Shades of T790M: Intratumor Heterogeneity in EGFR-Mutant Lung Cancer

Abstract

In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechanisms of drug resistance. The authors provide a new paradigm for using quantitative assessment of the EGFR T790M:activation mutation allele frequency ratio to prognosticate responses to rociletinib and also demonstrate that plasma-based assessments of circulating tumor DNA can be used to monitor drug response and the emergence of drug resistance.

Figure 1. Schematic representation of acquired resistance to the third-generation EGFR inhibitor, rocelitinib

A first- or second-generation EGFR TKI eliminates the majority of EGFR TKI naïve clones with EGFR activating mutations (e.g. EGFR exon 19 deletion, EGFR L858R). After acquiring resistance to 1^st/2^nd generation EGFR TKIs (Acquired Resistance 1, AR1), both T790M positive and T790 wild-type clones may co-exist within in the “T790M positive” tumor, since at present, only a binary assessment for reporting T790M mutational status (T790M present/T790M absent) is used in a clinical setting. The original activating EGFR mutation is thought to be present in all the cells. Within the AR1 tumor, the T790 wild-type clones presumably harbor other (non-T790M) resistant mechanisms such as PI3K mutation, HER2 amplification, IGF-1R activation, small cell transformation, etc. The heterogeneous “T790M positive” tumor can be effectively treated with a third-generation EGFR TKI, such as rocelitinib, which has documented efficacy against EGFR activating and T790M mutations. After acquiring resistance to the 3^rd generation EGFR TKI (Acquired Resistance 2, AR2), some tumors will have T790M dominant resistance, with the original T790M clones now harboring additional alterations which mediate resistance to the 3^rd-generation EGFR TKI. In contrast, some tumors will have T790 wild-type (WT) resistance, with outgrowth of clones which contain the original EGFR mutation but lack T790M.