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Original Investigation
March 12, 2020

Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non–Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial

Author Affiliations
  • 1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • 2Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
  • 3Japan Clinical Oncology Group (JCOG) Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
  • 4Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan
  • 5Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan
  • 6Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
  • 7Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
  • 8Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
  • 9Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
  • 10Department of Thoracic Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Osaka, Japan
  • 11Division of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
  • 12Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
  • 13National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan
  • 14Department of Respiratory Medicine, Yokohama Municipal Citizen’s Hospital, Kanagawa, Japan
  • 15Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
  • 16Internal Medicine III, Wakayama Medical University, Wakayama, Japan
  • 17Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
JAMA Oncol. Published online March 12, 2020. doi:10.1001/jamaoncol.2019.6828
Key Points

Question  Is treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance noninferior compared with docetaxel monotherapy with regard to overall survival for elderly patients with advanced nonsquamous non–small cell lung cancer (NSCLC)?

Findings  This phase 3 randomized clinical trial including 433 elderly patients with a median age of 78 years met its primary end point and demonstrated noninferiority of carboplatin-pemetrexed treatment followed by pemetrexed maintenance compared with docetaxel monotherapy in terms of overall survival for chemotherapy-naive elderly patients with advanced nonsquamous NSCLC.

Meaning  The combination of carboplatin and pemetrexed followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.

Abstract

Importance  Few clinical trials have been specifically designed for elderly patients with advanced non–small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.

Objective  To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.

Design, Setting, and Participants  This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy–naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.

Interventions  Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.

Main Outcomes and Measures  The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.

Results  Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.

Conclusion and Relevance  Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.

Trial Registration  University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460

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