Choosing Treatment After Osimertinib for Patients With EGFR-Mutated NSCLC With MET Amplification

• In EGFR-mutated non–small cell lung cancer (NSCLC), treatment with the tyrosine kinase inhibitor (TKI) osimertinib has routinely demonstrated superior survival rates; however, resistance is inevitable.
• MET deregulation, including the amplification of the gene (METamp), is the most common mechanism of osimertinib resistance.
• Dual anti-EGFR/anti-MET inhibition may be an optimal approach upon osimertinib disease progression, with amivantamab-based strategies showing particular promise.

Question: In patients with advanced EGFR-mutated NSCLC, if liquid biopsy shows METamp post–osimertinib treatment, would it be appropriate to consider combination amivantamab?

Answer: Third-generation TKIs have been—so far—the most accepted first-line treatment for EGFR-mutated advanced NSCLC. In the FLAURA trial, osimertinib achieved longer progression-free survival (PFS), overall survival (OS), and intracranial control rates compared with first-generation EGFR TKIs.^1,2 Recently, in the same setting, combination strategies of third-generation EGFR TKI with chemotherapy or amivantamab (an EGFR/MET bispecific antibody) have reported prolonged PFS compared with osimertinib monotherapy; however, OS data are still immature, and worldwide approval of these combinations is not yet standard.^3,4 Therefore, osimertinib as monotherapy remains a standard of care in many countries. However, resistance is inevitable, mostly occurring within 19 months after treatment initiation.^5,6

Platinum doublet chemotherapy is usually offered after progression on third-generation TKIs.⁷ However, characterizing the mechanisms of resistance could provide valuable insights for selecting subsequent personalized treatments, which may favorably impact patients’ outcomes compared with unselected tailored options, and also aid enrollment on clinical trials.⁸ Therefore, rebiopsy is recommended upon third-generation EGFR TKI disease progression, when feasible.⁹

MET deregulation, including METamp, is the most common mechanism of osimertinib resistance, accounting for approximately 25% of cases.¹⁰ Clinical data suggest that acquired METamp is an early event of resistance.¹¹

When METamp occurs at progression on third-generation TKI, dual anti-EGFR/anti-MET inhibition appears to be the optimal approach compared with anti-MET alone.¹² Phase 1/2 clinical trials testing a MET TKI in combination with osimertinib report an overall response rate (ORR) of up to 50% and a median PFS of 5.0 months (Table).^12-14 Confirmatory phase 3 trials like SAFFRON (NCT05261399) that are comparing dual TKIs with platinum pemetrexed chemotherapy are ongoing. However, in the other phase 3 trial testing the same approach, GEOMETRY-E (NCT04816214), enrollment was halted based on business considerations of the funding company; the randomized part was not initiated. Read more.