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The FDA's Oncologic Drugs Advisory Committee (ODAC) will meet Thursday to consider whether results from the support a favorable benefit-risk assessment for adult patients with previously untreated large B-cell lymphoma (LBCL) treated with a modified version of R-CHOP with polatuzumab vedotin (Polivy).

A issued in advance of the meeting suggested that FDA reviewers believe there are a number of issues in that "raise uncertainty about the benefit-risk of polatuzumab vedotin in this frontline, curative-intent setting."

Polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, combined with bendamustine and rituximab for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (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 in combination with bendamustine and rituximab or bendamustine and rituximab alone for 6 cycles. At the end of therapy, the complete response rate in the combination arm was 40% compared with 18% with bendamustine and rituximab alone.

POLARIX -- the confirmatory trial to determine polatuzumab vedotin's clinical benefit -- included 879 patients with previously untreated intermediate- or high-risk DLBCL randomized to a modified 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, or standard R-CHOP.

Genentech, which sponsored POLARIX, noted that the trial met its primary endpoint, with a statistically significant improvement in progression-free survival (PFS) with polatuzumab vedotin plus R-CHP relative to the patients treated with standard R-CHOP (HR 0.73, 95% CI 0.57-0.95, P=0.02).

"These results were statistically significant and clinically meaningful," the company said, adding that safety and tolerability were comparable between the two regimens.

However, FDA reviewers pointed out that the 1- and 2-year PFS rates in the two treatment arms differed by just 4.1% and 6.5%, respectively, and called the PFS improvement "modest."

"Although the modest PFS difference is in the setting of a substitution trial, these results must be considered along with the other efficacy results, OS [overall survival] results, and toxicity when considering the overall benefit-risk of polatuzumab in combination with R-CHP," they wrote.

In the final prespecified analysis, 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 of DLBCL not otherwise specified, the reviewers continued, adding that "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, is a reflection of safety and efficacy and adds to the uncertainties in benefit-risk."

Genentech has argued that "given the expected immaturity" of the OS results, other prespecified secondary endpoints, such as modified event-free survival, "take on greater weight to supplement the PFS observation as evidence of meaningful clinical benefit."

FDA reviewers suggested that while the trial showed a statistically significant benefit for that endpoint with polatuzumab vedotin plus R-CHP (HR 0.75, 95% CI 0.58-0.96, P=0.02), the treatment effect was "modest," with the 2-year point estimate differing by 6.2%.

ODAC members will be asked to vote on whether the benefit-risk of polatuzumab vedotin is favorable in patients with previously untreated LBCL (including DLBCL not otherwise specified), given the results of the POLARIX trial.

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