EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study.

Abstract

7522 Background: When EGFR compound mutants (exon 19 deletions or L858R plusT790M) are present at the time of clinical resistance to erlotinib, patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The H1975 cell line, harboring L858R plus T790M prior to treatment, is sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer Discovery 2011), though the compound mutant may become dominant after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med 2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). No differences in OS were observed.123 p with remaining available pre-treatment tumor tissue were re-analyzed for the concomitant presence of the T790M mutation with an allelic discrimination Taqman assay in the presence of a PNA clamp designed to inhibit the amplification of the exon 20 wild-type (wt) allele. This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was 12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy arm (P<0.0001). OS was not reached for p with mutant T790M in the erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt T790M in the chemotherapy arm (P=0.04). Conclusions: Our unexpected finding that p with EGFR compound mutants attain the maximum benefit from erlotinib suggests a need for more sensitive assays to detect EGFR compound mutants and for studies of inhibitors targeting the EGFR T790M mutation. Whole genome sequencing may provide greater understanding of the genetic factors involved in the differences in OS.

Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations

“…In a retrospective analysis of the EURTAC trial, which compared the efficacy of erlotinib versus chemotherapy in patients with EGFR-mutant lung cancer, the median OS of patients with a preexisting T790M mutation was found to be superior to that of patients without a preexisting T790M mutation in both treatment groups. 16 However, in the study by Su et al, there was no difference in survival noted between patients with or without the T790M mutation. 13 In contrast to prior studies, the current study revealed that patients with T790Mnegative tumors had inferior survivals compared with patients with T790M-positive tumors.…”

“…Chemotherapy), which used TaqMan assay in the presence of a peptide nucleic acid clamp, detected the mutation in 47 of 123 patients (38.2%). 15,16 More recently, Su et al provided data regarding the T790M mutation frequency by using a next-generation sequencing (NGS) method as a validation test. 13 In that study, the investigators compared mass spectrometry (MS) genotyping assays with standard direct sequencing in terms of the ability to detect T790M mutations present at a low frequency in tissue samples obtained before and after EGFR-TKI therapy.…”

Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition

“…After prolonged exposure to EGFR-TKIs, the T790M mutant allele becomes enriched, resulting in AR to EGFR-TKIs (1). Rosell et al (5) reported that among AR NSCLC patients, T790M-positive patients had better outcomes (longer PFS and OS) than T790M-negative patients when treated with chemotherapy, indicating that tumors with AR due to the T790M mutation are more sensitive to chemotherapy. Kuo et al (4) observed that patients with AR to EGFR-TKIs Figure 3.…”

“…Previous studies have revealed that chemotherapy efficacy may depend on the underlying mechanisms of AR to EGFR-TKIs. Rosell et al (5) observed that in patients with secondary T790M, tumors were more sensitive to Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition chemotherapeutic drugs, thus prolonging progression-free survival (PFS) and overall survival (oS). In contrast, NSCLC cells with EMT and patients with EMT-positive tumors were less sensitive to chemotherapy or radiotherapy (6).…”

Differential MicroRNA Expression between EGFR T790M and L858R Mutated Lung Cancer

“…Some studies revealed that patients who acquired the EGFR T790M mutation after TKI therapy had longer survival, suggesting that the T790M mutation may be related to indolent biology and slow tumor growth [ 32 , 33 ]. In the EURTAC (EURopean TArceva vs Chemotherapy) study, the survival of patients with a pre-existing T790M mutation was superior to that of patients without it [ 34 ]. Fujita et al .…”