Marine-Derived Drug Anchors Chemo Regimen in SCLC Trial

Ariela Katz
Published: Thursday, Jun 01, 2017
Anna F. Farago, MD, PhD

Anna F. Farago, MD, PhD

Lurbinectedin (PM01183 or PM1183), a transcription inhibitor that induces DNA double-strand breaks, is being combined with doxorubicin in a phase III trial for 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.

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. 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 the combination of vincristine, cyclophosphamide, and doxorubicin (CAV) (Figure). The primary endpoint of the trial is progression-free survival, with overall survival (OS) and the OS rate at 12, 18, and 24 months as secondary endpoints.


Figure 1. Lurbinectedin in Small Cell Lung Cancer

Lurbinectedin in Small Cell Lung Cancer

Lurbinectedin inhibits RNA polymerase II, an enzyme essential for the transcription process that is overactivated in certain tumors.1 By blocking trans-activated transcription, lurbinectedin induces a cascade of events promoting apoptosis.

Lurbinectedin may also modulate the tumor microenvironment to promote an antitumor response.2 The drug, 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.

Investigators believe that since the mechanism of action of lurbinectedin and other biologics differs from standard cytotoxic chemotherapy, it is possible that SCLC tumors that have become resistant to standard chemotherapy may remain sensitive to lurbinectedin, said Anna F. Farago, MD, PhD, principal investigator for the ATLANTIS trial.

Although chemotherapy combinations are a mainstay of treatment for patients with SCLC, recurrence rates after platinum-based first-line therapy are high and 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 Farago, an attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital in Boston 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.

“There is a great need for improved treatment for these patients,” Farago added. “SCLC accounts for about 15% to 20% of the 1.6 million annual new cases of lung cancer worldwide, so that’s a tremendously large number of patients.”

Doxorubicin itself has shown some activity in SCLC, according to Farago, and it is part of several combination therapies, including CAV, that are 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 is aimed at defining whether the novel combination is superior to other second-line options.

The rationale for the trial stems from a phase I dose escalation study of the lurbinectedin/doxorubicin combination in a variety of solid tumor types, including SCLC. The results, which were presented at the 2015 American Society of Clinical Oncology Annual Meeting, showed an overall response rate of 67%, including a 10% complete response rate, among 21 patients with SCLC treated with the combination as second-line therapy and a generally tolerable adverse event (AE) profile.2

“The caveats, of course, are that this is a very small cohort and this is a phase I study with a selective patient population,” said Farago. “Nonetheless, this was certainly a signal of activity in this population and, I think appropriately, the sponsor was interested in looking at this treatment strategy in this population in more detail.”

The most notable AEs in the phase I trial were neutropenia and febrile neutropenia; incidence of grade 3/4 neutropenia of 96% while the rate of febrile neutropenia was 24% for grade 3 and 5% for grade 4.2 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.

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