Author of

• 10801

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  P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 2
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10803

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    P1.11-002 - Toxicity of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) in the Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC): A Meta-analysis (ID 292)

    09:30 - 09:30  |  Author(s): M. Links
    • Abstract

    Background
    We performed a meta-analysis to evaluate the risk of toxic death, treatment discontinuation and grade 3 or 4 (G3/4) adverse events (AEs) of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of advanced non-small cell lung cancer (NSCLC).

    Methods
    Randomized trials comparing EGFR-TKI monotherapy or combination EGFR-TKI-chemotherapy with chemotherapy or placebo were included. We extracted data on toxicity events, and computed pooled relative risks (RR) adjusted for median treatment duration as the ratio of the risks in the EGFR-TKI arm versus the control group. Three treatment comparisons were analysed: EGFR-TKI versus placebo, EGFR-TKI versus chemotherapy, EGFR-TKI-chemotherapy versus chemotherapy. All statistical tests were two-sided.

    Results
    Thirty-five trials (16,507 patients) were included. EGFR-TKI was associated with 1.7% risk of toxic death (95% CI 1.4-2.0). Compared with EGFR-TKI, we demonstrated no difference in risk of toxic death for placebo (RR 1.15, 95% CI 0.08-1.86, p=0.86) or chemotherapy (RR 0.77, 95% CI 0.50–1.16, p=0.22), but higher risk for EGFR-TKI-chemotherapy compared to chemotherapy (RR 4.23, 95% CI 1.12-14.41, p=0.03). The risks of treatment-related discontinuation and G3/4 AEs were lower for EGFR-TKI than chemotherapy (RR 0.41, 95% CI 0.34-0.50, p<0.001; RR 0.35, 95% CI 0.32-0.38, p<0.001 respectively) but higher for EGFR-TKI than placebo (RR 2.43, 95% CI 1.73-3.40, p<0.001; RR 1.18, 95% CI 1.04-1.33, p=0.008) and for EGFR-TKI-chemotherapy than chemotherapy (RR 1.99, 95% CI 1.66-2.39, p<0.001; RR 1.50, 95%CI 1.32-1.70, p<0.001).

    Conclusion
    EGFR-TKI therapy in advanced NSCLC has a low incidence of toxic death and similar safety to chemotherapy with fewer serious AEs. Likelihood of benefit and careful consideration of toxicity profiles should inform treatment selection. Improved toxicity reporting in future trials would allow better quantification of EGFR-TKI-associated toxicity.

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    P1.11-003 - Exon 19 deletions, smoking history and gender as additional predictive factors for treatment benefit with EGFR Tyrosine Kinase Inhibitors in patients harbouring activating EGFR mutations: A Meta-analysis of 1432 patients in six randomised trials. (ID 1789)

    09:30 - 09:30  |  Author(s): M. Links
    • Abstract

    Background
    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now recognised as the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Many studies consistently demonstrated superior tumour response and progression-free survival (PFS) over chemotherapy. However, there are still ongoing questions whether there are any significant differences in treatment outcomes between patients of different ethnicity, gender, age, performance status, smoking history, tumour histology and different subtypes of EGFR mutation. We performed a meta-analysis to assess the impact of these factors on the PFS benefit of EGFR-TKIs in advanced NSCLC patients harbouring activating EGFR mutations.

    Methods
    An electronic search of all randomised controlled trials comparing efficacy of first-line therapy of EGFR-TKI vs chemotherapy in advanced NSCLC patients harbouring EGFR mutation was performed. We extracted the published hazard ratio (HR) and the 95% confidence interval (CI) for PFS, if available, or obtained unpublished data, for subgroups defined by each factor. For each subgroup, pooled estimates of treatment efficacy of EGFR-TKI vs chemotherapy were calculated with the fixed-effects inverse variance weighted method. The predictive effect of each factor was analysed by a test for interaction between the factor and treatment effect; P<0.05 was considered statistically significant. All statistical tests were two-sided.

    Results
    We included 6 eligible studies, with two trials for each of these different EGFR-TKIs - Gefitinib, Erlotinib, and Afatinib – with a total of 1432 patients. As expected, overall the use of EGFR-TKIs in this mutated population significantly prolonged PFS as compared with chemotherapy (HR 0.37, 95% CI 0.32 to 0.43, P<0.001). While mutations at both Exon 19 (deletions) and at Exon 21 (L858R point mutations) were associated with significantly prolonged PFS, the benefit with Exon 19 mutations was greater: HR 0.26, 95% CI 0.21 to 0.31, P<0.001; as contrasted to Exon 21: HR 0.42, 95% CI 0.34 to 0.52, P<0.001 (treatment-EGFR mutation interaction P=0.001). Smoking status also showed differential benefit in this mutated population: never smokers: HR 0.30, 95% CI 0.26 to 0.36, P<0.001; contrasted to current or ex-smokers: HR 0.48, 95% CI 0.37 to 0.61, P<0.001; treatment-smoking history interaction P=0.003). There was also a trend for greater benefit for females with EGFR-TKI therapy as contrasted to males (HR [females] 0.32, 95% CI 0.27 to 0.38, P<0.001; HR [males] 0.42, 95% CI 0.33 to 0.53, P<0.001; treatment-gender interaction P=0.06). Interestingly, several parameters were not significant predictors of PFS benefit with EGFR-TKI treatment in this mutated population: performance status (ECOG 0 and 1 vs 2; interaction P=0.86); age (<65 vs ≥65 years; interaction P=0.58); ethnicity (Asian vs others; interaction P=0.18); and tumour histology (adenocarcinoma vs others; interaction P=0.52).

    Conclusion
    While EGFR-TKIs significantly prolong PFS in all advanced NSCLC patients harbouring classic activating EGFR mutations when compared with chemotherapy, other molecular and demographic factors have a further influence on benefit. Exon 19 deletions, never-smoking history, and possibly female gender were all associated with longer PFS in these patients when treated with EGFR-TKIs as compared with chemotherapy. These findings should enhance better trial design in future clinical trials.