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Irinotecan + Cisplatin versus Etoposide + Cisplatin for High-Grade Neuroendocrine Carcinoma of the Lung

2020 Year in Review - Neuroendocrine Tumors - Neuroendocrine Tumors

The randomized phase 3 JCOG1205/1206 trial did not demonstrate superiority of irinotecan + cisplatin versus etoposide + cisplatin in patients with completely resected high-grade neuroendocrine carcinomas (HGNECs) of the lung.

For HGNECs of the lung (including small-cell lung cancer [SCLC] and large-cell neuroendocrine carcinoma [LCNEC]), adjuvant chemotherapy with etoposide + cisplatin is the standard of care. A phase 3 Japanese study previously demonstrated the superiority of irinotecan + cisplatin to etoposide + cisplatin in extensive-stage SCLC.1 The randomized phase 3 JCOG1205/1206 trial was initiated to evaluate the efficacy and safety of irinotecan + cisplatin versus etoposide + cisplatin in patients with completely resected HGNEC of the lung; the results of this trial were reported at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

Eligibility criteria included completely resected HGNEC, with pathological stage I to IIIA and Eastern Cooperative Oncology Group performance status 0 to 1. Eligible patients were randomized (1:1) to receive the etoposide (100 mg/m2 on days 1-3) plus cisplatin (80 mg/m2 on day 1) regimen or the irinotecan (60 mg/m2 on days 1, 8, and 15) plus cisplatin (60 mg/m2 on day 1) regimen; stratification was by sex (female vs male), pathological stage (I vs II-IIIA), histology (SCLC vs LCNEC), and institution. The primary end point was investigator-assessed relapse-free survival (RFS); secondary end points included overall survival (OS), adverse events (AEs), serious AEs, and secondary malignancies.

A total of 221 patients were enrolled in the trial and randomly assigned to the etoposide + cisplatin arm (N = 111) or the irinotecan + cisplatin arm (N = 110). In the second interim analysis, it was estimated that there was only a 15.9% predictive probability that irinotecan + cisplatin would be significantly superior to etoposide + cisplatin at the time of the primary analysis. Because of the futility of the trial, the Data and Safety Monitoring Committee recommended its early termination.

With a median follow-up of 24.1 months, the 3-year RFS was similar between the etoposide + cisplatin and irinotecan + cisplatin arms (65.4% vs 69.0%; hazard ratio [HR], 1.076; 95% confidence interval [CI], 0.666-1.738; P = .619); median RFS was not estimable in both arms. Similar trends were observed in the subgroup analyses by histology for 3-year RFS of the SCLC subgroup (65.2% vs 66.5% in the etoposide + cisplatin and irinotecan + cisplatin arms, respectively; HR, 1.029; 95% CI, 0.544-1.944) and LCNEC (66.5% vs 72.0%; HR, 1.072; 95% CI, 0.517-2.222). However, when assessed by pathological stage, patients with stage I disease showed a 56% lower risk for relapse with irinotecan + cisplatin treatment compared with etoposide + cisplatin (83.0% vs 68.9%; HR, 0.641; 95% CI, 0.288-1.426). The 3-year OS was 84.1% versus 79.0% (HR, 1.539; 95% CI, 0.760-3.117). The treatment completion rate was 87.4% for the etoposide + cisplatin arm and 72.7% for the irinotecan + cisplatin arm.

Grade 3/4 AEs were higher in the etoposide + cisplatin arm (40.4% vs 31.2%), as were serious AEs (2.8% vs 1.8%); however, AEs led to higher rates of study terminations in the irinotecan + cisplatin arm (24.8% vs 11%). Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and febrile neutropenia were more frequent in the etoposide + cisplatin arm, whereas grade 3/4 diarrhea or anorexia were more frequent in the irinotecan + cisplatin arm. One treatment-related death resulting from tracheal bleeding was reported in the irinotecan + cisplatin arm.

These results indicate that the JCOG1205/1206 study failed to demonstrate the superiority of irinotecan + cisplatin versus etoposide + cisplatin in RFS for patients with completely resected HGNEC, suggesting that etoposide + cisplatin remains the standard of care for these patients.

Source: Kenmotsu H, et al. J Clin Oncol. 2020;38(15_suppl). Abstract 9006.

Reference
1. Noda K, et al. N Engl J Med. 2002;346:85-91.

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Last modified: July 22, 2021