The FDA’s Oncologic Drugs Advisory Committee voted 11 to 2 that the benefit/risk profile of polatuzumab vedotin-piiq (Polivy) for injection is favorable for the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL).¹

On August 16, 2022, the FDA accepted a supplemental biologics license application for polatuzumab vedotin-piiq combined with rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated DLBCL based on findings from the phase 3 POLARIX clinical trial (NCT03274492).

In the study, investigators observed a clinically meaningful improvement in progression-free survival (PFS) with the polatuzumab vedotin combination vs rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).

With polatuzumab vedotin and R-CHP, patients had a 27% reduction in the risk of disease progression vs standard of care, and at a median follow-up of 28.2 months, the hazard ratio for the improvement in PFS for polatuzumab vedotin/R-CHP was 0.73 (95% CI, 0.57-0.95; P < .02).

The POLARIX results have already led to an approval of polatuzumab vedotin and R-CHP for the treatment of adult patients with previously untreated relapsed or refractory DLBCL by the European Commission, which brings the total approvals of polatuzumab vedotin to 70 countries. Based on results of the ODAC meeting and the POLARIX study, the committee decided that the benefit/risk profile of polatuzumab in patients with previously untreated DLBCL was favorable.

“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 diffuse large B-cell lymphoma relapse or do not respond to initial treatment,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, told Targeted Oncology^TM. “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 United States.”

POLARIX Trial

The international, randomized, double-blind, placebo-controlled POLARIX study is a confirmatory trial intended to verify the clinical benefit of polatuzumab. The trial included a total of 879 patients aged 18 to 80 years of age. Patients were enrolled in the study if they had CD20-positive DLBCL, were previously untreated, had a ECOG performance status of 0 to 2, an International Prognostic Index score between 2 and 5, and adequate hematologic, renal, hepatic, and cardiac function.2

The patients were randomly assigned 1:1 to receive either polatuzumab vedotin/RHP or R-CHOP.3 Investigators assessed the primary end point of PFS and the key secondary end points of percentage of patients with a complete response (CR), the percentage of patients who are progression free, event-free survival (EFS), overall survival (OS), disease-free survival (DFS), duration of response, time to deterioration, and quality-of-life outcomes. Additional end points of the study were the percentage of patients with adverse events (AEs), serum concentration of polatuzumab vedotin, plasma concentration of polatuzumab vedotin conjugate, and the percentage of patients with an anti-drug antibody to polatuzumab vedotin.

Findings from POLARIX showed that the 2-year investigator-assessed EFS was 75.6% (95% CI, 71.5%-79.7%) for patients in the experimental arm compared with 69.4% (95% CI, 65.0%-73.8%) in the control arm. For the difference in EFS, the hazard ratio was 0.75 (95% CI, 0.58-0.96; P = .02).³ Additionally, there was no significant difference in the percentage of patients who achieved a CR at the end of treatment. Patients given the combination with polatuzumab vedotin had a 78.0% CR rate vs 74.0% in the R-CHOP arm.

With the polatuzumab vedotin/R-CHP combination, investigator-assessed DFS was improved vs R-CHOP, and the hazard ratio of relapse or death was 0.70 (95% CI, 0.50-0.98). No significant difference was observed in OS outcomes, as the estimated 2-year OS in the polatuzumab vedotin/R-CHP arm was 88.7% (95% CI, 85.7%-91.6%) vs 88.6% (95% CI, 85.6%-91.6%) in the R-CHOP arm (HR, 0.94; 95% CI, 0.65-1.37; P = .75).

Safety was also similar between arms. Grade 3/4 AEs were observed in 57.7% of the experimental arm vs 57.5% of the standard of care arm, serious AEs were reported in 34.0% vs 30.6%, respectively, and grade 5 AEs were seen in 3.0% vs 2.3%, respectively. Moreover, AEs led to dose reduction in 9.2% of patients treated with the experimental combination vs 13.0% of patients treated with R-CHOP. Grade 3/4 AEs, which were the most frequent in the experimental group vs the control group included neutropenia (28.3% vs 30.8%), febrile neutropenia (13.8% vs 8.0%), and anemia (12.0% vs 8.4%), respectively.³

FDA Stance

In 2019, the combination of polatuzumab vedotin, bendamustine, and rituximab (Rituxan) was granted an accelerated approval by the FDA for patients with relapsed/refractory DLBCL. This approval came from findings of the phase 1b/2 GO29365 study (NCT02257567), which showed that 40% of patients receiving the combination with polatuzumab vedotin achieved a CR.

The FDA is holding this ODAC meeting to address concerns with the POLARIX study and the regimen of polatuzumab plus R-CHP for patients with previously untreated LBCL. Results from POLARIX have led the FDA to have concerns about the benefit-risk of polutuzumab in this setting. The primary issues discussed by the FDA at the meeting included the modest PFS benefit with the combination of polutuzumab and R-CHP, OS results, other efficacy end points, and the heterogeneity of the study population.

First, there was a modest PFS benefit with polatuzumab plus R-CHP compared with R-CHOP with a hazard ratio of .73 (95% CI, 0.57-0.95; P = .0177), but it is questionable whether the rate is clinically meaningful or not. Additionally, the PFS benefit did not translate to a benefit in CR or OS rates. At the final prespecified analysis of OS and with a median follow-up of 39.7 months, there was no improvement in OS for the polatuzumab plus R-CHP group. Though the Kaplan Meier survival curves were similar between arms, rates were numerically lower in the experimental arm.

The FDA also raised concerns with the modified EFS because although it was statistically significant, the treatment effect was modest, with a percentage point difference of 6.2 after 2 years. The difference in CR rate by BICR was not statistically significant and the overall response rates (ORRs) were similar between arms. This lack of improvement in CR rates between arms raises concerns about the treatment effects of the combination.

Lastly, 84% of patients in the study population had DLBCL not otherwise specified (NOS). Eleven percent had either high-grade B-cell lymphoma (HGBL) NOS or HGBL with MYC and BCL2 and/or BCL6 translocations, and 5% had other low-grade B-cell lymphomas (LGBLs). The treatment effect of polatuzumab plus R-CHP seemed to be heterogeneous across different subtypes of non-Hodgkin lymphoma (NHL). The PFS hazard ratios were 0.75 for DLBCL, 0.48 for HGBL, and 1.93 for other LBCLs, and the OS hazard ratios were 1.02, 0.42, and 1.89, respectively. The FDA believes it is important to acknowledge that this is an exploratory post hoc evaluation with sample size limitations. The results favored the experimental treatment in the DLBCL NOS whereas the control arm was favored for the other LBCL subgroup. Additionally, the combination of polatuzumab and R-CHP showed benefits when considering CR rates in the HGBL subgroup.

For patients with DLBCL NOS, results across all end points were marginal or not indicative of positive treatment effect. With these results, there is high uncertainty in the point estimates as noted by the wide confidence intervals.

“The outcomes of POLARIX raise a number of important topics for discussion. These include the modest improvement in the primary outcome measure of progression-free survival, lack of improvement in overall survival due to the limited number of events, and lack of improvement in CR rate. Results of other prespecified secondary end points were modest and had limitations. Additionally, the heterogeneity of the study population and observed treatment effects may impact generalizability of the findings,” said Yvette Kasamon, MD, clinical team leader, Division of Hematologic Malignancies II, Office of Oncologic Diseases, during the meeting.

Applicant Position

The POLARIX study, which assessed replacing vincristine in the R-CHOP regimen with polatuzumab vedotin, was designed to determine whether this regimen could improve the outcome for patients in the first-line setting. According to the applicant, POLARIX showed that patients given treatment with polatuzumab vedotin plus R-CHP have reduced risk of disease progression, disease relapse or death by 27% relative to patients treated with R-CHOP (P = .0177). These results are statistically significant and clinically meaningful, and the safety and tolerability were also comparable between the regimens. Based on the favorable benefit-risk seen in the POLARIX study, the manufacturer is hoping for FDA approval in the first-line setting.

The applicant highlighted that POLARIX met its primary end point. For OS, a key secondary end point in POLARIX, approximately 60% of first-line patients with DLBCL are cured, and most patients will experience deaths unrelated to DLBCL. However, phase 3 trials that evaluate OS as an end point can take approximately 10 years to complete.

When compared to R-CHOP, polatuzumab plus R-CHP led to an HR for overall mortality of 0.94 (95% CI, 0.67-1.33; P = .7326) that was not statistically significant. There is no indication of OS detriment with polatuzumab plus R-CHP. Given the expected immaturity of the OS results, other pre-specified secondary end points take on greater weight to supplement the PFS observation as evidence of meaningful clinical benefit.

In POLARIX, patients assigned to polatuzumab plus R-CHP also had a statistically significant and clinically meaningful improvement in EFS vs patients treated with R-CHOP. Additionally, while not statistically significant, CR rates at end of treatment were numerically higher with the experimental regimen vs control. ORR at end of treatment were also higher in the experimental arm vs control, and remissions were more sustained.

By evaluating the safety, efficacy, and health-related quality of life, the applicant believes there is substantial evidence supporting the combination of polatuzumab plus R-CHP and this providees a clinically meaningful benefit with a comparable safety profile to R-CHOP.

“POLARIX is a positive study and met its primary end point of progression-free survivial. A more durable progression-free survival was observed with pola+R-CHP and had a higher proportion of patients without disease progression at 2 years,” said Jamie Hirata, PharmD, global development leader of polatuzumab vedotin, Genentech, during the meeting. “Pola+R-CHP and R-CHOP have a comparable safety profile as demonstrated in this double line, placebo-controlled trial. The POLARIX efficacy and safety results together demonstrate a positive benefit/risk with Pola+R-CHP with patients with diffuse B-cell lymphoma.”

Decision

Once both sides explained their stance on main issues with polatuzumab in this indication, the voting question of whether polatuzumab is favorable or not in this patient population was raised to ODAC.

ODAC ultimately decided that given the results of the POLARIX trial, the benefit/risk profile of polatuzumab is favorable in patients with DLBCL.

REFERENCE:

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. March 9, 2023. Accessed March 9, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/march-9-2023-meeting-oncologic-drugs-advisory-committee-meeting-announcement-03092023

2. A study comparing the efficacy and safety of polatuzumab vedotin with rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in participants with diffuse large b-cell lymphoma (POLARIX). Clinical trials.gov. Updated May 21, 2022. Accessed August 16, 2022. https://bit.ly/3poiuwi

3. 3. Tilly H, Morscauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large b-cell lymphoma. N Engl J Med. 2022;386:351-363. doi:10.1056/NEJMoa2115304