Patients with untreated advanced EGFR-mutant non–small cell lung cancer showed an improvement in progression-free survival with the combination of gefitinib, a TKI that targets EGFR, with carboplatin plus pemetrexed compared with gefitinib alone, according to the results of the NEJ009 study.
Patients with untreated advanced epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer showed an improvement in progression-free survival (PFS) with the combination of gefitinib (Iressa), a tyrosine kinase inhibitor (TKI) that targets EGFR, with carboplatin plus pemetrexed compared with gefitinib alone, according to the results of the NEJ009 study.
The PFS seen in individuals who received the gefitinib combination was 20.9 months compared with 11.9 months in the gefitinib monotherapy group (HR, 0.49; 95% CI, 0.39-0.62;P< 0.001). There was also a better overall response rate (ORR) in patients who received the combination. The combination group had an ORR of 84% compared with 67% in the monotherapy group (HR, 0.72; 95% CI, 0.55-0.95;P<.001).
The study randomized 345 subjects with newly diagnosedEGFR-mutant NSCLC to either gefitinib (250 mg) oral, once a day, plus carboplatin (AUC 5) and pemetrexed (500 mg/m2) given in a 3-week cycle, or 250 mg of gefitinib alone given orally on a daily basis. These treatment protocols continued until progressive disease evaluated by RECIST version 1.1 criteria. The goal of the study was primarily to evaluate PFS, PFS2, and overall survival (OS). The secondary end points were ORR and quality of life (QOL). Patients were from 47 different locations across Japan and were followed from 2011 to 2015.
Patients between the ages of 20 and 75 were eligible to enroll in the NEJ009 study if they had a histological diagnosis of NSCLC (squamous cell carcinoma). Individuals with postoperative recurrence were also eligible. Additionally, patients were required to have an ECOG performance status of 0 to 1, normal marrow, liver, and renal function and a life expectancy of 3 months or more.
The key exclusion criteria included the presence of a gene mutation that resists EGFR, present symptomatic brain metastasis, interstitial pneumonia or pulmonary fibrosis, and having had radiotherapy for the primary lesion or gefitinib or pemetrexed as pre- or postoperative adjuvant therapy.
At baseline and through the course of treatment, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, a questionnaire to measure QOL, was completed in both study groups. The baseline measurements were similar in both groups. At 8-week follow-up, patients who received gefitinib with carboplatin plus pemetrexed had lower QOL scores; however, after about 6 months, investigators found that the combination did not impair QOL overall. The 36-month EORTC QLQ-C30 showed a poor QOL-related prognosis in patients who were treated with gefitinib alone.
The study investigators worked their end point analyses based on a predetermined hierarchical sequential testing method. The method compared PFS to determine which group of subjects had a superior decrease in risk of progression or death. PFS2 was then used to confirm any superiority found in a treatment option used in the study. Based on the confirmation of superiority in the beginning steps of this method of analysis, the investigators also tested for OS superiority in one treatment group of the other. No evidence of superiority would have led to a negative trial.
In the PFS2 assessment, the median PFS was 20.9 months in the combination group and 18.0 months in the monotherapy group. This difference was not significant, according to the study investigators. However, the study included a modified analysis that subtracted beyond the period of disease progression, and in this analysis, the gefitinib monotherapy group achieved a longer PFS2 than the combination group (HR, 0.59; 95% CI, 0.47-0.75;P<.001).
The patients were followed for a median of 45 months. In patients who received gefitinib/carboplatin/pemetrexed, the median OS was longer than in patients treated with gefitinib alone (50.9 vs 38.8 months; HR, 0.72; 95% CI, 0.55-0.95;P= .021).
Gefitinib monotherapy resulted in a higher rate of grade 3 or higher toxicities (65.3% v 31.0%). There was a total of 341 adverse events, 171 occurred as a resulted of the gefitinib monotherapy and 170 occurred in patients treated with the combination. In the gefitinib-only group, the most common all-grade toxicities were rash (n = 138), liver dysfunction (n = 102), and diarrhea (n = 67). Fifty-three of the AEs seen with gefitinib were grade 3 or higher, with the most common being liver dysfunction (n = 38).
Patients who had gefitinib with carboplatin plus pemetrexed mainly experienced anemia (n = 113), rash (n = 110), and liver dysfunction (n = 103). There were 111 grade 3 or higher AEs seen in the combination group, most commonly neutropenia (n = 53).
Gefitinib was approved for the treatment of NSCLC in 2002. Since then, preclinical studies, like the retrospective I-CAMP study, have shown efficacy for when an EGFR TKI is added to chemotherapy. These signals have led to phase II and III studies in Japan that are testing the idea. To date, there has been the phase III IPASS trial, and the NEJ002 study. Both studies have shown an improvement in PFS with the addition of the EGFR TKI, gefitinib.
Hosomi Y, Morita S, Sugarwara S, et al; North-East Japan Study Group. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for NonSmall-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study [published online November 4, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.01488.