Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment

Abstract

In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR-positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (sEGFRma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the sEGFRma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) (P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported.

Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

“…These results therefore do not only support the finding that disappearance of the primary EGFR mutation in plasma is associated with a better outcome in first line [24,25], but also confirm its predictive value in the second line for osimertinib-treated patients with EGFR p.T790M [26]. The concept of losing detectable EGFR mutations in plasma in association with better outcome was recently also demonstrated at other centers [26], but often with less sensitive techniques (e.g., Cobas ® ) than our NGS panel [25,27], or cross-sectional at a single time point rather than sequentially analyzed as a change in time [28,29]. In our second line cohort, isolated EGFR p.T790M loss in plasma at week 6 was associated with decreased PFS (5.1 vs. 18.8 months).…”

The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

“…However, still limited data are available correlating results from liquid biopsies with response to molecularly targeted treatment or resistance. Different assays can be used, such as real-time polymerase chain reaction (PCR), digital droplet PCR (ddPCR), and next-generation sequencing (NGS) [ 5 , 6 ]. For the most frequently targeted genes in lung cancer, such as EGFR , a high concordance rate of more than 90% has been shown between alterations detected in liquid biopsy and matched tissue samples [ 7 , 8 ].…”

Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer

“…Buttitta et al evaluated ctDNA dynamics in plasma of EGFR-mutated patients harboring a T790M mutation and treated with osimertinib as second-line therapy [10]. Sixty-four patients were strictly monitored during the first month of therapy, and plasma was analyzed by using the EGFR Cobas test, showing a substantial decrease in sensitizing EGFR mutant allele down to not detectable value in 89% of cases.…”

“…Finally, liquid biopsy could provide interesting insights into response to systemic therapies. Several studies have suggested a correlation between the dynamic modification of ctDNA over time and the objective response to targeted agents or immunotherapy [10][11][12][13][14][15][16][17]. The duration of immunotherapy in long responder patients after two years of treatment is debated.…”