An independent panel of advisers voted to approve Genentech’s Polivy after internal FDA staff raised concerns regarding the efficacy and risk-benefit profile as a first-line treatment for large B-cell lymphoma.
Pictured: Roche building against blue sky backdrop/Grand Warszawski/Shutterstock
An independent panel voted to approve Genentech (Roche)’s Polivy (polatuzumab vedotin-piiq) as a first-line treatment for large B-cell lymphoma (LBCL) after FDA staff raised concerns regarding the efficacy and risk-benefit profile of the treatment earlier in the week.
The Oncologic Drugs Advisory Committee, a group of independent advisers, voted 11-to-2 to support a favorable benefit-risk profile for Polivy in front-line LBCL as part of a five-drug regimen.
In briefing documents released ahead of the meeting, ODAC called Polivy’s progression-free survival (PFS) benefit “modest” in this indication. The advisers also noted the lack of improvement in overall survival (OS) and complete response (CR).
Polivy is an antibody-drug conjugate that binds to the CD79b protein, which is only found on B-cells and delivers its cytotoxic payload into these cells. This mechanism of action and its promising performance in the Phase Ib/II GO29365 study earned accelerated approval from the FDA in June 2019 for diffuse LBCL (DLBCL).
To keep the ADC on the market, Genentech ran the Phase III POLARIX trial, which positioned Polivy as a “new standard of care for the first-line treatment of DLBCL,” Levi Garraway, M.D., Ph.D., chief medical officer and head, Global Product Development, Genentech, said at the time.
The trial combined Polivy with four other drugs – Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone – yielding an experimental regimen dubbed pola+R-CHP. Efficacy was primarily measured as PFS and was compared against the standard of care in DLBCL, a regimen called R-CHOP.
POLARIX showed that pola+R-CHP significantly improved PFS by 27%, indicating that the study met its primary endpoint. These data formed the basis for Genentech’s supplemental Biologics License Application to the FDA, seeking to push Polivy into the frontline.
“POLARIX provides substantial evidence of effectiveness and safety by demonstrating that pola+R-CHP provides a clinically meaningful benefit with a comparable safety profile to R-CHOP,” Genentech wrote in the briefing documents for Thursday’s meeting.
The FDA’s Concerns
While Polivy’s PFS benefit satisfied statistical significance, FDA staffers found the magnitude of its effect to be modest and wrote, “It is questionable whether this rate of difference is clinically meaningful.”
The advisers also flagged Polivy’s lack of benefits in CR and OS. At a median follow-up time of 39.7 months, the pola+R-CHP regimen only reduced the risk of death by 6% relative to R-CHOP, an effect that fell short of statistical significance.
In some cases, especially during POLARIX’s early time points and in the subgroup of patients with DLBCL, OS data favored the R-CHOP arm.
“While there is uncertainty associated with the point estimates due to low event rates, lack of improvement in OS, particularly in the context of frontline therapy for LBCL, reflects safety and efficacy and adds to the uncertainties in benefit-risk,” the advisers wrote.
They also noted that Polivy did not result in significantly higher CR rates and likewise had a modest benefit in terms of disease-free survival, duration of response and event-free survival.
