Lurbinectedin Displays Superior Risk/Benefit Ratio Over Topotecan in SCLC

Solange Peters, MD, PhD

Patients with small cell lung cancer (SCLC) who had a chemotherapy-free interval (CTFI) of at least 30 days and no central nervous system (CNS) metastases had a positive benefit/risk ratio when they received lurbinectedin (Zepzelca) vs topotecan, according to findings from a post hoc analysis of a phase 2 basket trial (NCT02454972) and the phase 3 ATLANTIS trial (NCT02566993) published in Lung Cancer.¹

Patients treated with lurbinectedin in the basket study (n = 83) achieved an investigator-assessed overall response rate (ORR) of 41% (95% CI, 30.3%-52.3%) compared with 25.5% (95% CI, 17.2%-35.3%) among a matched population of patients treated with topotecan (n = 98) in the ATLANTIS trial (P = .0382), which was statistically significant. The median investigator-assessed duration of response (DOR) was 5.3 months (95% CI, 3.5-5.9) vs 3.9 months (95% CI, 3.0-5.7), respectively (log-rank P = .7323). Additionally, the median overall survival (OS) was 10.2 months (95% CI, 7.6-12.0) vs 7.6 months (95% CI, 6.1-10.3), respectively (log-rank P = .3037), and the median investigator-assessed progression-free survival (PFS) was 4.0 months (95% CI, 2.6-4.7) vs 4.2 months (95% CI, 3.0-4.8), respectively.

Lurbinectedin is an alkylating agent that received accelerated approval from the FDA on June 15, 2020, for the treatment of adult patients with metastatic SCLC who experienced disease progression on or after platinum-based chemotherapy. The regulatory decision was based on data from a cohort of 105 patients from the phase 2 basket trial.²

The cohort basket study included in the post hoc analysis enrolled adult patients with SCLC who experienced relapse following treatment with only 1 prior line of platinum-containing chemotherapy; patients were allowed to have received other therapies besides chemotherapy in the second line. Once enrolled, patients received intravenous lurbinectedin 3.2 mg/m² every 3 weeks.The primary end point was confirmed ORR per RECIST 1.1 criteria by investigator assessment, and secondary end points included DOR, clinical benefit rate, disease control rate, PFS, OS, and safety.¹

ATLANTIS enrolled patients with SCLC who experienced relapse following treatment with 1 prior platinum-containing chemotherapy regimen and had a CFTI of at least 30 days. Eligible patients were randomly assigned 1:1 to receive lurbinectedin 2.0 mg/m² plus doxorubicin 40 mg/m2 or topotecan 1.5 mg/m² daily on days 1 to 5 every 3 weeks with dose reductions for patients with a creatinine clearance less than 60 mL/min. The primary end point was OS. Secondary end points included PFS by independent review committee (IRC), and ORR and DOR per RECIST 1.1 by IRC, as well as safety.

The post hoc analysis examined a matched cohort of patients from both trials with a CTFI of at least 30 days and no CNS metastases. The baseline patient characteristics were well balanced between the lurbinectedin and topotecan groups; the median age was 60 years (range, 41-83) vs 63 (range, 37-77), respectively. Most patients in both groups were male (57.8% vs 61.2%), White (79.5 % vs 89.8%), had a ECOG performance status of 0 or 1 (96.4% vs 99.0%), were current or former smokers (91.6 % vs 93.9 %), and had extensive stage disease (100% vs 87.8%). The median CTFI was 3.9 months (1.1-16.1) vs 4.2 months (95% CI, 1.0-24.2), respectively, and most patients in both arms had a CTFI of 90 days or more (71.1% vs 70.4%).

Additional findings from the post hoc analysis showed that the ORR by IRC was 33.7% (95% CI, 23.7%-44.9%) compared with 25.5% (95% CI, 17.2%-35.3%) in the lurbinectedin and topotecan cohorts, respectively (P = .2533). The IRC-assessed median DOR was 5.1 months (95% CI, 4.8-5.9)vs4.3 months (95% CI, 3.0-5.6), respectively (P = 0.6102), and the IRC-assessed median PFS was 3.7 months (95% CI, 2.6-4.6) compared with 4.1 months (95% CI, 2.9-4.7), respectively.

In terms of safety, any-grade adverse effects (AEs) were present at a rate of 97.6% vs 99.0% in the lurbinectedin and topotecan cohorts, respectively. Grade 3 or higher AEs (55.4% vs 90.8%), any-grade treatment-related AEs (TRAEs; 88.0% vs 93.9%), grade 3 or higher TRAEs (41.0% vs 82.7%), AEs leading to dose reduction (24.1% vs 49.0%), AEs leading to treatment discontinuation (3.6% vs 18.4%), and AEs leading to death (1.2% vs 8.2%) occurred in both arms, respectively.

The most common any-grade TRAEs in the lurbinectedin cohort included anemia (95.2%), lymphopenia (86.7%), and increased creatine level (85.4%). The most common any-grade AEs in the topotecan cohort included anemia (96.9%), thrombocytopenia (92.9%), and leukopenia (91.8%).

“Lurbinectedin is more active, as measured by all usual outcomes metrics, and is clearly less toxic and better tolerated than topotecan. An ongoing confirmatory phase 3 trial, LAGOON (NCT05153239), is evaluating lurbinectedin as single agent or in combination with irinotecan vs topotecan or irinotecan in the population of adult patients [with SCLC] who have failed 1 prior platinum-containing line with CTFI of at least 30 days and controlled asymptomatic CNS metastases,” the study authors wrote in conclusion.

References

1. Peters S, Trigo J, Besse B, et al. Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥30 days and without central nervous metastases. Lung Cancer. 2024;188:107448. doi:10.1016/j.lungcan.2023.107448
2. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. FDA. June 15, 2020. Updated June 16, 2020. Accessed February 15, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer