Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma

Abstract

ObjectiveOral tyrosine kinase inhibitor has been shown to prolong progression-free survival (PFS) in epidermal growthfactor receptor (EGFR) mutation positive adenocarcinoma; however, the comparator arm has not included the current standard adenocarcinoma regimen (pemetrexed carboplatin induction followed by maintenance pemetrexed) and patients from Indian subcontinent. Hence, this study was carried out in Indian patients to compare gefitinib with the above-mentioned chemotherapy regimen.MethodsThis was an open-labelled, randomised, parallel group study comparing gefitinib (250 mg orally daily) with pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) doublet intravenous induction chemotherapy regimen followed by maintenance pemetrexed (500 mg/m2) in patients with EGFR-activating mutation-positive stage IIIB or stage IV adenocarcinoma lung in the first-line setting. The primary endpoint for the study was PFS. 260 patients were required to demonstrate a 50% improvement in PFS of gefitinib over chemotherapy, with 80% power and 5% type 1 error. With an expected 5% dropout rate, the sample size was 290 patients.ResultsThe median PFS in gefitinib arm was 8.4 months (95% CI 6.3 to 10.5 months) compared with 5.6 months (95% CI 4.2 to 7.0 months) in pemetrexed–carboplatin arm (HR: 95% CI 0.513 to 0.851; p −0.001). The impact of gefitinib on PFS was seen across all subgroups. There was no statistically significant difference in overall survival between the two arms. Haematologicalgrade3–4toxicities likeanaemia,neutropaenia and thrombocytopaenia were common in the pemetrexed–carboplatin arm while grade3–4 acneiform rash and diarrhoeawere common in the gefitinib arm.ConclusionThe study confirms the superiority of gefitinib in prolonging PFS against the most active chemotherapy regimen of pemetrexed–carboplatin followed by maintenance pemetrexed in EGFR-mutated lung adenocarcinoma. The median PFS in Indian patients in gefitinib arm is similar to that reported in east Asians and Caucasians.

Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors

“…Most importantly, skin toxicities influence anti-cancer therapies adherence of patients. Gefitinib induced skin toxicity led to drug interruption of 6.9% patients (4). Herein, skin adverse events perhaps present the greatest concern with EGFRIs use.…”

Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis

“…Despite being substrates for P-gp efflux, it was demonstrated that erlotinib [33] and gefitinib [34] enter brain metastatic parenchyma, and numerous case reports show prolonged survival and positive outcomes using these first-line EGFR-tyrosine kinase inhibitors [35,36]. Gefitinib has been shown to be superior to carboplatin-pemetrexed therapy in prolonging progression-free survival in EGFRmutated brain metastases [37]. However, in our in vitro study, PC-9-Br showed significant resistance to gefitinib.…”

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

“…We completed a single-centre, phase-3, double arm, parallel-group, open-label exploratory randomised study comparing pemetrexed with carboplatin and oral TKI in EGFR mutation positive lung cancer patients (Clinical trial registry of India: CTRI/2015/08/006113). We have reported its results [ 10 ]. This was a post hoc analysis planned with a primary objective to compare the progression-free survival between exon 19 deleted and exon 21L858R-mutated cohort when treated with pemetrexed carboplatin.…”