target resistance mechanisms can be KRAS mutation, MET amplification, BRAF or RET fusions; and transformation mechanisms include small cell, squamous, and pleiomorphic.

From a prospective standpoint, the phase 2 ELIOS trial (NCT03239340) characterized resistance mechanisms arising after first-line osimertinib.2 In the study, 154 patients were enrolled at a median age of 62 years (range, 35-87). At data cutoff patients had disease progression. Median progression-free survival (PFS) was 16.4 months (95% CI, 12.7-20.3).

The main acquired resistance mechanisms according to the investigators, were MET amplification (17%) and EGFR C797S (15%). “The findings underscored the importance of obtaining a biopsy after first-line osimertinib Schneider emphasized.

For off-target resistance, strategies to bypass pathway activation include MET amplification and acquisition of oncogenic fusions Schneider said.3 Specifically, clinical trials that combine EGFR and MET inhibition represent viable approaches. Clinicians can also consider off-label osimertinib plus crizotinib (Xalkori). Read more.