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

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.

Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review

“…However, median OS was significantly longer in Del-19-positive (24.5 months) than in L858R-positive patients (18.1 months; p = 0.002). In a multivariate analysis, EGFR mutation type significantly predicted longer OS (HR 0.43; p = 0.001) [20].…”

“…Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are common in NSCLC and are associated with low levels of tumor cell TS expression [ 17 ], suggesting that pemetrexed would be consistently effective against nonsquamous NSCLC with these genomic alterations. Indeed, multiple studies have shown that pemetrexed is effective against nonsquamous NSCLC with targetable driver mutations [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

Untitled

“…The patients with exon 19 population had better response outcome with gefitinib. [44] Exon 20-mutated NSCLC is an uncommon variant. [45] Even though the numbers were limited, the study by Noronha et al had exon 20 positive patients treated with pemetrexed platinum, paclitaxel platinum, or TKI.…”