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Original Investigation
May 14, 2020

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation–Positive Non–Small Cell Lung Cancer: A Multicenter Phase 2 Trial

Author Affiliations
  • 1Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan
  • 2Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
  • 3Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan
  • 4Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
  • 5Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan
  • 6Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan
  • 7Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan
  • 8The Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
  • 9Department of Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
  • 10Department of Respiratory Medicine, Kasumigaura Medical Center, Tsuchiura, Japan
  • 11Department of Respiratory Medicine, Iwate Prefectural Central Hospital, Morioka, Japan
  • 12Department of Respiratory Medicine, Japanese Red Cross Ise Hospital, Ise, Japan
  • 13Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
JAMA Oncol. Published online May 14, 2020. doi:10.1001/jamaoncol.2020.1250
Key Points

Question  How safe and effective is low-dose erlotinib for elderly or frail patients with epidermal growth factor receptor mutation–positive non–small cell lung cancer?

Findings  In this single-arm, multicenter phase 2 trial of 80 patients with epidermal growth factor receptor mutation–positive non–small cell lung cancer, results showed that the objective response rate of low-dose erlotinib was 60.0%, while the adverse events observed were mild, with few patients exhibiting those of grade 3 or higher.

Meaning  Low-dose erlotinib may be a treatment option for elderly or frail patients with non–small cell lung cancer.


Importance  Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation–positive non–small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective  To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation–positive non–small cell lung cancer.

Design, Setting, and Participants  Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation–positive non–small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions  Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes and Measures  The primary end point was the independent review committee–confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results  Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions and Relevance  Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation–positive non–small cell lung cancer and can be a valid treatment option.

Trial Registration  UMIN-CTR Identifier: UMIN000015949

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