Lurbinectedin/Doxorubicin Misses OS End Point in Relapsed SCLC, But Shows Superior Safety Vs SOC

The combination of lurbinectedin (Zepzelca) and doxorubicin produced comparable efficacy to that of standard-of-care (SOC) vincristine, cyclophosphamide, and doxorubicin (CAV) or topotecan in patients with relapsed small cell lung cancer (SCLC), missing the primary end point of the phase 3 ATLANTIS trial (NCT02566993).¹ However, the doublet did showcase a superior safety and tolerability profile.

Results, presented in a press briefing during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer, showed that the median overall survival (OS) in the investigative and control arms was 8.6 months (95% CI, 7.1-9.4) and 7.6 months (95% CI, 6.6-8.2), respectively, in the intent-to-treat population (HR, 0.967; 95% CI, 0.815-1.148; P = .7032). The mean OS in these arms was 10.6 months and 9.9 months, respectively.

“We did not see a [significant] improvement in efficacy, and the trial did not meet the primary end point; however, we did confirm the safety profile [of lurbinectedin,] even when adding doxorubicin,” lead study author Luis Paz-Ares, MD, PhD, chair of the Medical Oncology Department at the Hospital Universitario 12 de Octubre, associate professor at the Universidad Complutense de Madrid, and head of the Lung Cancer Unit at the National Oncology Research Center, said during the press briefing. “Lurbinectedin [was more tolerable], particularly in terms of myelosuppression, than SOC. More importantly, new combinations of lurbinectedin and other cytotoxic agents are currently being explored in this setting.”

SCLC is the most aggressive form of lung cancer and mostly occurs in smokers, according to Paz-Ares. Additionally, although the disease has proved to be sensitive to chemotherapy and radiation, responses are short and those who relapse have a survival of just 6 to 8 months.² Much has been learned about the biology of the disease, but treatment options remain limited, Paz-Ares added.

In June 2020, the FDA approved single-agent lurbinectedin for use in the treatment of adult patients with metastatic SCLC with disease progression following platinum-based chemotherapy, at a dose of 3.2 mg/m2 every 3 weeks. The regulatory decision was based on results from a phase 2 basket trial (NCT02454972), in which the agent elicited higher response rates in those who were platinum sensitive and had a chemotherapy-free interval (CTFI) of 90 days or more compared with those who were platinum resistant and had a CTFI of less than 90 days; these rates were 45.0% and 22.2%, respectively.³

A phase 1 dose-escalation study (NCT01970540) was conducted to investigate lurbinectedin in combination with doxorubicin, based on synergistic activity observed in in vitro assays. Results showed that the combination elicited an overall response rate (ORR) of 36%, a median progression-free survival of 3.3 months, and a median OS of 7.6 months in patients with second-line SCLC. When excluding patients with refractory disease with a CTFI of 30 days or less, the ORR achieved with the regimen was 46%, the median PFS was 5.1 months, and the median OS was 10.2 months. “These results were promising compared with historical data for topotecan and CAV,” Paz-Ares noted.

Based on results from this study, it was determined that the recommended dosing for the regimen in the second-line setting is 40 mg/m2 of doxorubicin and 2.0 mg/m2 of lurbinectedin to be given on day 1 of every 3-week cycle. Investigators launched ATLANTIS to examine the combination vs standard of care in a phase 3 setting.

To be eligible for enrollment, patients had to have a confirmed diagnosis of SCLC and have received 1 prior line of chemotherapy. Additionally, patients needed to have an ECOG performance status of 2 or less, and measurable disease per RECIST criteria. Those with a CTFI of less than 30 days were excluded.

A total of 600 patients were randomized 1:1 to receive either lurbinectedin plus doxorubicin at the recommended dose, or topotecan at a dose of 1.5 mg/m2 on days 1 to 5 of every 3-week cycle, or CAV on day 1 of every 3-week cycle. Primary prophylaxis with granulocyte colony stimulating factor was mandatory for both arms. Patients received treatment until progressive disease or intolerable toxicity.

Patients were stratified by ECOG performance status (0 vs ≥1), CTFI (≥180, 179-190, <90), central nervous system involvement (yes vs no), prior treatment with PD-L1/PD-1 agents (yes vs no), and investigator preference for the control arm.

The primary end point of the study was OS.

Additional data showed that the median PFS, as assessed by an independent review committee, was 4.0 months in both the investigative arm (95% CI, 2.8-4.2) and the control arm (95% CI, 3.0-4.1; HR, 0.831; 95% CI, 0.693-0.996; P = .0437). Additionally, at PFS rate at 6 months was 31.3% (95% CI, 25.8%-36.9%) in the investigative arm vs 24.4% (95% CI, 19.1%-30.1%) in the control arm. At 12 months, these rates were 10.8% (95% CI, 7.1%-15.3%; P = .0851) and 4.4% (95% CI, 2.1%-8.1%; P = .0129), respectively.

Regarding safety, treatment-related adverse effects (TRAEs) of any grade were reported in 88.4% of patients in the investigative arm (n = 303) and 92.0% of those in the control arm (n = 289). Notably, lower rates of grade 3 or greater TRAEs were reported in the lurbinectedin arm vs the control arm, at 47.2% and 75.4%, respectively. Moreover, lower rates of grade 4 TRAEs were reported with lurbinectedin vs SOC (16.2% and 54.7%, respectively); the same was true regarding grade 3 or higher serious AEs (12.5% vs 28.7%), treatment discontinuation associated with AEs (7.6% vs 15.6%), and deaths associated with AEs (0.3% vs 3.5%).

Additionally, lower rates of grade 3 or higher hematologic AEs were reported in the investigative arm vs the control arm, including anemia (14.5% vs 31.1%), neutropenia (37.0% vs 69.2%), and thrombocytopenia (13.9% vs 31.1%).

The most frequently reported grade 3 or higher non-hematologic AE was fatigue; this was experienced by 8.6% of patients in the investigative arm and 10.7% of those in the control arm.

References

1. Paz-Ares L, Ciuleanu TE, Navarro A, et al. Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: phase III randomized ATLANTIS trial. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Abstract PL02.03.
2. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014
3. Paz-Ares LG, Perez JMT, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial. J Clin Oncol. 2019;37(suppl 15):8506. doi:10.1200/JCO.2019.37.15_suppl.8506