Mechanisms of Resistance: FLAURA2 and MARIPOSA

The most common mechanism of resistance observed after frontline osimertinib treatment can be quite varied, including on-target mutations, off-target mechanisms, and even histologic transformations. Among on-target mutations, alterations such as C797S and mutations at positions 718, 721, and 724 are frequently identified when re-biopsying patients at progression. Amplification of the MET gene is also a prominent resistance mechanism, which underscores the importance of therapies targeting MET as part of frontline or subsequent treatment strategies. Another challenging resistance pattern is small cell transformation, which can be difficult to detect without a tissue biopsy but may be hinted at by liquid biopsy findings like RB1 and TP53 alterations. Due to the complexities involved, guidelines emphasize the need for tissue biopsies upon progression whenever feasible, complemented by liquid biopsies to gain a comprehensive understanding of resistance mechanisms and guide precision medicine approaches.

In clinical practice, liquid biopsies analyzing circulating tumor DNA (ctDNA) are routinely performed at progression, but tissue biopsies remain crucial, particularly for detecting MET amplification, which current liquid assays may miss. Resistance patterns observed after combination therapies, such as those involving fluoropyrimidine-based regimens, appear to mirror those seen post-osimertinib, with MET amplification continuing to dominate. Interestingly, some patients show no clearly identifiable resistance mutations, highlighting the heterogeneity of resistance biology. This variability presents both challenges and opportunities in tailoring subsequent treatments and reinforces the importance of thorough molecular profiling at resistance.

Recent data from studies like Mariposa provide encouraging insights into how newer combination therapies may alter tumor biology and resistance evolution. Analysis of matched baseline and progression ctDNA samples demonstrated that patients treated with the Mariposa regimen had significantly fewer acquired MET amplifications and EGFR-resistant mutations such as C797S compared to other regimens. Additionally, there was a numerical reduction in TP53 mutations and RB1 loss-of-function alterations, which are linked to small cell transformation. These findings suggest that upfront combination strategies may delay or modify resistance mechanisms, potentially improving long-term outcomes and changing the landscape of precision treatment in this setting.