Gefitinib Plus Chemotherapy Proves Effective in EGFR-Mutated Non–Small Cell Lung Cancer


Compared with gefitinib monotherapy, a combo regimen of gefitinib plus chemotherapy generated superior time to second progression in untreated non–small cell lung cancer.

For untreated patients with EGFR-positive non–small cell lung cancer, adding chemotherapy to treatment with gefitinib (Iressa) may be more effective in prolonging time to second progression (PFS2) vs treatment with gefitinib alone, according to an updated analysis of the phase 3 NEJ009 trial (UMIN000006340) published in the Journal of Clinical Oncology.1

Notably, the preplanned PFS2 analysis was inappropriate because of the influence of post–progressive disease treatment period that was included only for the gefitinib group. The corrected definition of PFS2 in the gefitinib group omitted this period.

Findings showed that patients treated with gefitinib plus chemotherapy (n = 169) achieved a corrected median PFS2 of 20.9 months (95% CI, 18.0-24.0) compared with 18.0 months (95% CI, 16.3-20.7) for patients treated with gefitinib alone (n = 172; HR, 0.77; 95% CI, 0.62-0.97; P = .027).

An additional analysis of PFS2 with the same definition showed that the updated median PFS2 was 32.5 months (95% CI, 29.0-36.6) for the gefitinib plus chemotherapy group vs 20.7 months (95% CI, 17.9-24.6) for the gefitinib alone group (HR, 0.58; 95% CI, 0.46-0.73; P < .001).

“These persistent survival benefits confirmed that combination therapy with EGFR-TKI and chemotherapy boosted the tumor response and duration of response than EGFR-TKI monotherapy in patients with EGFR-mutated NSCLC,” wrote lead study author Eisaku Miyauchi, MD, PhD, a physician in the Department of Respiratory Medicine at Tohoku University Hospital in Sendai, Japan, and colleagues.

In July 2015, the FDA approved single-agent gefitinib for the frontline treatment of patients with metastatic, EGFR-positive NSCLC with an exon 19 deletion or exon 21 (L858R) substitution.2 The multicenter, open-label NEJ009 trial evaluated single-agent gefitinib with or without chemotherapy to investigate the efficacy and safety of the 2 regimens.

Previous findings from the trial showed that the combination elicited an overall response rate (ORR) of 84% compared with 67% for gefitinib alone, and the median progression-free survival (PFS) for the combination and single-agent was 20.9 months and 11.9 months, respectively.3

The trial enrolled patients aged 20 to 75 years with chemotherapy-naïve stage IIIB or IV or relapsed nonsquamous NSCLC harboring EGFR mutations. Patients were also required to have an ECOG performance status of 0 or 1, plus adequate organ function.3

Patients were excluded from the trial if they had serious concomitant systemic disorders, interstitial pneumonia, another primary malignancy, preexistence of an EGFR T790M mutation, symptomatic brain metastases, or pregnancy.

Once enrolled, patients were randomly assigned 1:1 to gefitinib alone or gefitinib plus chemotherapy. All patients received 250 mg of oral gefitinib once per day, and patients in the combination arm also received carboplatin area under the curve 5 and 500 mg/m2 of pemetrexed in a 3-week cycle for up to 6 cycles, followed by concurrent gefitinib and pemetrexed maintenance. If patients in the combination arm were intolerant of gefitinib or chemotherapy, they were permitted to continue treatment on the remaining agents. Protocol called for treatment to end at disease progression, though patients were allowed to continue treatment at investigator discretion.

Notably, since osimertinib (Tagrisso) was approved for the treatment of EGFR T790M–mutated NSCLC, 21.8% and 23.3% of patients in the combination arm and gefitinib arm, respectively, received osimertinib in any treatment line. In the gefitinib group, 26.7% of patients did not receive platinum-based chemotherapy in any setting.

The coprimary end points of the trial included PFS, PFS2, and overall survival (OS). Secondary end points consisted of ORR, safety, and quality of life.

Baseline characteristics of age and sex were consistent across the 2 arms. The majority of patients never smoked (56.5% and 56.4% in the combination and gefitinib arms, respectively), had an ECOG performance status of 0 (57.6% and 62.2%), had adenocarcinoma (98.8% and 98.8%), had stage IV disease (81.8% and 79.7%), did not have brain metastases (70.6% and 77.9%), did not have liver metastases (90% and 93%), and had an EGFR exon 19 deletion (54.7% and 55.2%).

Updated OS data showed that there was no significant difference between the 2 groups. In the combination arm, the mean OS, 2-year OS rate, and 5-year OS rate were 49.0 months, 77.1%, and 39%, respectively. Those data were 38.5 months, 69%, and 34%, respectively, in the gefitinib arm (HR, 0.822; 95% CI, 0.639-1.058; P = .127).

“In the subgroup analysis, the OS benefit for [gefitinib plus chemotherapy] and gefitinib [alone] was comparable in the overall patient population, including the type of EGFR activation mutation and metastatic sites. However, larger numerical between-group differences in the HRs for OS were observed between male and female patients,” study authors noted.

Additionally, the 5-year restricted mean survival time (RMST) was 43.6 months in the combination group compared with 38.6 months for the gefitinib group (P = .017). The 7-year RMST was 51.6 months and 45.3 months in the combination arm and gefitinib arm, respectively (P = .037). The RMST analysis revealed a statistically significant 6.3-month survival advantage for the combination regimen over a 7-year follow-up period.

Regarding safety, 66.5% of patients in the combination arm experience at least 1 grade 3 or higher treatment-related adverse effect (TRAE) compared with 31% in the gefitinib arm (odds ratio, 0.23; 95% CI, 0.15-0.36; P < .001). One grade 1 TRAE (infection) occurred in the combination group, and no new instances of interstitial lung disease were reported.

“The [gefitinib plus chemotherapy] regimen improved PFS and PFS2 with an acceptable safety profile than [compared] with gefitinib alone. Clinical trials are ongoing to compare efficacy of osimertinib monotherapy with osimertinib combined with platinum plus pemetrexed as first-line treatment for patients with untreated NSCLC with EGFR mutations,” study authors concluded.


  1. Miyauchi E, Morita S, Nakamura A, et al. Updated analysis of NEJ009: gefitinib-alone versus gefitinib plus chemotherapy for non–small-cell lung cancer with mutated EGFR. J Clin Oncol. Published online August 12, 2022. doi: 10.1200/JCO.21.02911
  2. Iressa approved by US FDA for first-line treatment of patients with advanced EGFR mutation-positive non-small cell lung cancer. News release. AstraZeneca. July 13, 2015. Accessed August 24, 2022.
  3. Hosomi Y, Morita S, Sugawara S, et al. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol. 2020;38(2):115-123. doi:10.1200/JCO.19.01488

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