Addition of Pemetrexed vs Vinorelbine to Adjuvant Cisplatin for Nonsquamous NSCLC

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In the Japanese phase III JIPANG trial reported in the Journal of Clinical Oncology, Kenmotsu et al found that adjuvant therapy with pemetrexed/cisplatin did not result in superior recurrence-free survival but was better tolerated than vinorelbine/cisplatin in patients with completely resected stage II to IIIA nonsquamous non–small cell lung cancer (NSCLC).

Study Details

In the multicenter open-label trial, 804 patients were randomly assigned between March 2012 and August 2016 to receive pemetrexed at 500 mg/m2 on day 1 plus cisplatin at 75 mg/m2 on day 1 (n = 402), or vinorelbine at 25 mg/m2 on days 1 and 8 plus cisplatin at 80 mg/m2 on day 1 (n = 402) every 3 weeks for four cycles. A total of 784 patients, consisting of 389 in the pemetrexed/cisplatin group and 395 in the vinorelbine/cisplatin group, were considered eligible and constituted the modified intent-to-treat population. Among these, 52% had stage IIIA disease and 24% had EGFR-mutant disease. The primary endpoint was recurrence-free survival in the modified intent-to-treat population.

Recurrence-Free Survival


  • No significant difference in recurrence-free survival was observed between patients treated with pemetrexed/cisplatin and vinorelbine/cisplatin.
  • Grade ≥ 3 adverse events, primarily hematologic, occurred in 47.4% vs 89.4% of patients.

Median follow-up was 45.2 months. Median recurrence-free survival was 38.9 months for patients in the pemetrexed/cisplatin group vs 37.3 months in the vinorelbine/cisplatin group (hazard ratio [HR] = 0.98, P = .474), with 2- and 3-year rates of 58.3% vs 60.7% and 51.1% vs 50.2%, respectively. In post hoc analyses, hazard ratios were: 1.38 (95% confidence interval [CI] = 0.95–1.99) among patients with EGFR-mutant disease and 0.87 (95% CI = 0.69–1.09) in those with wild-type disease (P = .046 for interaction); and 0.90 (95% CI = 0.65–1.23) in stage II and 1.05 (95% CI = 0.82–1.34) in stage IIIA disease  (P = .442 for interaction).

Median overall survival was not reached in either group. At time of analysis, 71 patients in the pemetrexed/cisplatin group and 75 patients in the vinorelbine/cisplatin group had died (HR = 0.98, P = .434). Survival at 3 years was 87.2% vs 83.5%.

Adverse Events

Grade ≥ 3 adverse events occurred in 47.4% of patients in the pemetrexed/cisplatin group vs 89.4% of the vinorelbine/cisplatin group (P < .01), with grade 3 or 4 events occurring significantly (all P < .05) more frequently in the vinorelbine/cisplatin group, including febrile neutropenia (11.6% vs 0.3%), neutropenia (81.1% vs 22.7%, grade 4 in 56.6% vs 3.3%), anemia (9.3% vs 2.8%), and white blood cell count decrease (51.0% vs 5.9%, grade 4 in 9.3% vs 0.3%). One death in each group was considered treatment-related, consisting of sudden death in one patient receiving vinorelbine/cisplatin and pneumonitis in one patient receiving pemetrexed/cisplatin.

The investigators concluded, “Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.”

Hirotsugu Kenmotsu, MD, PhD, of the Division of Thoracic Oncology, Shizuoka Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by staff members of the West Japan Oncology Group Data Center and Pharma-Valley Center and by the Japan Agency for Medical Research and Development. Pemetrexed was provided by Eli Lilly. For full disclosures of the study authors, visit

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