Liposomal Irinotecan vs Topotecan for Relapsed Small Cell Lung Cancer: RESILIENT Phase 3 Trial

Authors: David R. Spigel, Afshin Dowlati, Yuanbin Chen, Alejandro Navarro, James Chih-Hsin Yang, Goran Stojanovic, Maria Jove, Patricia Rich, Zoran G. Andric, Yi-Long Wu, Charles M. Rudin, Huanyu Chen, Li Zhang, Stanley Yeung, Fawzi Benzaghou, Luis Paz-Ares

Published in the Journal of Clinical Oncology on April 22, 2024

Introduction:

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer characterized by rapid doubling time and early metastases. Despite initial response to first-line platinum-based chemotherapy, most patients experience relapse within 1-2 years, highlighting the need for effective second-line treatment options. The phase 3 RESILIENT trial aimed to compare the efficacy and safety of liposomal irinotecan, a novel liposomal formulation of irinotecan designed to prolong drug exposure, with the standard second-line therapy topotecan in patients with relapsed SCLC after progression on or following first-line platinum-based chemotherapy.

Study Design and Methods:

• Randomized, open-label, phase 3 trial enrolling 461 patients with SCLC
• Eligibility: Radiologically confirmed disease progression on/after first-line platinum-based chemotherapy, ECOG PS 0-1, life expectancy >12 weeks
• Randomization 1:1 to:
  1. Liposomal irinotecan 70 mg/m2 IV every 2 weeks (6-week cycle)
  2. Topotecan 1.5 mg/m2 IV daily for 5 days, every 3 weeks (6-week cycle)
• Primary endpoint: Overall Survival (OS)
• Key secondary endpoints: Progression-Free Survival (PFS) per BICR, Objective Response Rate (ORR) per BICR, safety

Results:

• Median OS: 7.9 months (liposomal irinotecan) vs. 8.3 months (topotecan); HR 1.11 (95% CI 0.90-1.37), P=0.31
• Median PFS per BICR: 4.0 months (liposomal irinotecan) vs. 3.3 months (topotecan); HR 0.96 (95% CI 0.77-1.20), nominal P=0.71
• ORR per BICR: 44.1% (liposomal irinotecan) vs. 21.6% (topotecan), nominal P<0.0001
• Complete/partial responses: 5.2%/38.9% (liposomal irinotecan) vs. 3.0%/18.5% (topotecan)
• Grade ≥3 Treatment-Emergent Adverse Events (TEAEs): 62.4% (liposomal irinotecan) vs. 87.9% (topotecan)
• Liposomal irinotecan: diarrhea (13.7%), neutropenia (8.0%), decreased neutrophil count (4.4%)
• Topotecan: neutropenia (51.6%), anemia (30.9%), leukopenia (29.1%), thrombocytopenia (29.1%)

Key Highlights:

• Liposomal irinotecan doubled ORR compared to topotecan (44.1% vs. 21.6%), with non-overlapping 95% CIs.
• Lower incidence of grade ≥3 TEAEs and TEAE-related discontinuations with liposomal irinotecan vs. topotecan.
• The safety profile of liposomal irinotecan is consistent with the known profile, and diarrhea is the most frequent grade ≥3 related to TEAE.

Conclusions:

• While the primary endpoint of OS was not met, liposomal irinotecan demonstrated similar PFS and a significantly higher ORR compared to topotecan in patients with relapsed SCLC after progression on or following first-line platinum-based chemotherapy.
• The favorable safety profile of liposomal irinotecan, with a lower incidence of severe toxicities than topotecan, supports its potential as an effective and well-tolerated second-line treatment option for patients with relapsed SCLC.
• These findings provide a rationale for further investigating liposomal irinotecan, potentially in combination with other therapies, to improve treatment outcomes in the relapsed SCLC setting.

Summary By Amalya Sargsyan, MD 

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer