The FDA’s Oncologic Drugs Advisory Committee voted 11 to 2 that data from the phase 3 POLARIX trial support a favorable benefit-risk profile for polatuzumab vedotin-piiq in patients with previously untreated large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 2 that data from the phase 3 POLARIX trial (NCT03274492) support a favorable benefit-risk profile for polatuzumab vedotin-piiq (Polivy) in patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS).1
“I voted yes. This trial did meet its primary end point of PFS and while there was a lack of congruence among the prespecified end points, I believe the benefits outweigh the risks and that polatuzumab vedotin should be an option for first-line treatment of DLBCL with curative intent, especially noting that patients would be spared more toxic and complicated salvage therapies,” Neil Vasan, MD, PhD, assistant professor in the Division of Hematology and Oncology, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center in New York, New York, said.
“Today’s committee decision to recognize the potential of this Polivy combination as a first-line treatment option is important since four in 10 people with DLBCL relapse or do not respond to initial treatment,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, stated in a press release.2 “We believe the clinical benefit demonstrated in the POLARIX study may improve outcomes for many people with newly diagnosed DLBCL and look forward to continued collaboration with the FDA to make this treatment option available in the U.S.”
During the meeting, the FDA questioned the benefit-risk profile of polatuzumab vedotin plus rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (R-CHP), flagging three main concerns regarding the supplemental biologics license application (sBLA) for the proposed indication of the CD79b-directed antibody-drug conjugate (ADC) in combination with R-CHP for the frontline treatment of patients with DLBCL.
In June 2019, the FDA granted an accelerated approval to polatuzumab vedotin for use in combination with bendamustine and rituximab (Rituxan; BR) for the treatment of patients with relapsed/refractory DLBCL who have received at least 2 prior therapies.3 The approval of the agent was based on findings from the phase 1b/2 GO29365 trial (NCT02257567), in which 40% of patients receiving the polatuzumab vedotin regimen achieved complete response (CR)—the primary end point of the study––compared with 18% of patients in the BR-alone arm.
In August 2022, the FDA accepted an sBLA for the combination of polatuzumab vedotin and R-CHP for the treatment for patients with previously untreated DLBCL.4
The sBLA was based on data from the POLARIX trial, which showed that polatuzumab vedotin plus R-CHP led to a 27% reduction in the risk of disease progression, relapse, or death compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with newly diagnosed DLBCL (HR, 0.73; 95% CI, 0.57-0.95; P = .0177).5
To be eligible for enrollment in the pivotal trial, patients had to have previously untreated LBCL, an International Prognostic Index score between 2 and 5 representing low-intermediate to high-risk disease, no central nervous system disease, and no primary mediastinal large B-cell lymphoma. Notably, the trial represented several types of LBCL, including DLBCL NOS, high-grade B-cell lymphoma (HBCL) with MYC and BCL2 and/or BCL6 rearrangements, HGBL NOS, and other low-grade B-cell lymphomas, including T-cell/histiocyte-rich LBCL, Epstein–Barr virus (EBV)–positive DLBCL, ALK-positive LBCL, and HHV8-positive DLBCL.
Patients were randomly assigned 1:1 to receive 1.8 mg/kg of polatuzumab vedotin plus R-CHP plus placebo for 6 cycles (n = 440) or R-CHOP plus placebo for 6 cycles (n = 439). Both arms received an additional 2 cycles of rituximab thereafter.
Investigator-assessed PFS served as the trial’s primary end point. Key secondary end points included modified event-free survival (EFS), CR rate, and overall survival (OS).
Primary End Point Showcases Modest Activity
Although the trial met its primary end point of PFS, the FDA questioned the contributive effect of polatuzumab vedotin to the R-CHP regimen. POLARIX was designed to show the superiority of polatuzumab vedotin plus R-CHP to R-CHOP, but without data regarding the contribution of effect of vincristine in CHOP, interpretation of polatuzumab vedotin’s benefit is challenging, the FDA said.
Additional data from the trial showed that the 1- and 2-year PFS rates were 83.9% (95% CI, 80.1%-87.1%) and 76.7% (95% CI, 72.3%-80.5%) with the polatuzumab vedotin regimen vs 79.8% (95% CI, 75.6%-83.3%) and 70.2% (95% CI, 65.5%-74.4%) with R-CHOP. However, the FDA pointed out that the original data analysis was not censored for new anti-lymphoma treatment or 2 or more missed assessments. After censoring for both variables, the difference in the 2-year PFS rate dropped from 6.5% to 4.9% (HR, 0.77; 95% CI, 0.59-1.01; P = .0541).
Moreover, subgroup analysis showed variable efficacy with the polatuzumab vedotin regimen, with hazard ratios ranging from 0.34 (95% CI, 0.13-0.85) in the activated B-cell DLBCL subset to 1.93 (95% CI, 0.66-5.64) in the other large B-cell subset.
Secondary End Points Result in Subpar Efficacy
The FDA also cited lack of OS improvement at final analysis, where at a median follow-up of 39.7 months, the median OS was not reached in either arm (HR, 0.94; 95% CI, 0.67-1.33). At 2 years, the OS rate was 88.7% in both arms. Similar variability in OS results were seen with the polatuzumab vedotin regimen in subgroup analysis, with hazard ratios ranging from 0.27 (95% CI, 0.06-1.26) in the activated B-cell DLBCL subset to 1.89 (95% CI, 0.35-10.33) in T-cell/histiocyte-rich LBCL and EBV-positive DLBCL.
Moreover, the CR rate was 78.0% (95% CI, 73.8%-81.7%) with polatuzumab vedotin vs 74.0% (95% CI, 69.7%-78.1%) with R-CHOP, reflecting an absolute difference of 3.9% (95% CI, –1.9-9.7) but a P value of .1557 showing “no difference,” the FDA said. “Efficacy claims based on numerically higher CR rate are unsupported,” they added.
Modified EFS results were also presented. Similar to the primary PFS result, the difference was modest (HR, 0.75; 95% CI, 0.58-0.96; P = .0244). The 1- and 2-year EFS rates with polatuzumab vedotin were 82.5% (95% CI, 78.9%-86.1%) and 75.6% (95% CI, 71.5%-79.7%) vs 78.7% (95% CI, 74.8%-82.6%) and 69.4% (95% CI, 65.0%-73.8%) with R-CHOP.
Addition of Polatuzumab Vedotin to R-CHP Leads to Heterogeneous Treatment Effect
Further illustrating the variable effect of polatuzumab vedotin across enrolled subtypes, the FDA presented outcomes for PFS, OS, and CR in the DLBCL NOS; HGBL NOS, double-hit/triple-hit; and other LBCL subsets (Table).
Safety findings were also presented, showing a higher incidence of serious adverse effects (AEs), grade 3 or greater AEs, and fatal AEs with polatuzumab vedotin.
“The incidence of febrile neutropenia, infections, nausea, and diarrhea was at least 5% higher in the polatuzumab vedotin and R-CHP arm, [and the] incidence of neutropenia [was likely] underestimated [since] labs were required only at the beginning of each cycle,” the FDA stated.
“PFS in and of itself has no particular value. It is a surrogate end point. It gets its value because it demonstrates an improvement in OS, or an improvement in quality of life, neither of which we have here. So, we go to a secondary end point, a surrogate end point, and that is toxicity of the regimen,” Louis Diehl, MD, professor of medicine, Duke University in Durham, North Carolina, said. “The control group, the R-CHOP group is going to have more CAR T and more transplant, [so] they are going to have more toxicity, and that’s what I see this drug regimen preventing. That’s why I voted yes.”
In conclusion, the FDA added that although patient-reported outcomes were included in the trial and no major differences were observed between arms, the assessment strategies were inadequate to measure tolerability.
“The question today before the committee relates to improving on a very effective standard of care in LBCL,” Ravi Madan, MD, said. “Historically, R-CHOP has been a regimen that has been very hard to improve on largely because of its roughly 70% efficacy rate. The data reviewed today with R-CHP and polatuzumab vedotin does meet its end point of PFS relative to R-CHOP and while PFS is not always meaningful, in this case, I think it is. While the 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 and impractically large study.”
Madan, branch head, genitourinary malignancies, director, Prostate Cancer Clinical Research Section Program, and physician-scientist, Early Investigator Program Center for Cancer Research National Cancer Institute at the National Institutes of Health in Bethesda, Maryland, concluded by stating, “I understand the FDA’s concern about OS, but those timelines seem too protracted to evaluate in a meaningful way. I do have concerns about the increased risk of febrile neutropenia, but it is not a novel toxicity and I’m optimistic that the community can deal with that effectively. If there are going to be improvements in the care of LBCL patients, it may need to start with seemingly small incremental but clinically meaningful and statistically significant steps such as this.”