Pharmamar’s Pivotal Small-Cell Lung Cancer Trial is Finally Confirmed a Dud, But Will the FDA Pull Zepzelca From The Market ? .
A much-delayed readout from a study conducted in an incredibly intractable tumour type would typically raise red flags for biotech investors. Thus those anticipating the failure of Pharmamar’s Atlantis trial were proved right today – no survival benefit was found for small-cell lung cancer patients treated with Zepzelca.
The big problem here is that Atlantis could have turned Zepzelca’s accelerated approval, won earlier this year with the help of US partner Jazz Pharmaceuticals, into a full marketing licence. The FDA would now seem to have grounds to pull the drug from the market, although few expect that to happen.
Jazz shares dipped only 1% on the news. Zepzelca sales are not hugely important to the company for now, although the cancer drug is projected to become its biggest seller once the narcolepsy treatment Xyrem loses patent protection in 2023. Supportive sellside analysts covering Jazz brushed off today’s failure, claiming that that Atlantis was never designed as a confirmatory trial, and saying that the risk of the FDA pulling Zepzelca from the market was low.
Unmet need
It is certainly true that the US regulator rarely flexes its muscles in this way, and in a disease like small cell lung cancer this would be even more surprising. A couple of checkpoint inhibitors have managed to tease out a benefit in a first-line setting; however, a patient’s prognosis is typically bleak (Surprise! There’s a tumour in which Keytruda doesn’t work, January 7, 2020).
Zepzelca as monotherapy won approval earlier this year – two months ahead of schedule – in a second-line setting based on an overall response rate of 35%. This was derived from a single-arm study, however, thus the need for a confirmatory trial.
Mr Besman said Jazz would be handling further negotiations with the FDA, and would not be drawn on whether Atlantis might yield enough evidence to satisfy the regulator, or what any subsequent confirmatory trial might look like.
It seems highly unlikely that Atlantis will suffice, however. The study tested Zepzelca plus doxorubicin versus topotecan or the CAV chemo regimen in a second-line setting. No overall survival signal was seen, “though there was no adverse effect on OS with the experimental arm”, the company said.
This is presumably an attempt to reassure doctors wondering whether Zepzelca should still be used in any setting. As to why Atlantis failed, Mr Besman said there was no one reason he could point to. “The trial was conducted well, it was well powered, the control arm behaved as expected, and there were no new safety signals,” he told investors.
Key secondary endpoints and subgroup analyses “favoured” the active arm, the company said, so it sounds as though very little will be salvaged from the full data, when they are published.
Assuming the FDA chooses to give Zepzelca another chance, this means physicians will be left to decide whether there is sufficient evidence to warrant the drug’s ongoing use. After a stronger than expected US launch, Jazz investors will be keen to see that Atlantis does not change the drug’s outlook.
Even if the FDA does demand another confirmatory trial, it will be Jazz’s Spanish partner that has to run it and pay for it. Throw in the fact that positive phase III data were probably going to be required to convince European regulators to approve Zepzelca, and it is clear that Pharmamar is the biggest casualty of Alantis’s sinking.