Lurbinectedin regimen fails to prolong OS but shows activity in small cell lung cancer
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Lurbinectedin plus doxorubicin did not improve OS among patients with small cell lung cancer, according to results of the randomized phase 3 ATLANTIS trial.
However, the findings — presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer — did show the combination is active among this patient population after failure of one previous line of platinum-based chemotherapy.
“Promising data in the preclinical setting of lurbinectedin [Zepzelca; Jazz Pharmaceuticals, PharmaMar] showed the agent had a direct antitumor effect plus the ability to reshape the tumor microenvironment to be more immunogenic,” Luis Paz-Ares, MD, PhD, chair of the department of medical oncology at Hospital Universitario in Madrid, told Healio. “Then there were encouraging single-agent data in the relapsed disease setting that showed a relative risk of 34%, particularly in sensitive disease. The associated toxicity profile is also quite favorable, and the initial combination studies of lurbinectedin plus doxorubicin were effective.”
The multicenter ATLANTIS trial enrolled 613 patients with ECOG performance status of 2 or less and confirmed diagnosis of limited- or extensive-stage SCLC. All patients had failed one prior platinum-containing regimen.
Paz-Ares and colleagues assigned half of patients (n = 307; median age, 63 years; 57.3% men) to lurbinectedin dosed at 2 mg/m² plus doxorubicin dosed at 40 mg/m² on day 1 every 3 weeks. The other half (n = 306; median age, 63 years; 56.5% men) was assigned to investigator’s choice of topotecan dosed at 1.5 mg/m² on days 1 to 5 every 3 weeks or the combination of cyclophosphamide, doxorubicin and vincristine on day 1 every 3 weeks. Treatment in both groups continued until disease progression or unacceptable toxicity.
OS served as the primary endpoint. The difference in OS between the two groups, OS and PFS among patients with or without central nervous system involvement, and PFS, objective response rate and duration of response as assessed by independent review committee served as secondary endpoints.
Results showed median OS of 8.6 months with the lurbinectedin regimen vs. 7.6 months with the control regimen (HR = 0.96; 95% CI, 0.81-1.14). Median PFS was 4 months for both groups.
However, the lurbinectedin group had a higher ORR than the control group (31.6% vs. 29.7%) and longer median duration of response (5.7 months vs. 3.8 months; HR = 0.58; 95% CI, 0.41-.81).
The observed treatment-associated adverse events reflected the known profile of lurbinectedin, with fewer events observed in the experimental group compared with the control group (88.4% vs. 92%). Researchers also reported fewer grade 3 or higher events in the experimental group (66% vs. 86.5%), including lower rates of grade 3 or higher anemia (14.5% vs. 31.1%), neutropenia (69.2% vs. 37%) or thrombocytopenia (31.1% vs. 13.9%).
“Although the primary endpoint of the ATLANTIS trial was not met — OS data were superimposable between both treatment groups — we did observe some hints of differential activity, particularly in cases of sensitive relapse. These data altogether support further investigation of lurbinectedin in small cell lung cancer,” Paz-Ares said. “Current ongoing research includes identifying whether there are biomarkers that could predict lurbinectedin benefit and the best way to deliver the agent — as a single agent or in combination with other agents. New combinations of lurbinectedin with other cytotoxic agents, such as irinotecan and immune checkpoint inhibitors, are being investigated as we speak.”
Perspective
Back to TopAlthough the trial did not meet the primary endpoint, it is important to keep in mind we see a separation of the curve when we look at duration of response. The combination potentially offers a more prolonged response in a subset of patients. Equally important is the adverse event profile — the combination treatment had a much better profile compared with topotecan. The ATLANTIS study matters hugely for this community because lurbinectedin is a great drug with a good safety profile and has a unique mechanism of action. All of this makes it a greater partner to combine with other agents. Although we did see a potential role for this combination in a subset of patients, for another group of patients we did not see this drug move the needle enough, and it is still not clear what the impact is for the first-line immunotherapy and chemotherapy combination on the response in the second-line setting with this combination.
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Paz-Ares L, et al. Abstract PL02.03. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer (virtual meeting); Sept. 8-14, 2021.
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