Impact of exon 19 versus exon 21 EGFR-activating mutation on outcomes with upfront pemetrexed-carboplatin chemotherapy.

Vanita Noronha,Amit Joshi,Anant Ramaswamy,Kumar Prabhash,Anuradha Chougule,Ashay Karpe,Nilendu Purandare,Vikas Talreja,Vijay Patil,Amit Janu,Supriya Goud,Abhishek Mahajan,Sucheta More,Rajiv Kumar,Arun Chandrasekharan,Atanu Bhattacharjee,Alok Goel,Nikhil Pande

doi:10.3332/ecancer.2017.776

Vanita Noronha, Amit Joshi + Show 16 more

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https://doi.org/10.3332/ecancer.2017.776

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Journal: ecancermedicalscience	Publication Date: Oct 24, 2017
Citations: 2	License type: cc-by

Affiliation: Tata Memorial Hospital

Abstract

BackgroundEGFR mutation subtype is a recognised factor impacting outcomes of patients receiving oral tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Evidence for the effect of this factor on outcomes in patients receiving pemetrexed is limited.MethodsWe completed a study comparing pemetrexed–platinum combination versus oral TKI in EGFR mutation-positive patients in lung cancer. We analysed the impact of EGFR mutation subtype, specifically, exon 19 and 21 on the PFS and OS of patients treated with pemetrexed (500 mg/m2 on day 1) and carboplatin (AUC 5 on day 1) as first-line therapy. Patients underwent axial imaging for response assessment on D42, D84, D126 and subsequently every two months till progression. Patients post-progression were treated with gefitinib.ResultsFifty-one patients (36%) had exon 21 mutation, while 92 patients (64%) had exon 19 mutation. Response rates in evaluable patients was 47.7% in exon 19 patients (41 patients, n = 86) and 42.9 % in exon 21 patients (18 patients, n = 42). There was a significant increase in median overall survival for patients with exon 19 mutations (24.5 months, 95% CI: 21.3–27.7 months ) over the exon 21-mutated patients (18.1 months, 95% Cl: 13.5–22.6 months, p = 0.002). This differential impact was due to second-line gefitinib having a differential outcome on these mutations.ConclusionPemetrexed-based chemotherapy does not have a differential impact on exon 19- or exon 21-mutated patients. However, second-line treatment with gefitinib has a favourable response and outcome in exon 19-mutated patients.

Highlights

The heterogeneity in EGFR mutations in terms of biology and potential response to treatment has been a work in progress from the time of the discovery of these mutations in non-small-cell lung cancer (NSCLC) [1]
Pemetrexed-based chemotherapy does not have a differential impact on exon 19- or exon 21-mutated patients
Deletion in exon 19 and L858R substitution on exon 21 constitute a majority of these mutations and they predict for a high response rate to tyrosine kinase inhibitors

Summary

Introduction

The heterogeneity in EGFR mutations in terms of biology and potential response to treatment has been a work in progress from the time of the discovery of these mutations in NSCLC [1]. Deletion in exon 19 and L858R substitution on exon 21 constitute a majority of these mutations and they predict for a high response rate to tyrosine kinase inhibitors These mutations were termed as classic activating mutations [2, 3]. Multiple studies have established that upfront tyrosine kinase inhibitors (reversible or irreversible) are the treatment of choice in patients with classic activating mutations. These studies have clubbed exon 19 deletions and exon 21 L858R mutations together [4,5,6]. A recent meta-analysis of over 2500 patients with classic activating mutations reported that patients with exon 19 deletions have better progressionfree survival compared to exon 21 L858R mutations, when treated with irreversible TKIs [8]. Evidence for the effect of this factor on outcomes in patients receiving pemetrexed is limited

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Conclusion