The majority of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC) initially respond to first-line osimertinib (Tagrisso); however, acquired resistance to this tyrosine kinase inhibitor (TKI) is almost inevitable. Understanding and addressing these resistance mechanisms is crucial for improving patient outcomes.
Identifying Resistance Mechanisms
According to Timothy F. Burns, MD, PhD, of the University of Pittsburgh and UPMC Hillman Cancer Center, acquired resistance occurs when a patient initially responds to treatment but the disease starts growing again, typically within 6 months to a year or more. He emphasizes the importance of liquid or tissue biopsy at the time of resistance to identify the underlying mechanism.
Vamsidhar Velcheti, MD, of NYU Langone's Perlmutter Cancer Center, notes that resistance mechanisms to third-generation EGFR TKIs like osimertinib are highly heterogeneous. These mechanisms include secondary EGFR mutations (on-target) that reduce osimertinib's effectiveness, and mutations outside of EGFR (off-target), such as MET amplifications.
One of the most common resistance mechanisms is the C797S mutation. FLAURA trial data indicated that approximately 7% of patients acquired this mutation in plasma samples. Other mechanisms include EGFR amplification, MET amplifications, HER2 amplification, and KRAS mutations. Histologic transformation to small cell lung cancer or squamous cell NSCLC can also occur.
Current Treatment Options
If sequencing does not reveal MET or RET amplification or other targetable alterations in patients resistant to osimertinib, the next line of standard care involves another EGFR-targeting agent in combination with chemotherapy. Amivantamab (Rybrevant), a bispecific antibody targeting both EGFR and MET, is a viable option in this setting.
Amivantamab received FDA approval in combination with carboplatin and pemetrexed for patients whose disease progressed on or after an EGFR inhibitor. The MARIPOSA-2 trial demonstrated significantly improved progression-free survival (PFS) with amivantamab-chemotherapy compared to chemotherapy alone. Burns noted a 64% response rate in these patients. Amivantamab monotherapy after osimertinib has shown approximately a 30% response rate in studies.
Emerging Strategies
The antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) is a promising treatment for EGFR inhibitor-resistant disease. The hypothesis is that tumors resistant to EGFR TKIs tend to increase HER3 expression. In the HERTHENA-Lung02 trial, HER3-DXd significantly improved median PFS versus chemotherapy in patients with metastatic EGFR-mutated NSCLC who had previously received an EGFR inhibitor.
Datopotamab deruxtecan (Dato-DXd), an ADC targeting TROP2, is also under investigation. In the phase II TROPION-Lung05 trial, Dato-DXd elicited a confirmed objective response rate (ORR) of 35.8% in patients with actionable genomic alterations. Among patients with EGFR mutations, the ORR was 43.6%, with a median duration of response of 7 months.
Future Directions
Velcheti emphasizes the need for more data to determine when to continue targeting EGFR and when to switch to other drug classes. The phase II ORCHARD trial will test different agents in combination with osimertinib based on identified TKI resistance mechanisms. These agents include savolitinib, gefitinib (Iressa), Dato-DXd, necitumumab (Portrazza), and other drugs specific to MET alterations or C797X mutations.
Burns concludes that with multiple lines of therapy available, having more treatment options is beneficial for patients with EGFR-mutant NSCLC.
