Polatuzumab Vedotin Wins FDA ODAC Endorsement by 11:2 Vote for First-Line LBCL Based on POLARIX Trial

At around 5:00 PM EST on March 9, 2023, the 2nd FDA ODAC (Oncologic Drugs Advisory Committee) meeting of 2023 concluded, with the expert panel voting 11 to 2.SupportBased on the data results of the POLARIX study, the combination of Polatuzumab Vedotin with Rituximab + Cyclophosphamide + Doxorubicin + Prednisone (R-CHP) regimen demonstrates an ideal benefit-risk ratio in previously untreated large B-cell lymphoma (LBCL) patients [including Diffuse Large B-Cell Lymphoma-Not Otherwise Specified (DLBCL NOS)].

Figure: ODAC Voting Results

Regarding the discussion topics and voting results of this ODAC, the pharmaceutical cube Med WeChat public account will collaborate with the DeepMed database onWednesday, March 22nd, 18:30A live discussion on the current status of first-line treatment and the R&D landscape for Diffuse Large B-Cell Lymphoma (DLBCL), with more insights.Mysterious Heavyweight GuestGuest Appearance in the "DeepMed Live Studio," Everyone is Welcome to Reserve and Watch.

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▌Background Review

DLBCL, the most common subtype of non-Hodgkin lymphoma (~40%), despite the significant efficacy of the R-CHOP regimen as the first-line standard treatment, still sees about 40% of patients experiencing relapse or primary refractory disease. Unfortunately, over the past two decades, researchers have initiated numerous studies attempting to improve the first-line treatment outcomes of DLBCL through intensified treatment, consolidation therapy, maintenance therapy, optimization of anti-CD20 antibodies, and combination with novel targeted drugs, but the vast majority of these studies have not demonstrated significant benefits.

Figure: Important Phase 3 Clinical Studies and Primary Endpoint Results of First-Line Treatment for DLBCL. Note: Although the R-ACVBP and HDT/ASCT regimens reached their primary endpoints, the former has significant toxicity, and the latter did not show OS benefits; lenalidomide maintenance therapy only demonstrated EFS benefits in elderly patients and did not show OS benefits.

Polatuzumab vedotin is an anti-CD79b antibody-drug conjugate developed by Genentech (Roche). On June 10, 2019, the FDA approved it based on the GO29365 study.Accelerated Approval (AA)Approved its combination with bendamustine + rituximab (pola-BR) for the treatment of relapsed or refractory (R/R) DLBCL NOS in patients who have received ≥2 prior treatment regimens.

POLARIX (study GO39942) is a subsequent global, multicenter, randomized, double-blind, placebo-controlled Phase III confirmatory study where previously untreated LBCL patients were randomly assigned to receive either Pola-R-CHP (polatuzumab vedotin combined with R-CHP) or R-CHOP regimen. The primary endpoint is PFS, and secondary endpoints include event-free survival (EFS), complete response (CR) rate, OS, and safety.

During the 2021 ASH conference, the POLARIX study results showed that, with a median follow-up of 28.2 months, the 2-year PFS in the Pola-R-CHP group significantly improved compared to the R-CHOP group: 76.7% vs 70.2% (HR=0.73, 95% CI 0.57-0.95, p=0.02), but no significant differences were observed in OS or CR rates between the two groups.

At this ODAC meeting, further long-term follow-up (median follow-up time 39.7 months) results showed that the Pola-R-CHP group demonstrated sustained PFS benefit (HR=0.76), while OS (HR=0.94, P=0.73) is still immature. Based on the POLARIX study, Genentech submitted polatuzumab vedotin in combination with R-CHP for the treatment of previously untreated adult DLBCL patients to the FDA.Supplemental Biologics License Application（BLA 761121/Supplement 008）。

Details of the POLARIX Study. Image source: DeepMed Database

Based on the POLARIX study, the pola-R-CHP regimen has been approved by more than 60 countries for first-line treatment of DLBCL, including European countries, Canada, Japan, and China, and has been recognized in multiple clinical practice guidelines (Note: Europe, Japan, and China approved the first-line DLBCL indication for Polivy on 2022-05-25, 2022-08-24, and 2023-01-13 respectively. Currently, this regimen has been incorporated into several guidelines, including those from CSCO and NCCN).

Global Approval Status of Pola-R-CHP as First-Line Treatment for DLBCL

▌FDA：Modest PFS benefit，No improvement in OS

At the beginning of the meeting, the FDA reiterated the evidence standards used for new drug review: sufficient information demonstrating the drug's efficacy under the target conditions.Safety; under adequate and well-controlled conditions, the drug demonstratesEfficacy, and forSingle Randomized Study Supporting Review，The results must be sufficiently robust and convincing.（sufficiently robust and compelling）. And provide explanations on the following FDA concerns:

1. Modest PFS benefit in the Pola-R-CHP group:

Although the Pola-R-CHP group showed a statistically significant PFS benefit compared to the R-CHOP group, the extent of this benefit was modest: HR= 0.73, 95%CI 0.57-0.95, P=0.0177 (two-sided α=0.05). The improvement in 1-year and 2-year PFS rates in the Pola group compared to the control group were 4.1% and 6.5%, respectively. Whether this degree of PFS improvement is clinically meaningful needs to be considered in conjunction with other efficacy data, including OS and safety. The FDA conducted various sensitivity analyses to assess the robustness of the PFS results; however, regardless of the method used, the upper limit of the HR confidence interval was close to or exceeded 1, and the PFS benefit did not translate into improvements in CR rate and OS.

PFS Sensitivity Analysis. Image from FDA

2. OS Results:

In the pre-specified final OS analysis, with a median follow-up of 39.7 months, the Pola-R-CHP group failed to demonstrate a statistically significant OS benefit (HR=0.94, 95% CI: 0.67-1.33). At an earlier assessment time point, the OS rate in the Pola-R-CHP group was numerically even lower than that in the R-CHOP group. The HR for the most prevalent subtype, DLBCL NOS, was 1.02. The lack of OS benefit reflects deficiencies in safety and efficacy, especially in the context of first-line treatment for LBCL, and increases the uncertainty of the benefit-risk profile. The FDA does not agree that PFS is an established surrogate endpoint for OS in previously untreated LBCL patients. Furthermore, the FDA reiterated its requirement for OS data to support full approval.

Final OS Results of the POLARIX Study

3. Other efficacy endpoints:

Other endpoint indicators, while supportive, still have limitations. The EFS results, although statistically significant (HR=0.75, 95%CI: 0.58-0.96, P=0.0244), show only modest benefit, with a 6.2% improvement at the 2-year mark. At the end of treatment, there were no statistically significant differences in CR rates (78.0% vs 74%, P=0.1557) or ORR (84.5% vs 80.9%) between the two groups; the numerical increases alone are not supportive. The 2-year DFS (81.8% vs 77.4%) and DOR (75.7% vs 71.7%) also showed only modest benefits and, due to the lack of control for Type I error, can only be considered exploratory analyses.

4. Heterogeneity of the study population:

DLBCL exhibits significant heterogeneity internally. Both the POLARIX study and the intended indication for application encompass DLBCL in a broad sense (the FDA considers it should be LBCL), including DLBCL NOS, high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements as well as HGBL NOS, and other LBCL subtypes (T-cell/histiocyte-rich LBCL, EBV+ DLBCL, ALK+ DLBCL, and HHV8+ DLBCL). Not all histological subtypes were included in the POLARIX study.

In the POLARIX study population, 84% were DLBCL NOS, 11% were HGBL NOS or HGBL with MYC and BCL2 and/or BCL6 rearrangements, and 5% were other types of LGBL. The treatment effect of Polatuzumab Vedotin showed heterogeneity across subtypes, with HR values for PFS being 0.75 in DLBCL NOS, 0.48 in HGBL, and 1.93 in other LBCLs. The HR values for OS were 1.02, 0.42, and 1.89, respectively. It should be noted that due to the limitation of sample size, this is only an exploratory post-hoc analysis. The results suggest that in the HGBL subgroup, Polatuzumab Vedotin combined with R-CHP showed a trend of benefit, including CR rate. Notably,For HGBL, R-CHOP is not the most "ideal" treatment regimen, and stronger therapeutic options are often recommended in clinical practice.For patients with DLBCL NOS, who account for the largest proportion, all endpoint indicators are either marginal or show no clear positive benefit. Additionally, due to the wide confidence intervals, the assessment remains highly uncertain.

FDA also noted that the POLARIX study attempted to replace vincristine in the R-CHOP regimen with polatuzumab vedotin. However, since prior studies have not explored the role of vincristine in the R-CHOP regimen, this "replacement strategy" makes it difficult to interpret the contribution of polatuzumab vedotin. Additionally, although the overall safety profiles of the two groups were similar, the incidence rates of febrile neutropenia, infections, nausea, and diarrhea in the pola-R-CHP group increased by at least 5%. The incidence of peripheral neuropathy was comparable between the two groups (53% vs 54%), but the resolution rate was lower in the pola group (58% vs 67%). Moreover, the FDA stated that sufficient dose exploration had not been conducted in treatment-naïve DLBCL patients in earlier studies.

▌Sponsor: Clinically meaningful benefit, Best chance of cure

For patients with DLBCL, disease progression and recurrence are their primary concerns, and subsequent treatments (such as CAR-T, etc.) add to the burden. Improving first-line treatment options to cure more DLBCL patients remains a significant unmet need.

As the first Phase III clinical trial to yield positive results in the frontline treatment of DLBCL in 20 years, the POLARIX study demonstrated a statistically significant PFS benefit. Compared with the R-CHOP regimen, the pola-R-CHP regimen reduced the risk of disease progression, death, or recurrence by 27%, achieving "Clinically Meaningful PFS Target:": Reducing the risk of disease progression, recurrence, or death by 25%, translating to a 5-7% improvement in 24-month PFS. Assuming there are 27,360 newly diagnosed DLBCL patients in the U.S., the 6.5% improvement in 2-year PFS demonstrated in the pola-R-CHP group could prevent over 1,700 patients annually from experiencing disease progression or recurrence. Additionally, the safety profile of the pola-R-CHP group is comparable to R-CHOP. Since receiving AA in 2019, more than 12,000 patients have been treated with Polivy.

POLARIX, as a global multicenter study, was conducted in collaboration with the Lymphoma Study Association (LYSA) and the Lymphoma Academic Research Organization (LYSARC). It also had a steering committee composed of globally renowned lymphoma experts who jointly participated in the design and execution of the POLARIX study while maintaining close communication with the FDA. Previous studies have shown that Phase III clinical trials using OS as an endpoint require approximately 10 years to complete. As a clear and widely recognized endpoint, the POLARIX study, like most other studies, chose PFS as the primary endpoint. Long-term follow-up results indicate that the Pola group demonstrated sustained PFS benefits compared to the control group. OS, as a key secondary endpoint, has not yet shown statistical differences; however, after a median follow-up of approximately 40 months, only about 15% of enrolled patients had died. Currently, OS data is not yet mature and must be supplemented by other pre-specified secondary endpoints as evidence supporting the clinical benefit of PFS.

Results for other secondary endpoints showed a statistically significant improvement in EFS. Although the CR rate did not reach statistical significance (two-sided p-value = 0.1557), the CR rate was numerically higher in the pola-R-CHP group at the end of treatment, being 78.0% (95% CI: 73.8-81.7) compared to 74.0% (95% CI: 69.7-78.1) in the R-CHOP group. Similarly, the ORR at the end of treatment was also numerically higher, being 84.5% (95% CI: 80.8-87.8) and 80.9% (95% CI: 76.9-84.4), respectively. Notably, patients in the pola-R-CHP group experienced more durable responses. The overall safety profiles of the two groups were comparable, although the incidence rates of febrile neutropenia and infection were higher in the polatuzumab vedotin plus R-CHP group, this did not increase patient mortality. Patient-reported outcomes regarding quality of life were similar between the two groups. Therefore, the sponsor considers that, overall, the polatuzumab vedotin combination regimen provides clinically meaningful benefits with a safety profile similar to R-CHOP.

11:2, Based on the POLARIX study, Pola-R-CHP demonstrates an ideal benefit-risk ratio in previously untreated LBCL patients (including DLBCL NOS).

After the FDA and sponsors' presentations, the experts present engaged in a heated discussion on multiple issues, including PFS and OS conditions for different IPI patients, specific details of pathological testing during the study, the rationale for HGBL patients receiving the R-CHOP regimen as the control group, recurrence patterns of patients treated with pola-R-CHP, the meaning of "Modest" and "Clinically meaningful," and the patient populations suitable or unsuitable for pola-R-CHP treatment, etc. Ultimately, they expressed opinions on the following two pre-set questions:

1. Based on the results of the POLARIX study, evaluate the benefit-risk profile of Polatuzumab Vedotin combined with the R-CHP regimen in patients with LBCL (including DLBCL NOS).

2: Based on the POLARIX study data, especially the OS results, is additional follow-up data needed to clarify the benefit-risk profile of Polatuzumab Vedotin in frontline LBCL treatment?

Regarding the first question, the expert panel agreed that PFS is a clear endpoint recognized by hematology experts in the United States and globally. However, concerns were raised about the use of local pathology testing in the POLARIX study, whether HGBL patients in the control group received appropriate treatment regimens, and the heterogeneity of the study population's treatment. As for the second question, the panel stated that PFS alone cannot adequately demonstrate "live longer, live better" outcomes and that OS and QoL data are also needed. Based on the current KM curve for OS, the panel is concerned that longer follow-up may not necessarily show differences in OS, especially since previous studies have indicated that survival curves for patients achieving 2-year PFS align closely with estimated levels. Extended follow-up might prevent patients who aim to reduce the risk of disease progression within two years from accessing the drug and could also overlook the true value of Pola treatment.

After approximately five hours of discussion, ultimately, a total of 5 ODAC experts and 8 invited experts (including solid tumor experts, hematological tumor experts, patient educators, biostatisticians, clinical pharmacy experts, translational medicine experts, and patient representatives) supported the favorable benefit-risk profile of Pola-R-CHP in previously untreated LBCL patients (including DLBCL NOS) based on the POLARIX study, with a vote of 11 to 2. Although the ODAC's decision does not necessarily represent the final opinion of the FDA, after this discussion, a glimmer of hope has emerged for first-line treatment of DLBCL.

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