As a second-line treatment for patients with small cell lung cancer (SCLC), lurbinectedin plus doxorubicin failed to improve overall survival in the multicenter ATLANTIS trial, but it did provide other benefits, Luis Paz-Ares, MD, PhD, and colleagues reported at the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer (Abstract PL02.03).
Lurbinectedin is a novel anticancer agent that inhibits transactivated transcription and modulates the tumor microenvironment. In 2020, lurbinectedin dosed at 3.2 mg/m2 every 3 weeks received accelerated approval from the U.S. Food and Drug Administration for patients with metastatic SCLC whose disease has progressed on or after platinum-based chemotherapy. Its observed synergy with doxorubicin formed the rationale for the ATLANTIS study.
Luis Paz-Ares, MD, PhD
“ATLANTIS did not meet the primary endpoint, though comparable efficacy results were observed for the experimental regimen of lurbinectedin plus doxorubicin and the control arm of topotecan or CAV (cyclophosphamide, doxorubicin, vincristine). The experimental arm showed superior safety and tolerability compared to the control arm, with a significantly lower incidence of hematologic toxicities,” reported Dr. Paz-Ares, of the Hospital Universitario 12 de Octubre in Madrid.
Application of a model based on exposure-response analysis predicted that single-agent lurbinectedin at 3.2 mg/m2 (its approved dose) would have yielded significantly higher response rates and significantly longer survival vs topotecan or CAV, Dr. Paz-Ares said.
Additionally, ATLANTIS confirmed chemotherapy-free interval as the most important prognostic factor for the second-line treatment of SCLC. Patients whose interval exceeded 180 days—ie, those with sensitive relapse—derived significant benefit from the experimental regimen.
About ATLANTIS
ATLANTIS was a 17-site trial involving 631 patients with SCLC. Patients had good performance status and limited- or extensive-stage disease; had received one prior platinum-based doublet; and had a chemotherapy-free interval of at least 30 days. Median time from lung cancer diagnosis to random assignment was 9 months. Almost half the patients had bulky disease, and 15% had central nervous system involvement. Six percent had received a checkpoint inhibitor as well as chemotherapy. Median time to disease progression on prior chemotherapy was 7.4 months.
Patients were randomly assigned to the experimental arm of lurbinectedin at 2 mg/m2 plus 40 mg/m2 of doxorubicin every 3 weeks or the control arm of investigator’s choice of chemotherapy: either cyclophosphamide at 1,000 mg/m2, doxorubicin at 45 mg/m2 plus vincristine at 2 mg (CAV) every 3 weeks, or at topotecan 1.5 mg/m2 every 3 weeks.
Benefits Did Not Include Overall Survival
Median overall survival was 8.6 months in the experimental arm vs 7.6 months in the control arm (hazard ratio [HR] = 0.967, P = .7032).
“You can see these curves were superimposable,” Dr. Paz-Ares said, “but there was some improvement in progression-free survival.”
Median progression-free survival by independent review was 4.0 months (95% confidence interval [CI] = 3.0–4.1) with lurbinectedin/doxorubicin and 4.0 months (95% CI = 3.0–4.1) with control treatment (HR = 0.831, P = .0437). At 12 months, 10.8% of the patients in the experimental arm had not experienced disease progression compared to 4.4 % of the control arm (P = .0129).
Objective response rates were 31.6% with lurbinectedin/doxorubicin and 29.7% with topotecan or CAV. Median duration of response was 5.7 vs 3.8 months (HR = 0.581, P = .0012).
Chemotherapy-Free Interval May Be Important
The Forest plot of relevant subsets revealed the importance of the chemotherapy-free interval in predicting benefit. Patients with a very short interval (< 90 days) clearly derived little benefit from either approach, as median progression-free survival was 1.6 months in the experimental arm and 2.8 months in the control arm (HR = 1.3). Median overall survival for this group was 5.7 months and 5.3 months, respectively (HR = 1.122).
On the other hand, those with a prolonged chemotherapy-free interval (≥ 180 days) clearly benefited from lurbinectedin/doxorubicin, as their median progression-free survival was 8.2 months vs 4.5 months for standard-of-care treatment (HR = 0.469, 95% CI = 0.327–0.674) and median overall survival was 12.7 months and 9.8 months, respectively (HR = 0.847, 95% CI = 0.605–1.187).
KEY POINTS
- Lurbinectedin plus doxorubicin did not improve overall survival (the primary endpoint) in the ATLANTIS trial.
- The combination did improve progression-free survival and duration of response and was better tolerated than chemotherapy.
- Lurbinectedin will continue to be studied in other combinations, including irinotecan and checkpoint inhibitors.
Better Tolerability
“On a more positive side, the safety profile of the experimental treatment was better,” said Dr. Paz-Ares. “Importantly, there was half the rate of neutropenia.”
Patients treated in the experimental arm had significantly less grade 3 and 4 adverse events than those receiving topotecan or CAV (47% vs 75%). These were largely hematological, including less grade ≥ 3 anemia (14% vs 31%, P < .0001), neutropenia (37% vs 69%, P < .0001), febrile neutropenia (4% vs 8%, P = .0377) and thrombocytopenia (14% vs 31%, P < .0001). These events occurred in spite of mandatory use of prophylaxis granulocyte colony–stimulating factor in both arms.
Treatment delays, reductions, and discontinuations were also much more frequent with topotecan or CAV. No major differences were observed in nonhematologic toxicities, he reported.
Exposure-Response Analysis Suggests Benefit of Single Agent
Since a statistically significant relationship between lurbinectedin pharmacokinetic exposure (AUC) and overall survival has been observed in the second-line treatment of SCLC, investigators performed an exposure-response analysis, developing a model to assess the contribution of the drug to survival and to measure the impact of prognostic factors. The model was used to predict survival with 3.2 mg/m2 lurbinectedin as a single agent in patients of the ATLANTIS experimental arm compared to control patients.
This regimen showed superiority over the standard therapy in the overall population and in patients with sensitive relapse (chemotherapy-free interval = ≥ 90 days), thus confirming the activity in the phase III randomized, controlled setting.
Charles Rudin, MD, PhD
Charles Rudin, MD, PhD, Hassenfeld Professor and Chief of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, commented that while ATLANTIS “joins the ranks of negative phase III studies in patients with recurrent SCLC,” it also “offers support for the efficacy of lurbinectedin,” especially as a single agent. While demonstrating similar outcomes to the standards of care, it has a superior safety profile, especially regarding hematologic toxicity.
“Lurbinectedin offers a new platform on which to build better combination options for patients with recurrent SCLC,” he said, reminding listeners, “The oncologist’s glass is always half full.”
Importantly, new combinations of lurbinectedin with other cytotoxic agents, such as irinotecan and immune checkpoint inhibitors, are being explored and are expected to return better results.
Disclosure: Dr. Paz-Ares serves on the board of Altum Sequencing and GEnomica. He has received honoraria or travel fees from AstraZeneca, AstraZeneca Spain, Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche/Genentech, Bayer, Amgen, Blueprint, Celgene, Guardant, Merck Serono, Mirati, Novartis, PharmaMar, and Takeda. He reported other relationships with HMP, Ipsen, Merck, Novartis, Sanofi and Servier. Dr. Rudin has consulted for AbbVie, Amgen, Astra Zeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly and Syros and has served on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics.
