Lurbinectedin Shows Superiority Over Topotecan in SCLC

"In this analysis, the results with lurbinectedin reported in the SCLC cohort of a phase 2 basket trial were compared [with] data obtained with topotecan in [patients with] SCLC from a contemporary randomized phase 3 trial in a matched population, which was defined as patients with a CTFI ≥30 days and without CNS metastases," the study authors wrote.

The use of lurbinectedin (Zepzelca) in patients with small cell lung cancer (SCLC) with no central nervous system (CNS) metastases undergoing a chemotherapy-free interval (CTFI) of 30 days or longer was found to be superior to topotecan, according to results from a post hoc analysis published in Lung Cancer.¹

An overall response rate (ORR) of 41.0% was observed in the lurbinectedin group vs 25.5% in the topotecan arm (P = .0382). The ORR by independent review committee (IRC) assessment was 33.7% vs 25.5%, respectively (P = .2533).

“Lurbinectedin is more active, as measured by all usual outcomes metrics, and is less toxic and better tolerated than topotecan,” the study authors wrote.

Initially, lurbinectedin was evaluated in a phase 2 basket trial (NCT024554972), of which 9 cohorts of patients were evaluated. Based on results from one of the cohorts that enrolled 105 patients, lurbinectedin was approved by the FDA for metastatic SCLC in June 2020.² The basket study was analyzed for the lurbinectedin subgroup of the post hoc analysis, and the phase 3 ATLANTIS study (NCT02566993) was analyzed for the topotecan subgroup.

Patients were enrolled in the basket study if they had an ECOG performance status of 2 or less and pathologically confirmed SCLC with relapse after a previous platinum-containing regimen. Lurbinectedin was administered at 3.2 mg/m² during 1-hour intravenous infusions every 3 weeks. The primary end point was ORR, and secondary end points included duration of response (DOR), clinical benefit rate, and disease control rate (DCR).

In the ATLANTIS study, patients needed to meet the same eligibility criteria as those for the basket study. This trial examined lurbinectedin plus doxorubicin vs physician’s choice chemotherapy. Lurbinectedin was given at a reduced dose of 2.0 mg/m² plus doxorubicin at 40 mg/m². Topotecan was given at 1.5 mg/m² every 3 weeks on days 1 to 5. Patients were allowed dose reductions of topotecan if they had creatinine clearance of less than 60 mL/minute. The primary end point was overall survival (OS), with secondary end points being progression-free survival by IRC, ORR, and DOR.

The basket study occurred from October 2015 to November 2020, and the ATLANTIS study occurred between August 2016 and February 2020. Looking between the lurbinectedin and topotecan-matched populations, the median age was 60 vs 63 years, the DCR was 97.6% vs 88.7%, and the median CTFI during first-line chemotherapy was 3.9 months vs 4.2 months. The rate of patients with resistant disease to CTFI from 30 to 90 days was 28.9% vs 29.6%.

Lurbinectedin showed a nominal significance level of 0.05 compared with topotecan when assessing ORR. The median DOR by investigator assessment was 5.3 months for lurbinectedin vs 3.9 months for topotecan (log-rank P = .7323), compared with 5.1 months vs 4.3 months by IRC assessment (P = .6102). The median OS between treatments was 10.2 months vs 7.6 months (log-rank P = .3037).

The rate of grade 3 or higher adverse effects (AEs) was 55.4% with lurbinectedin treatment vs 90.8% with topotecan treatment, with 41.0% vs 82.7% relating to treatment. Dose reductions due to AEs occurred in 24.1% vs 49.0%, AEs leading to discontinuation occurred in 3.6% vs 18.4%, and AEs led to death in 1.2% vs 8.2%.

The most common AEs included fatigue and gastrointestinal events, with investigators noting grade 3 or higher AEs more commonly occurring with topotecan. Of note, febrile neutropenia was more commonly seen in the topotecan arm (6.1%) vs the lurbinectedin arm (2.4%) even though G-CSF was mandatory.

Grade 3 or higher hematologic malignancies included anemia (12.0% vs 54.1%), leukopenia (30.1% vs 68.4%), neutropenia (47.0% vs 75.5%), and thrombocytopenia (6.0% vs 52.0%) between the lurbinectedin and topotecan treatments, respectively.

Fewer patients in the lurbinectedin arm needed G-CSF support compared with topotecan (13.3% vs 22.4%). This also included red blood cell transfusions (10.8% vs 46.9%), platelet transfusions (2.4% vs 16.3%), and erythropoietin support (2.4% vs 12.2%).

“In this analysis, the results with lurbinectedin reported in the SCLC cohort of a phase 2 basket trial were compared [with] data obtained with topotecan in [patients with] SCLC from a contemporary randomized phase 3 trial in a matched population, which was defined as patients with a CTFI ≥30 days and without CNS metastases. With the inherent limitations of an indirect comparison, ATLANTIS can be considered an appropriate external control for efficacy and safety of topotecan in the selected patient population,” the authors included.

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. News release. FDA. June 15, 2020. Accessed February 27, 2024. https://shorturl.at/flwzD