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Despite the concerns of FDA staff, agency advisors endorsed the inclusion of polatuzumab vedotin (Polivy) in a modified version of R-CHOP for adults with previously untreated large B-cell lymphoma.

By a vote of 11-2 on Thursday, the agency's Oncologic Drugs Advisory Committee (ODAC) said findings from the phase III supported a favorable risk-benefit assessment for including the CD79b-directed antibody-drug conjugate as part of the first-line regimen.

During the meeting, FDA reviewers noted that while of progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), that improvement was "modest," and was accompanied by no improvement in overall survival (OS), as well as other secondary efficacy endpoints.

However, ODAC members on the whole were convinced that this version of the standard-of-care regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone), in which vincristine was replaced by polatuzumab vedotin (pola+R-CHP), achieved a clinically meaningful improvement in PFS relative to standard R-CHOP.

"I believe this gain in progression-free survival is clinically meaningful for patients, and also leads to a reduction in the need for subsequent therapy," said Grzegorz Nowakowski, MD, of the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, in explaining his "yes" vote. "And there were no major adverse toxicity signals, which would have been detrimental in this study."

"However," he added, "I would consider this regimen to be an option, rather than a standard, in the setting of a lack of overall survival difference from R-CHOP."

Ravi A. Madan, MD, of the National Cancer Institute in Bethesda, Maryland, pointed out that R-CHOP has historically "been a regimen very hard to improve on, largely because of its roughly 70% efficacy rate."

"The data reviewed today with R-CHP and polatuzumab does meet its endpoint of PFS relative to R-CHOP, and while PFS is not always meaningful, in this case I think it is," he added. "And while the data are not as robust as we're used to seeing in oncology settings, I'm not convinced you can have a robust improvement on a highly effective regimen such as R-CHOP without designing an impractically large study."

Polatuzumab vedotin in combination with bendamustine and rituximab (BR) for the treatment of adults with relapsed/refractory DLBCL not otherwise specified, after at least two prior therapies.

That approval was based on a study of 80 patients randomized 1:1 to polatuzumab vedotin plus BR or BR alone for 6 cycles. At the end of therapy, the complete response rate in the combination arm was 40% compared with 18% with BR.

POLARIX -- the confirmatory trial to determine polatuzumab vedotin's clinical benefit -- included 879 patients with previously untreated intermediate- or high-risk DLBCL randomized to pola+R-CHP or R-CHOP, and met its primary endpoint, with a statistically significant improvement in PFS with pola+R-CHP relative to standard R-CHOP (HR 0.73, 95% CI 0.57-0.95, P=0.02).

Although the difference in PFS was statistically significant, during the ODAC meeting, FDA reviewer Maryam Yazdy, MD, of the Division of Hematologic Malignancies 2 at the Office of Oncologic Diseases, noted that the effect size -- a 4.1% absolute improvement in PFS at 1 year, and 6.5% at 2 years -- "was modest."

"Furthermore, it remains challenging to assess the contribution of pola+R-CHP," given the fact that the activity of the drug it replaced -- vincristine -- is uncertain in the R-CHOP regimen, Yazdy said.

She also pointed out that there was no significant difference in secondary efficacy endpoints, such as complete response and patient-reported outcomes, and, most importantly, OS.

With a follow-up of 39.7 months, polatuzumab vedotin plus R-CHP failed to show improved OS, with an HR of 0.94 (95% CI 0.67-1.33), and an HR of 1.02 in the largest histological subgroup, DLBCL not otherwise specified.

"The lack of improvement in overall survival, particularly in the context of frontline therapy for diffuse large B-cell lymphoma, is a reflection of safety and efficacy, and adds to the uncertainty in benefit/risks," Yazdy said.

The Relevance of PFS and OS

Christopher Flowers, MD, of the University of Texas MD Anderson Cancer Center in Houston, who was an investigator for POLARIX, argued that not only was the PFS result "clinically meaningful," but that PFS, rather than OS, may be a more relevant endpoint in this first-line setting.

He pointed to an of 13 randomized trials showing that OS as an endpoint in first-line DLBCL would require more than a decade of follow-up. "In my view, this is an unacceptably long time to wait to determine whether a new therapy benefits patients," Flowers said. "With that said, PFS as an endpoint measures and reflects what is meaningful for patients."

He noted that the design of previous randomized trials supports an HR of 0.75 -- representing a 5%-7% improvement in PFS at 2 years -- as an indicator of clinical benefit, and that POLARIX met this standard.

"When we think about treatment for large B-cell lymphoma, first-line therapy offers the best chance for cure," Flowers said. "With R-CHOP as the only FDA-approved therapy, there remains an unmet need to reduce relapse and progression in first-line patients."

"At MD Anderson, we see approximately 500 newly diagnosed patients with large B-cell lymphoma every year," he added. "An improvement in PFS of 5%-7% means that 25 t0 35 of those patients might avoid relapse of disease or the need for subsequent treatment."

This argument was particularly compelling for several ODAC members.

"I think the importance of this drug -- what Dr. Flowers and others have been saying -- is that as frontline therapy, if we can cure more patients, that's a win," said Anthony Sung, MD, of Duke University School of Medicine in Durham, North Carolina. "I think if we can say to our patients, you have a greater chance of being cured with this regimen, I think that many patients would take it, and I think as a provider I would prescribe it."

However, Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, was unconvinced.

Sekeres, one of the two "no" votes, was particularly troubled by the fact that the initial lymphoma diagnosis in POLARIX was not confirmed by independent central review, nor was disease progression.

"I felt this trial didn't meet the basics of a large clinical trial in hematological malignancies," he said. "There wasn't confirmation of the diagnosis, and there wasn't confirmation of whether or not patients actually progressed before they were removed from the trial."

"Progression-free survival, in and of itself, in a disease that has comparatively lower mortality rates is okay, as long as it has supportive data, but I couldn't trust whether or not a patient has truly progressed on this study," he added.

While the FDA is not required to follow the advice of its advisory committees, it usually does.

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