Bucking FDA, independent panel backs Roche's lucrative lymphoma expansion bid for Polivy

Even after FDA staffers voiced serious doubts about Roche’s practice-changing application for Polivy in previously untreated diffuse large B-cell lymphoma (LBCL), a group of independent advisers to the agency has overwhelmingly endorsed the company’s vision. 

Thursday, the FDA’s Oncologic Drugs Advisory Committee voted 11 to 2 in support of a favorable benefit-risk profile for Polivy in front-line LBCL as part of a five-drug regimen.

The suport came in stark contrast to uncertainties raised by the FDA staff. In briefing documents ahead of Thursday’s advisory committee, the agency argued that Polivy’s ability to reduce disease progression or death over the standard R-CHOP regimen was moderate as demonstrated in the phase 3 POLARIX trial. The FDA also said the drug didn't show a definitive life extension benefit over the standard therapy.

The current standard of care for front-line LBCL is the well-established R-CHOP regimen. With its filing, Roche is angling for Polivy to replace the Oncovin (O) component in that treatment.

The FDA doesn’t have to follow the recommendations of its advisory committees, but it typically does. The endorsement could set Polivy up as the first new treatment for front-line diffuse large B-cell lymphoma (DLBCL) in nearly two decades. Roche and analysts have previously estimated the indication could be worth $2 billion in peak sales.

In the POLARIX study, Polivy’s combination with R-CHP cut the risk of progression or death by 27% over R-CHOP. Patient-reported treatment experiences were similar between the two treatment arms.

On overall survival, the Polivy combo only reduced the risk of death by 6% versus the standard therapy. In its review, the FDA noted the small survival benefit might have been driven by a subgroup of patients with high-grade B-cell lymphoma (HGBL). In POLARIX, 84% of patients had DLBCL, and 11% had HGBL.

As to safety, the FDA agreed with Roche’s conclusion that the overall safety profile of the Polivy regimen was comparable to R-CHOP.

The main argument Roche and its experts employed during Thursday’s hearing centered on reducing patients' need for subsequent therapies. In the R-CHOP arm, 30.3% patients required subsequent treatment, versus 22.5% for the Polivy regimen. However, this benefit wasn’t captured in Roche’s analysis of patient-reported outcomes as the trial stopped collecting quality-of-life measures upon a patient’s disease progression.

Despite the uncertainties, members of the FDA advisory committee generally agreed that although Polivy’s progression-free survival improvement was modest, POLARIX is indeed a positive trial. They largely concluded Polivy is an efficacious drug with no additional toxicity over R-CHOP.

As Anthony Sung, M.D., from the Duke University School of Medicine, said, “if we can cure more patients, it’s a win.”

Ravi Madan, M.D., from the National Cancer Institute, also noted the difficulty in beating the highly efficacious R-CHOP regimen.

“While the [POLARIX] data is not as robust as we’re used to seeing in oncology settings, I’m not convinced that you can have a robust improvement on a highly effective regimen such as R-CHOP without designing an impractically large study,” Madan said.

Improving care for LBCL “may need to start with seemingly small incremental but clinically meaningful and statistically significant steps such as this,” he added.

The positive vote has made an approval for Polivy in front-line LBCL increasingly likely, but changing two decades of practice is another matter.

“I would consider this regimen to be an option, rather than a standard,” Greg Nowakowski, M.D., from the Mayo Clinic, said of Polivy. “In a setting of lack of overall survival difference from R-CHOP, I would consider them equivalent.”

The FDA is scheduled to decide on Roche’s application in previously untreated DLBCL by April 2.