Polivy adcom: no overall survival, no problem

Roche’s blockbuster-in-waiting Polivy could be on its way to achieving those billion-dollar sales expectations. Not only did a US advisory panel yesterday vote in favour of its approval in first-line lymphoma, it did so by a surprisingly wide margin of 11 to two.

Of course, the FDA is not bound by the decisions of an adcom, so approval is far from assured, and it is noteworthy that briefing documents seemed negative, focusing on the supporting trial’s lack of an overall survival benefit. As this is something the agency has recently been cracking down on all eyes will now be on Polivy’s 2 April Pdufa date.

There had been doubts about the study in question, Polarix, ever since data from it were first presented at the 2021 Ash conference. Polivy, an anti-CD79b antibody-drug conjugate, carries accelerated US approval for at least third-line diffuse large B-cell lymphoma (DLBCL), but Polarix’s first-line use makes up about two thirds of the drug’s 2028 revenue forecast, which Evaluate Pharma sellside consensus puts at $1.5bn.

The adcom had been convened to explore Polivy’s approvability in the first-line setting, on top of a Rituxan-containing chemo regimen, but it is important to remember that Polarix is also the confirmatory trial for the drug’s third-line label. As such, numerous scenarios are now possible: first-line approval, full approval but only for third-line DLBCL, or withdrawal of the accelerated approval.

Not only was the lack of an OS benefit troubling, briefing documents questioned Polarix’s “modest” PFS advantage and heterogeneous patient population, which they suggested might affect generalisability.

Still, the adcom largely dismissed such fears, apparently being persuaded by PFS curves at 39.7 months’ median follow-up – longer than the 28.2 months in Polarix’s Ash presentation and NEJM paper. The PFS advantage is still evident at the later time point, with a 36-month landmark analysis showing a 7.7% advantage when giving Polivy on top of Rituxan and chemo.

As for lack of OS, the argument that subsequent therapy confounded the Polarix trial’s key secondary endpoint appears to have swung panellists. On progression a respective 23% and 30% of Polivy and control patients received therapy not specified in the protocol, including radiotherapy, transplant and Car-T, with an apparent imbalance in the first two.

Given Polarix’s relatively small sample size of 879 patients, it might be that any OS benefit would have been miniscule even without the confounding factors – not that this will necessarily sway the FDA, which could still ask Roche to carry out longer-term OS analyses, perhaps as a postmarketing commitment.

Forest plots presented suggested minimal benefit backing Polivy in the under-60s, female patients, low-risk patients, and those with bulky disease. How the FDA deals with these will become clear by 2 April, but for now – the 11-2 vote notwithstanding – a risk remains that Polivy’s first-line use might be narrower than the most bullish investors hope for.