Despite Failure to Meet Phase III Primary Endpoint, Jazz’s SCLC Drug Holds Promise

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Results from the randomized, Phase III ATLANTIS trial show Zepzelca™ (lurbinectedin), when combined with doxorubicin, was safe and produced clinical activity in adults with progressed small cell lung cancer (SCLC). While promising, the study showed no difference between this combination regimen and physician's choice of topotecan or cyclophosphamide/doxorubicin/vincristine (CAV) in terms of overall survival (OS).

Lurbinectedin, an alkylating drug designed to bind guanine residues within DNA, leads to disruption in the cell cycle. The drug, which is the result of a collaborative effort between Jazz Pharmaceuticals and PharmaMar, interferes with transcription factors involved in cancer cell growth and can lead to cell death.

In the ATLANTIS trial, a total of 613 patients with SCLC were enrolled at 154 sites across the globe. All patients had either limited or extensive stage SCLC, had experienced failure on one prior platinum-containing regimen or had presented with at greater than 30 days following the last dose of first-line chemotherapy to the occurrence of progressive disease.

Participants in the study were randomly assigned to either doxorubicin plus lurbinectedin 2.0 mg/m2, a dose lower than the FDA-approved dose of 3.2 mg/m2, or physician's choice consisting of topotecan or CAV.

The primary endpoint of ATLANTIS was OS. Key secondary endpoints included the difference in OS between the combination group and the CAV group, OS and progression-free survival (PFS) for patients with versus without central nervous system involvement, duration of response (DOR), and antitumor activity.

According to the researchers, the study did not meet the pre-specified criteria of significance for the primary endpoint of OS, indicating no difference was observed between the two treatment groups in terms of survival. The researchers noted, however, that there were no adverse effects on OS with the lurbinectedin combination regimen. In contrast, key secondary and subgroup analyses favored lurbinectedin/doxorubicin over the CAV arm.

Side effects associated with lurbinectedin include low white and red blood cell counts, liver issues, fatigue, elevated blood sugar, nausea, appetite loss, muscle and joint pain, reduced albumin blood levels, constipation, low sodium and magnesium levels, cough, vomiting and diarrhea.

In the study, there were no new safety signals with the experimental therapy, and safety data were consistent with the known profile of lurbinectedin. Compared with the control arm, patients assigned to lurbinectedin/doxorubicin had favorable safety and tolerability in regard to Grade III or higher drug related adverse events (AEs), deaths due to AEs, hematologic toxicity, dose reductions and treatment discontinuations due to AEs.

Although the study did not see a significant achievement of the primary endpoint, the ATLANTIS investigators suggest the believe the therapy still holds promise for patients. "Historically, patients with relapsed SCLC often face difficult odds due to the aggressive nature of the disease and they have had very limited treatment options. As a physician treating patients with SCLC, I'm confident in lurbinectedin as an effective new option in this traditionally challenging therapeutic area," said Alberto Chiappori, MD, senior member of oncology and medicine for the Department of Thoracic Oncology at the H. Lee Moffitt Cancer Center and Research Institute and ATLANTIS Phase 3 study investigator, in a statement.

In June, the U.S. Food and Drug Administration (FDA) provided accelerated approval for Jazz and PharmaMar’s lurbinectedin for the treatment of metastatic SCLC that has progressed either during or after platinum-based chemotherapy. This approval was based on clinical data from a 105-patient trial that showed lurbinectedin conferred an overall response rate of 35% and a median DOR of 5.3 months. Jazz and PharmaMar plan to provide the ATLANTIS trial data to the FDA to determine which confirmatory data are needed for lurbinectedin to receive full approval for SCLC.

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