Amivantamab-Lazertinib‘s Potential to Reshape NSCLC Treatment & the Importance of Ongoing Monitoring
The treatment landscape for EGFR-mutated non-small cell lung cancer (NSCLC) is evolving, with a focus on therapies that can delay or prevent the advancement of resistance. Currently,osimertinib is a standard first-line treatment,but most patients eventually experience disease progression. Research suggests that introducing a therapy addressing potential resistance mechanisms earlier in the treatment course may prolong the time patients remain on treatment and ultimately improve outcomes.
Recent data highlights the potential impact of amivantamab-lazertinib in this context, demonstrating a meaningful reduction in the emergence of acquired EGFR and MET resistance alterations compared to osimertinib alone. This finding has implications for both second-line treatment strategies and long-term disease management.
Historically, progression on osimertinib often led to the development of specific EGFR resistance mutations, such as C797S, L718x, and G724X. Clinical trials are underway to target these specific mutations, but the use of amivantamab-lazertinib appears to shift the landscape, possibly reducing the prevalence of these pathways and opening opportunities for exploring choice therapies like those targeting HER2 amplifications, which were observed more frequently after osimertinib progression. Similarly, a lower incidence of MET expression was observed with the combination therapy, potentially delaying rapid progression seen in some patients treated with osimertinib.
However, the data also reveals a crucial point: osimertinib treatment is associated with increased mutational heterogeneity upon progression. This means a wider variety of genetic alterations can emerge, complicating subsequent treatment decisions. This underscores the critical importance of re-biopsy and complete retesting for mutations at the time of progression. Identifying these new alterations allows physicians to tailor treatment strategies, potentially utilizing targeted therapies specific to the newly identified mutations.
The increased heterogeneity observed with osimertinib can also include loss of TP53 and/or RB1, potentially increasing the risk of small cell transformation, requiring a shift in treatment approach.
while amivantamab-lazertinib appears to decrease this heterogeneity, leading to more predictable progression patterns and potentially supporting the use of chemotherapy as a second-line option, retesting remains essential regardless of the initial treatment pathway to confirm the specific mutations present and guide subsequent therapy choices.
