For patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), dual inhibition of EGFR and MET may be the most effective strategy after disease progression on osimertinib, particularly for patients with MET gene amplification (METamp). Dr. Benjamin Besse, Dr. Lodovica Zullo, and Dr. Jordi Remon from the Gustave Roussy Institute analyze therapeutic strategies for METamp-driven resistance following osimertinib treatment in this article.

To date, third-generation tyrosine kinase inhibitors (TKIs) are the most widely recognized first-line treatment for advanced EGFR-mutated NSCLC. In the FLAURA trial, osimertinib demonstrated longer progression-free survival (PFS), overall survival (OS), and improved intracranial control compared to first-generation EGFR-TKIs. The MARIPOSA study revealed that a combination strategy of third-generation EGFR-TKI plus chemotherapy and Amivantamab (a bispecific EGFR/MET antibody) extended PFS compared to osimertinib monotherapy, although OS data remains immature and the combination therapy has not yet been globally approved as a standard treatment. Thus, osimertinib monotherapy remains the standard treatment in many countries; however, resistance typically emerges within 19 months of TKI initiation.

Historically, platinum-doublet chemotherapy was the go-to option after progression on third-generation TKIs. However, with the emergence of targeted therapy, personalized treatment based on resistance mechanisms has shown favorable impacts on treatment outcomes and helps guide clinical trial enrollment. Therefore, rebiopsy is recommended upon progression on third-generation EGFR-TKIs when feasible.

MET Dysregulation in Resistance

MET dysregulation, including MET amplification (METamp), accounts for approximately 25% of cases of resistance to osimertinib. Clinical data suggests that acquired METamp is an early event in resistance. When METamp occurs after third-generation TKI treatment, dual inhibition of EGFR and MET appears to be more effective than using MET inhibitors alone. Phase I/II trials have shown that combining MET-TKI with osimertinib resulted in an overall response rate (ORR) of 50% and a median PFS of 5.0 months. Validation trials such as SAFFRON (NCT05261399) are comparing osimertinib plus MET-TKI with platinum/pemetrexed chemotherapy. However, recruitment for the GEOMETRY-E (NCT04816214) trial has been paused.

Studies with Amivantamab-Based Therapies

In the context of progression on osimertinib, the Phase III MARIPOSA-2 trial demonstrated that combining Amivantamab with chemotherapy ± Lazertinib significantly extended PFS compared to chemotherapy alone. Specifically, PFS for the Amivantamab/chemotherapy group was 6.3 months versus 4.2 months in the chemotherapy group (HR=0.48, 95% CI: 0.36-0.64; P<0.001), and in the Amivantamab/Lazertinib/chemotherapy group, PFS reached 8.3 months versus 4.2 months in the chemotherapy group (HR=0.44, 95% CI: 0.35-0.56; P<0.001). Moreover, the response rate and intracranial PFS were significantly improved in the Amivantamab groups.

Amivantamab has now received FDA approval in combination with Lazertinib as a first-line treatment for patients with common EGFR-mutated advanced NSCLC. It is also approved in combination with carboplatin/pemetrexed for patients who progress on osimertinib. This first-line treatment strategy reduces MET-driven resistance, as demonstrated by ctDNA analysis in the MARIPOSA trial.

Role of Liquid Biopsies

Liquid biopsies can serve as an alternative to tissue biopsies, capturing tumor heterogeneity at the time of disease progression and providing essential information for therapeutic decision-making. Regarding METamp, preliminary studies using liquid biopsy NGS report METamp in up to 15% of cases with osimertinib resistance. However, subsequent findings have been inconsistent. In the CHRYSALIS-2 study, plasma NGS identified only one case of METamp among 87 patients with evaluable plasma samples. However, in the CHRYSALIS trial, five cases of METamp were detected among 45 patients using plasma/tissue NGS. Low concordance between tissue and plasma samples may be attributed to the absence of tumor shedding at the time of disease progression. Although plasma NGS has lower sensitivity for detecting METamp, a positive result is predictive for guiding treatment decisions.

Conclusion and Future Outlook

Considering that dual TKI regimens (EGFR-TKI + MET-TKI) have shown promising results in METamp-driven osimertinib resistance, it is reasonable to assume that targeting both EGFR and MET pathways can be effective. Additionally, Amivantamab exhibits immune activation and potential intracranial activity, with early data supporting its use in METamp tumors after osimertinib progression.

In summary, if liquid biopsy identifies METamp, an Amivantamab-based therapeutic strategy should be considered after osimertinib progression. However, the sensitivity of liquid biopsy for detecting METamp remains a concern. It is worth noting that the recent approval of the Amivantamab + Lazertinib combination as a first-line therapy may reduce the occurrence of METamp as an acquired resistance mechanism in the future.