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D. Giannarelli
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P1.10 - Poster Session 1 - Chemotherapy (ID 204)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.10-032 - Sensitivity and meta-regression analysis exploring potential outcomes predictors in randomized trials (RCTs) evaluating the benefit of 1st-line tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma. (ID 1670)
09:30 - 09:30 | Author(s): D. Giannarelli
- Abstract
Background
Patients affected by lung adenocarcinoma carrying a EGFR sensitizing mutation of significantly benefit from TKIs in terms of progression free survival (PFS), activity and symptoms control. The potential predictive role of clinico-pathological predictors should be investigated in order to optimize the benefit of the currently available drugs.Methods
A literature-based meta-regression and sensitivity analyses to investigate the differential effect of TKIs according to demographic and molecular factors, was accomplished, analyzing all RCTs exploring TKIs versus chemotherapy for 1[st]-line treatment of patients affected by EGFR mutant NSCLC.Results
9 trials (3,741 patients) were identified (EGFR mutant: 1,797). 9 RCTs were evaluable for PFS (1,790 patients) and response (1,733 patients); 7/9 for survival (1,075 patients). With regard to PFS and response, a significant interaction according to ethnicity (Asian versus Caucasian versus mixed, p=0.006 [Cochrane-Q 10.275] and p=0.047 [6.129], respectively), and trial design (retrospective versus prospective EGFR analysis, p=0.024 [5.067] and p<0.0001 [13.633]), was found. No difference was observed in term of survival. A significant interaction for response was found, with an Odds Ratio in favour of afatinib, erlotinib and gefitinib (versus chemotherapy) of 2.70 (95% CI 2.11-3.45), 2.67 (95% CI 1.81-3.93) and 1.81 (95% CI 1.46-4.78).Interaction [Cochrane-Q] P value Interaction [Cochrane-Q] P value PFS Response Overall (ERL vs GEF vs AFA) [4.266] p=0.188 [9.924] p=0.007 ERL vs AFA [3.321] p=0.068 [0.056] p=0.813 ERL vs GEF [9.714] p=0.054 [5.169] p=0.023 AFA vs GEF [0.002] p=0.962 [7.351] p=0.007 Conclusion
Although limited by the retrospective nature and the heterogeneity, these data indicate a differential effect of TKIs according to the design and the ethnicity, and in response according to TKIs. These data may constitute the background to develop a clinical predictive model to better estimate the expected benefit when using EGFR TKIs in patients with EGFR mutant NSCLC
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P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.06-028 - ERCC1 mRNA expression and KRAS mutation status in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (ID 2405)
09:30 - 09:30 | Author(s): D. Giannarelli
- Abstract
Background
In a previous report of EGFR WT advanced NSCLC patients treated with first-line platinum-based chemotherapy we observed a worse clinical outcome for KRAS-mutants compared with KRAS WT patients (Metro et al. ESMO 2012). Here, we assessed whether this phenomenon could be due to different levels of ERCC1 expression.Methods
From a prospectively maintained database of EGFR WT advanced NSCLC patients diagnosed at a single Institution between January 2006 and November 2012, we identified the individuals who had a known KRAS mutation status and tissue available for assessment of ERCC1 mRNA expression. Total RNA was isolated from paraffin-embedded tumor specimens using RNeasy Mini kit and automatically purified by QiaCube instrument (Qiagen). Quantification of mRNA expression levels of ERCC1 was analyzed by real-time one-step RT-PCR using QuantiFast technology by RotorGeneQ instrument (Qiagen), and the results were compared considering β-actin as the internal reference gene.Results
One hundred and eleven patients were evaluable, 60 of which were KRAS-mutants. Among KRAS-mutants, the rate of codon 12/13/61 mutations were 80%/13.3%/6.7% respectively. Baseline patients characteristics were as follows: median age was 62 years (35-84), 36.9% were male, 63.9% were stage IV, 78.3% were PS 0 or 1, 87.3% were ever-smokers, and 71.1% had received a first-line platinum-based chemotherapy. More ever-smokers were present in the KRAS-mutant subgroup compared with WTs (90% versus 76.5%, respectively, P = 0.08). ERCC1 average scores ranged from 0.1 to 26.7, the values being not normally distributed (Kolmogorov-Smirnov test, P<0.0001). Median and mean overall ERCC1 values for all patients were 1.3 and 2.2 [standard deviation (SD) 3.4], respectively. There was no statistically significant difference in terms of ERCC1 median values betwen KRAS-mutants and KRAS WTs (1.4 vs. 1.3, respectively, P = 0.27). Nevertheless, mean ERCC1 expression levels were found to be significantly higher in KRAS-mutants compared with KRAS WTs [2.9 (SD 4.5) vs. 1.4 (SD 0.8), respectively, P = 0.02]. This finding was due to 7 KRAS-mutant patients (ERCC1 high) coming out with ERCC1 levels higher than 5.0, thus notably incresing mean ERCC1 values. In the group of patients treated with first-line platinum-based chemotherapy (n = 79), median progression-free survival was 1.9 months for KRAS-mutant, ERCC1 high patients (n = 6), 5.1 months for KRAS-mutant, ERCC1 low patients (n = 38), and 7.1 months for KRAS WT patients (n = 35) (P = 0.003).Conclusion
KRAS-mutant NSCLCs may express higher levels of ERCC1 compared with KRAS WTs, which could translate into poor sensitivity to first-line platinum-based chemotherapy. Combination strategies of platinum-based chemotherapy plus KRAS-targeting agents may represent an appealing upfront strategy for KRAS-mutants advanced NSCLCs, particularly in presence of concomitant expression of high ERCC1 levels.
