The phase III ATLANTIS trial is testing the investigational synthetic analogue lurbinectedin in combination with doxorubicin for use in patients with recurrent small cell lung cancer (SCLC) in the hopes of providing a superior option to the current standard-of-care second-line chemotherapy. SCLC accounts for between 15% and 20% of the 1.6 million annual new cases of lung cancer worldwide.
RATIONALEAlthough chemotherapy combinations are a mainstay of treatment for patients with SCLC, recurrence rates after platinum-based first-line therapy are high. Effective second-line options are limited.
“SCLC is a disease in which the outcomes have not improved in the past 30 years of treating patients,” said principal investigator Anna F. Farago, MD, PhD, an attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. “We haven’t seen any regimen superior to topotecan in the second-line setting, although several have been investigated.”
Doxorubicin has shown some activity in SCLC, according to Farago, and it is part of several combination therapies, including vincristine/ cyclophosphamide/doxorubicin (CAV), which is administered in later lines of treatment. However, there has not been a head-to-head comparison of lurbinectedin plus doxorubicin versus standard-of-care chemotherapy, so the design of the ATLANTIS trial aims to define whether the novel combination is superior to other secondline options.
TRIAL DESIGNLurbinectedin, which is administered intravenously, is a synthetic compound that is structurally related to trabectedin (Yondelis), a marine-derived agent that is FDA-approved for patients with metastatic liposarcoma or leiomyosarcoma. In the ATLANTIS trial, participants will be randomized either to the experimental arm of lurbinectedin plus doxorubicin or to 1 of 2 control arms consisting of either topotecan or CAV. The primary endpoint of the trial is progression-free survival.
ADVERSE EVENTSThe most notable adverse events (AEs) in a phase I dose escalation study of the lurbinectedin/ doxorubicin combination in a variety of solid tumor types were neutropenia and febrile neutropenia. Grade 3/4 neutropenia occurred in 96% of patients whereas the rate of febrile neutropenia was 24% for grade 3 and 5% for grade 4. After those AEs were noted in the first cohort of patients, investigators began administering granulocyte colony-stimulating factor (G-CSF) to all participants, Farago said. The phase III study requires that patients on all arms of the ATLANTIS trial receive G-CSF support prophylactically.
WHO IS ELIGIBLE?The ATLANTIS trial (NCT02566993) is seeking to enroll 600 patients with SCLC whose disease has progressed following 1 prior platinum-containing regimen and who have had a chemotherapy-free interval ≥30 days from the time of their last dose of first-line chemotherapy to progressive disease.
If successful, the lurbinectedin/doxorubicin combination could offer a strategy for improving survival, which would be a breakthrough for patients with SCLC. “The median survival from the time of diagnosis is 9 to 11 months for patients diagnosed with metastatic disease, even when patients are treated with the most aggressive therapies. The 5-year [overall survival] is less than 5%. There is a great need for improved therapies,” Farago said.
PharmaMar, a company based in Madrid, Spain, is also developing lurbinectedin for use in platinum-resistant ovarian cancer and other solid tumor types.