Treatment Courses for Third Generation EGFR TKI Resistance in Lung Cancer

At the virtual 2021 Personalized Therapies in Thoracic Oncology meeting, Lyudmila Bazhenova, MD, UC San Diego Moores Cancer Center, discussed managing resistance to third-generation EGFR tyrosine kinase inhibitors (TKI) for lung cancer.

Dr Bazhenova highlights two main categories of acquired resistance: on-target resistance and off-target resistance. She explained that on-target resistance happens when the tumor develops additional genetic alterations in the primary oncogenic target, such as secondary point mutations or gene amplification. Off-target resistance is when a tumor upregulates bypass signaling pathways through activation of alternative receptor tyrosine kinases, which leads to a change in tumor histology, increased growth factor production, or overexpression of drug efflux pumps.

“Resistance to osimertinib varies with line of therapy,” explains Dr Bazhenova, “if patients develop resistance after osimertinib used in first line you see less EGFR mediated resistance, more off-target resistance, similar rates od transformation, we also see more unknown mechanism of resistance.”

One of the most common resistance mechanisms to first-line osimertinib is the presence of the C797S mutation. Osimertinib, as well as afatinib, bind to C797S. Thus, a mutation in C797S inhibits the covalent binding of afatinib or osimertinib to the EGFR protein, therefore mediating resistance to second and third-generation EGFR inhibitors. However, first-generation inhibitors such as erlotinib and gefitinib are not affected because they have a different binding site.

Although the management of C797S mutation includes changing to first-generation TKI, this differs if a patient develops C797S after second-line osimertinib - meaning the patient also has a T790M mutation.
“In this situation, it would be important to know if your T790M and C797S are in trans [on different alleles] or in cis [on the same allele]. If the mutation is in trans, that would be sensitive to first and third-generation TKI, if the mutation is in cis then that would be resistant to your first and third-generation EGFR TKI”, informed Dr Bazhenova.

However, new compounds such as partritumab deruxtecan, a HER3 antibody-drug conjugate using topoisomerase I inhibitor payload, demonstrate promising results. In a study with 44 patients who recieved prior osimertinib therapy,  partritumab deruxtecan demonstrated an overall response rate (ORR) of 39%, a median duration of response (DOR) of 7.0 months, and a median progression-free survival (PFS) of 8.2 months. Responses were observed regardless of the resistance mechanism.
Another treatment in development, amivantamab, targets EGFR and cMET receptors with the potential to provide clinical benefit to TKI-resistant patients. In a study involving 58 patients with EGFR NSCLC, 28% of patients with different types of resistance saw a partial response.

“We have new exciting compounds such as amivantamab and partritumab deruxtecan, and in some patients localized therapy is appropriate,” concluded Dr Bazhenova. —Alexandra Graziano