The multicenter, randomized, controlled, phase 3 ATLANTIS study, which evaluated lurbinectedin (Zepzelca) in combination with doxorubicin versus physician's choice of topotecan or cyclophosphamide/doxorubicin/vincristine (CAV) for adult patients with small cell lung cancer (SCLC) whose disease progressed following 1 prior platinum-containing line of therapy, did not meet the pre-specified criteria of significance for the primary end point of overall survival (OS) in the intent-to-treat (ITT) population of patients, according to Jazz Pharmaceuticals and its partner PharmaMar, the developers of the agent.
The study compared lurbinectedin in combination with doxorubicin to the control arm, though there was no adverse effect on OS observed within the experimental arm. Trial participants received lurbinectedin at a dose of 2.0 mg/m2 in the combination arm, which is lower than the FDA approved dose of 3.2 mg/m2.
The phase 3 study enrolled a total of 613 patients at 154 sites primarily in the US, Canada, Latin America, and Western Europe from September 2016 through July 2018. Patients enrolled were 18 years or older with histologically or cytologically confirmed diagnosis of limited or extensive stage SCLC, had failed 1 prior platinum-containing regimen, and had a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) of 30 days or more.
Participants were randomized 1:1 to receive either lurbinectedin in combination with doxorubicin or physician's choice of topotecan, or cyclophosphamide/doxor ubicin/vincristine (CAV). The primary end point was OS. Secondary end points included the difference in OS for patients in the lurbinectedin/doxorubicin arm compared to patients treated with CAV, OS and progression-free survival (PFS) in patients with or without central nervous system (CNS) involvement, PFS by independent review committee (IRC), antitumor activity defined by objective response rate (ORR) per IRC, and duration of response per IRC.
Based on the study design, no additional hypotheses were formally tested. However, it is important to note that key secondary and subgroup analyses favored the lurbinectedin combination arm. Lurbinectedin monotherapy was not tested in the trial though.
Regarding safety, the safety data reported in this study was found to be consistent with the known safety profile of lurbinectedin monotherapy, and no new safety signals were observed. Moreover, the experimental arm demonstrated favorable safety and tolerability with regard to grade 3 or greater treatment related adverse events (AEs), deaths due to AEs, hematologic toxicity, dose reductions, and treatment discontinuations due to AEs, compared to the control arm.
"Bringing [lurbinectedin] to the US market earlier this year alongside our partner, PharmaMar, was an important advance for adults with metastatic SCLC, an aggressive disease with a historically poor prognosis," Robert Iannone, MD, MSCE, executive vice president of research and development at Jazz Pharmaceuticals, said in a press release. "While the combination of lurbinectedin and doxorubicin did not achieve the primary endpoint in this study, the overall results support the activity and tolerability of lurbinectedin in this line of therapy. We look forward to the further development of lurbinectedin in SCLC and other tumors, both as monotherapy and in combination."
Results from the ATLANTIS trial will be discussed with the appropriate regulatory authorities and will be presented at a future medical meeting.
Of note, the FDA approved lurbinectedin under accelerated approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval was based on ORR and duration of response demonstrated in an open-label, monotherapy clinical study.
Moving forward, Jazz Pharmaceuticals and PharmaMar will provide the ATLANTIS data to FDA and look forward to working with the agency to determine the confirmatory data that is needed for full approval.