As a second-line treatment for patients with small cell lung cancer, lurbinectedin plus doxorubicin failed to improve overall survival in the multicenter ATLANTIS trial but did provide other benefits, including better tolerability, researchers reported at the 2021 World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.1
“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 with the control arm, with a significantly lower incidence of hematologic toxicities,” reported Luis Paz-Ares, MD, PhD, of the Hospital Universitario 12 de Octubre, Madrid.
Lurbinectedin is … clearly effective, and the toxicity profile is mild as compared to topotecan and other standards of care.— Luis Paz-Ares, MD, PhD
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An exposure-response analysis predicted significantly higher response rates and significantly longer survival for single-agent lurbinectedin at 3.2 mg/m2 (the approved dose) vs control.2 Additionally, ATLANTIS confirmed the chemotherapy-free interval as an important prognostic factor for second-line small cell lung cancer.
Patients with a chemotherapy-free interval of at least 180 days had a median progression-free survival of 8.2 months vs 4.5 months for standard-of-care treatment (hazard ratio [HR] = 0.469; 95% confidence interval [CI] = 0.327–0.674) and a median overall survival of 12.7 months and 9.8 months, respectively (HR = 0.847; 95% CI = 0.605–1.187).
“Lurbinectedin is really an effective treatment. The activity is not overwhelming—as no agents are in this setting—but it’s clearly effective, and the toxicity profile is mild as compared with topotecan and other standards of care,” Dr. Paz-Ares commented.
Lurbinectedin is a novel anticancer agent that inhibits transactivated transcription and modulates the tumor microenvironment. In 2020, it received accelerated approval from the U.S. Food and Drug Administration given at 3.2 mg/m2 every 3 weeks for patients with metastatic small cell lung cancer progressing on or after platinum-based chemotherapy. Its observed synergy with doxorubicin formed the rationale for the ATLANTIS study.
ATLANTIS was a 17-site trial involving 631 patients with small cell lung cancer. Patients had a good performance status and limited- or extensive-stage disease, had received one prior platinum-based chemotherapy regimen, and had a chemotherapy-free interval of at least 30 days. The median time from lung cancer diagnosis to randomization was 9 months. Almost half the patients had bulky disease, and 15% had central nervous system involvement. A total of 6% had received a checkpoint inhibitor as well as chemotherapy. The 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) every 3 weeks or topotecan at 1.5 mg/m2 every 3 weeks.
Benefits Did Not Include Overall Survival
Median overall survival was 8.6 months in the experimental arm and 7.6 months in the control arm (HR = 0.967; P = .7032). “You can see these curves were superimposable,” Dr. Paz-Ares said. “There was, however, an improvement in progression-free survival.”
Median progression-free survival by independent review was 4.0 months with both lurbinectedin/doxorubicin (95% CI = 2.8–4.2 months) and topotecan or CAV (95% CI = 3.0–4.1 months; HR = 0.831; P = .0437). At 12 months, 10.8% of the experimental arm was progression-free compared with 4.4 % of the control arm (P = .0129).
Objective response rates were 31.6% with lurbinectedin/doxorubicin and 29.7% with topotecan or CAV. The median duration of response was 5.7 vs 3.8 months, respectively (HR = 0.581; P = .0012).
You can see these [overall survival] curves were superimposable. There was, however, an improvement in progression-free survival [with lurbinectedin plus doxorubicin].— Luis Paz-Ares, MD, PhD
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Chemotherapy-Free Interval May Be Important
Chemotherapy-free interval was an important predictor of 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), and median overall survival 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). Median overall survival was 12.7 months and 9.8 months, respectively (HR = 0.847; 95% CI = 0.605–1.187), he reported.
“On a more positive side,” Dr. Paz-Ares said, “the safety profile of lurbinectedin/doxorubicin was better. Importantly, with this regimen, there was half the rate of neutropenia and fewer serious adverse events and deaths.”
With lurbinectedin/doxorubicin, there were significantly fewer grade 3 or 4 adverse events as compared with topotecan or CAV (47% vs 75%). These effects were largely hematologic, 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 adverse events occurred despite the mandatory prophylactic use of 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 Points to Benefit of Single Agent
Since a statistically significant relationship between lurbinectedin pharmacokinetic exposure and overall survival has been observed in the second-line treatment of small cell lung cancer, 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.2 The model was used to predict survival with 3.2 mg/m2 of lurbinectedin as a single agent in the ATLANTIS experimental arm, compared with control patients.
This regimen showed superiority over standard therapy in the overall population, as well as in patients with sensitive relapse (chemotherapy-free interval ≥ 90 days), thus confirming the activity in a phase III randomized, controlled setting, Dr. Paz-Ares reported. In this model, hazard ratios for overall survival were 0.54 (95% CI = 0.41–0.72) in all patients, 0.40 (95% CI = 0.28–0.57) in patients with sensitive relapse, and 0.94 (95% CI = 0.57–1.56) in those with resistant disease.
“The exposure-response analysis predicted significantly higher response rates and significantly longer survival for single-agent lurbinectedin (3.2 mg/m2) in the experimental arm of ATLANTIS vs the control arm,” he said. “This model suggests that if patients had been treated with single-agent lurbinectedin, they would have benefited, particularly those with sensitive relapse. Of course, this is only a model.”
New combinations of lurbinectedin with other cytotoxic agents, such as irinotecan, and immune checkpoint inhibitors are being explored.
DISCLOSURE: Dr. Paz-Ares serves on the boards of Altum Sequencing and Genomica; 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; and reported other relationships with HMP, Ipsen, Merck, Novartis, Sanofi, and Servier.
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. 2021 World Conference on Lung Cancer. Abstract PL02.03. Presented September 9, 2021.
2. Fudio S, Perez-Ramos L, Wang Q, et al: Exposure-response analysis of lurbinectedin alone or with doxorubicin in overall survival in small cell lung cancer. 2021 World Conference on Lung Cancer. Abstract P63.02. Presented September 8, 2021.
Charles M. Rudin, MD, PhD, Hassenfeld Professor and Chief of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, commented that although ATLANTIS1 “unfortunately joins the ranks of negative phase III studies in patients with recurrent small cell lung cancer,” there are “some...