Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT).

Purpose: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation.
Patients and Methods: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m ² on day 1) plus vinorelbine (25 mg/m ² on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS).
Results: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively.
Conclusion: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.
Competing Interests: Hirohito TadaHonoraria: Chugai Pharma Tetsuya MitsudomiHonoraria: AstraZeneca, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Taiho Pharmaceutical, Lilly, Novartis, MSD K.K., Kyowa Hakko Kirin, Amgen, Daiichi-Sankyo, Guardant Health, Ethicon, Thermofisher Scientific Biomarkers, Merck KGaA, Janssen Oncology, TakedaConsulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Chugai Pharma, Ono Pharmaceutical, MSD Oncology, Lilly, Novartis, Amgen, Daiichi Sankyo, Thermo Fisher ScientificResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Pfizer (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Sanofi/Aventis (Inst), Daiichi Sankyo (Inst), MSD K.K. (Inst), Kyowa Hakko Kirin (Inst) Toshihiro MisumiSpeakers' Bureau: Chugai Pharma, AstraZeneca Kenji SugioHonoraria: AstraZeneca, Chugai PharmaResearch Funding: Covidien Japan, Lilly Japan Masahiro TsuboiHonoraria: AstraZeneca Japan, Chugai Pharma, Taiho Pharmaceutical, Teijin Pharma, Johnson & Johnson, Novartis, MSD K.K., Ono Pharmaceutical, Bristol Myers Squibb Japan, MedtronicResearch Funding: Boehringer Ingelheim (Inst), Merck (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai/Roche (Inst) Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Kyowa Kirin Shinji AtagiHonoraria: Chugai Pharma, MSD K.K., Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Lilly Japan, Pfizer, Bristol Myers Squibb Japan, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Merck, Novartis, Thermo Fisher ScientificResearch Funding: MSD K.K. (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Lilly Japan (Inst), Pfizer (Inst), Bristol Myers Squibb Japan (Inst), Roche (Inst), Merck (Inst) Toshiaki TakahashiHonoraria: AstraZeneca KK, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K., Pfizer, Boehringer Ingelheim, Roche, Takeda Pharmaceutical Co Ltd, Yakult HonshaResearch Funding: AstraZeneca KK (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K. (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim (Inst) Hidetoshi HayashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck SeronoConsulting or Advisory Role: Lilly, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Pfizer, Merck Serono, Shanghai HaiHe Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie (Inst), AC Medical (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Lilly Japan (Inst), EPS Associates Co, Ltd (Inst), GlaxoSmithKline (Inst), Japan Clinical Research Operations (Inst), Kyowa Hakko Kirin (Inst), Merck Serono (Inst), Novartis (Inst), Otsuka (Inst), Parexel (Inst), Pfizer (Inst), PPD-SNBL (Inst), Quintiles Inc (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Yakult Honsha (Inst)Patents, Royalties, Other Intellectual Property: Sysmex Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (Inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Hiroshige YoshiokaHonoraria: Lilly, Chugai Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Novartis, Kyowa Kirin Co, Ltd, Daiichi Sankyo, Nippon Kayaku, Delta-Fly Pharma, PfizerConsulting or Advisory Role: Delta-Fly Pharma Kazuhisa TakahashiSpeakers' Bureau: AstraZeneca Ichiro YoshinoHonoraria: Johnson & Johnson, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Shionogi, Astra Zeneca, Intuitive Surgical, Daiichi Sankyo, Boehringer Ingelheim, Covidien/MedtronicConsulting or Advisory Role: Astra Zeneca, Intuitive Surgical, Covidien/MedtronicResearch Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Shionogi (Inst) Kazuhiko NakagawaHonoraria: AstraZeneca KK, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Lilly, Pfizer, Bristol Myers Squibb, Novartis, CareNet, Taiho Pharmaceutical, Yodosha, Nikkei Business Publications, Inc, Kyorin, Takeda, Medical Review Co, Ltd, MSD K.K., AbbVie, Merck, Roche Diagnostics, Bayer Yakuhin, Nippon Kayaku, Amgen, Kyowa Kirin Co, Ltd, Medical Mobile Communications Co, Ltd, 3H Clinical Trial, Astellas Pharma, Yomiuri Telecasting Corporation, Medicus Shuppan, publishers Co, Ltd, Thermo Fisher Scientific, Hisamitsu Pharmaceutical Co, Inc, Nichi-iko, Nanzando Co, Ltd, Daiichi Sankyo Co, LtdConsulting or Advisory Role: Pfizer, Kyorin Pharmaceutical Co, Ltd, Lilly Japan, Ono Pharmaceutical, Astellas Pharma, TakedaResearch Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Pfizer (Inst), Takeda (Inst), Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Parexel International Corp. (Inst), A2 Healthcare (Inst), Novartis (Inst), IQvia (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca KK (Inst), Kissei Pharmaceutical (Inst), EPS Holdings (Inst), Bayer Yakuhin (Inst), MSD K.K. (Inst), Pfizer (Inst), Otsuka (Inst), Syneos Health (Inst), EPS International (Inst), PRA Health Sciences (Inst), PPD-SNBL (Inst), Covance (Inst), GlaxoSmithKline K.K. (Inst), Sysmex (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Japan Clinical Research Operations (Inst), Sanofi (Inst), Medical Research Support (Inst), ICON (Inst), CMIC (Inst), Kyowa Kirin Co, Ltd (Inst)No other potential conflicts of interest were reported.