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M. Mariotti
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-006 - Role of TP53 Mutations in Determining Primary Resistance to First-Line Tyrosine Kinase Inhibitors in EGFR-Mutated NSCLC Patients (ID 3861)
14:30 - 14:30 | Author(s): M. Mariotti
- Abstract
Background:
Patients with non-small-cell lung cancer (NSCLC) carrying specific mutations at epidermal growth factor receptor (EGFR) gene are usually sensitive to treatments with tyrosine kinase inhibitors (TKIs). However, not all EGFR-mutated patients respond equally to TKI treatments, and approximately 20-30% show primary resistance. Although the mechanisms responsible for acquired resistance are known, those responsible for primary resistance are not completely understood. In this study we aimed to assess the role of TP53 mutations in a cohort of advanced EGFR-mutated NSCLC patients receiving first-line TKIs. We analyzed TP53 gene status in relation to outcome in terms of overall response rate, disease control rate (DCR), response duration, progression free survival (PFS) and overall survival (OS).
Methods:
We retrospectively analyzed 136 patients with advanced EGFR-mutated NSCLC treated with first-line TKIs from January 2012 to April 2015. Exons 5-8 of TP53 gene were amplified by PCR and sequenced by direct sequencing on 123 patients. DCR was defined as the sum of complete response, partial response and stable disease. The survival endpoints examined were PFS and OS. PFS was defined as the time from start of first-line treatment to disease progression or death, whichever occurred first. OS was defined as the time from start of first-line treatment to death.
Results:
TP53 mutations were observed in 37 (30.1%) patients:10 (27.0%), 6 (16.2%), 9 (24.3%) and 12 (32.4%) in exons 5, 6, 7 and 8, respectively. DCR was 70% in TP53-mutated patients compared to 88% in TP53-wt patients (relative risk, RR: 3.17 [95% CI 1.21-8.48], p=0.019). In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation compared to 87% in exon 8 wt patients (RR 9.6 [2.71-36.63], p<0.001). Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared to other patients (4.2 months vs 12.5 months [p=0.058] and 16.2 months vs 32.3 months [p=0.114], respectively); these differences became significant in the subgroup of patients with EGFR exon 19 deletion (4.2 months vs 16.8 months [p<0.001] and 7.6 months vs not reached [p=0.006], respectively), hazard ratio (HR) 6.99 (95% CI 2.34-20.87, p<0.001) and HR 4.75 (95% CI 1.38-16.29, p=0.013), respectively.
Conclusion:
TP53 mutations, in particular exon 8 mutations and those defined as nondisruptive, reduce responsiveness to TKI treatment and induce a worse prognosis in EGFR-mutated NSCLC patients, especially in those carrying exon 19 deletions.
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P3.02b-035 - Cell Free Tumor DNA to Monitor Response to Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Non-Small Cell Lung Cancer (ID 4038)
14:30 - 14:30 | Author(s): M. Mariotti
- Abstract
Background:
Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcome of EGFR mutant non-small-cell lung cancer (mEGFR-NSCLC) patients. Monitoring the presence of EGFR sensitizing and resistance (such as T790M) mutations in response to treatment may have a clinical impact on the therapeutic strategy. Detecting these alterations in circulating free tumor DNA (cftDNA) can be an easier and more safe way to obtain information about the EGFR mutational status.
Methods:
Analyses have been conducted in NSCLC patients with a tissue-confirmed EGFR mutation, treated in first-line setting with TKIs. EGFR-sensitive and EGFR exon 20 mutations were analyzed in cftDNA extracted from plasma collected at baseline, after 8 and 20 days’ treatment, and every 4 months of therapy until progression. EGFR analyses were performed using PANAmutyper kit (PANAGENE).
Results:
Of the 16 mEGFR-NSCLC patients treated with first-line TKIs to date (4 with gefitinib, 2 with erlotinib and 10 with afatinib), 9 (56%) showed EGFR-sensitivity mutation at baseline in cftDNA: 6 had an exon 19 deletion, 1 an exon 21 L861Q mutation and 2 an exon 21 L858R mutation synchronous to exon 20 mutations (one insertion and one T790M point mutation). In these 2 last patients, exon 20 mutations were not identified in tumor tissue. The baseline mutation became undetectable in cftDNA in all the 6 patients with EGFR exon 19 deletion at different time point from the beginning of TKIs: in 5 patients after 21 days and in 1 after 8 days. All these patients had partial response at the first radiological evaluation. The subject harboring EGFR L858R mutation synchronous to exon 20 insertion was responsive to TKI and showed the disappearance of exon 20 insertion in cftDNA a the first clinical evaluation, whereas EGFR L858R disappeared after 4 cycles of treatment. Patient with EGFR L858R and T790M didn’t respond to TKI and progressed after 2 months of treatment. At present 3 out of 9 patients progressed but only one showed appearance of T790M in cftDNA during TKI. In the 7 mEGFR-NSCLC with undetectable cftDNA mutation at baseline no changes were seen during treatment.
Conclusion:
EGFR mutation analysis in cftDNA could give important information concerning the activity of TKIs. In particular the disappearance of mutation in cftDNA may be an early parameter of response that has to be validated in prospective trials. Moreover, cftDNA may give integrative information with respect to that obtained from tissue analysis, bypassing the problem of tumor heterogeneity.
