Jazz's $1B SCLC drug fails combo trial, quashing hopes of quick full approval. But how much does it matter?
Lurbinectedin was looking like a great turnaround story for Spanish biotech PharmaMar. More than a year after the drug flopped in a Phase III ovarian cancer study, it hit the mark for overall response rate in small cell lung cancer, attracted Jazz Pharma to gamble on a $1 billion pact and landed an accelerated approval earlier this year.
Until it failed the overall survival endpoint in a new Phase III study.
The partners said lurbinectedin, marketed as Zepzelca, didn’t meet the “pre-specified criteria of significance” for OS in the overall population. Patients were given either a combination of the drug and the chemotherapy doxorubicin, or just their physicians’ choice of topotecan or cyclophosphamide/doxorubicin/vincristine.
To be sure, the combo regimen isn’t what the FDA approved. Regulators gave their thumbs up to the monotherapy as a second-line therapy for patients who relapsed following platinum-based chemotherapy. An open-label study showed an ORR of 35.2%, while progression-free survival and OS were 4.6 months and 11.9 months, respectively.
But the disappointing outcome of the new study, dubbed ATLANTIS, may not ncessarily be a crushing blow, said Jack West, a lung cancer specialist at City of Hope.
First, people HATE topotecan (sometimes called “topotecan’t”) and see it as a very weak incumbent that has never clearly deserved its title as standard of care — at best, the results have always damned with faint praise. Second, the trial was with a chemo combo that may very well have been too toxic to allow optimal dosing of lurbinectedin and may have led to early termination of the combination and/or aggressive dose reductions. If the trial had been positive, I think there would have been very little interest in administering the combination, so I would consider lurbinectedin monotherapy as a distinct if somewhat overlapping question, and the fact that the phase 2 experience is over 100 patients makes me consider it clinically meaningful vs. a very dubious current standard of care. It wouldn’t hold up against a more worthy 2nd line standard.
Even though it wasn’t originally planned as confirmatory, Jazz had said that the FDA appeared ready to accept its data for that purpose.
It will now discuss with regulators what evidence they need for full approval. The drug was launched in the US in July.
“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,” Jazz EVP of R&D Robert Iannone said in a statement. “We look forward to the further development of lurbinectedin in SCLC and other tumors, both as monotherapy and in combination.”
Small cell lung cancer has been a difficult field for drug development, with the PD-(L)1 checkpoint inhibitors providing the first options in years.
Alberto Chiappori, an oncologist at Moffitt Cancer Center and an ATLANTIS investigator, said he’s still “confident” lurbinectedin is an “effective new option” for this area.
Jazz and PharmaMar emphasized that no new safety signals were reported, “there was no adverse effect on OS with the experimental arm” and that the dose tested was lower than the FDA-approved dose.