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Phase III POLARIX Study Shows Greater Progression-Free Survival With Pola-R-CHP Versus R-CHOP in Previously Untreated DLBCL

March 31, 2022

April 2022

In patients with previously untreated, intermediate-risk or high-risk diffuse large B-cell lymphoma (DLBCL), treatment with pola-R-CHP was associated with a lower risk of disease progression, relapse, or death compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), according to results from the phase III POLARIX study. Pola-R-CHP is a modified version of R-CHOP that replaces vincristine with polatuzumab vedotin. The report published in The New England Journal of Medicine was based on a late-breaking abstract presented at the 2021 American Society of Hematology Annual Meeting.

According to the researchers, led by Hervé Tilly, MD, PhD, of the Centre Henri Becquerel in Rouen, France, only 60% of patients with DLBCL achieve cure with R-CHOP, while the remaining 40% have refractory disease or experience relapse after initial response. Several trials in recent years have examined approaches to improve outcomes associated with R-CHOP in DLBCL, including chemotherapy intensification or rituximab, addition of maintenance therapy, use of second-generation anti-CD20 monoclonal antibody (mAb), and integration of new agents.

Dr. Tilly and colleagues noted that polatuzumab vedotin, an antibody–drug conjugate consisting of an anti-CD79b mAb conjugated by a protease-cleavable linker to monomethyl auristatin E, has demonstrated efficacy as a single agent and in combination with rituximab and bendamustine in previous trials in relapsed or refractory DLBCL.

Given the high rates of refractory or relapsed disease in the DLBCL population, the researchers investigated the efficacy and safety of the modified pola-R-CHP regimen versus R-CHOP in 879 patients. Patients were randomly assigned to receive either six cycles of pola-R-CHP (n=440) or R-CHOP (n=439); both arms also received two cycles of rituximab alone.

In the overall population, the median patient age was 65 (range = 19-80 years). Approximately one-third of patients had activated B-cell–like subtype DLBCL, and nearly two-thirds of patients had an International Prognostic Index (IPI) score between 3 and 5 at baseline. The pola-R-CHP and R-CHOP treatment arms were balanced with regard to IPI score, presence or absence of bulky disease, and centrally evaluated disease subtypes.

The median duration between diagnosis of DLBCL and treatment initiation was 26 days in the pola-R-CHP arm and 27 days in the R-CHOP group. During a median follow-up period of 28.2 months, a significantly greater proportion of patients in the pola-R-CHP group met the primary endpoint of surviving without disease progression (76.7% vs. 70.2%; p=0.02). The researchers reported that the risk of disease progression, relapse, or death was 27% lower with pola-R-CHP compared to R-CHOP.

At two years, however, there was no difference between groups in terms of overall survival (88.7% vs. 88.6%, respectively; hazard ratio for death = 0.94; 95% CI 0.65-1.37; p=0.75).

Safety outcomes were generally comparable between groups. The investigators said they detected no new safety signals, and the safety profile of the pola-R-CHP regimen was consistent with the known safety profiles of its individual components. The most frequent grade 3 or 4 adverse events included neutropenia (28.3% for pola-R-CHP vs. 30.8% for R-CHOP), febrile neutropenia (13.8% and 8.0%, respectively), and anemia (12.0% and 8.4%, respectively). Treatment delay and discontinuation was similar between the two groups.

The researchers noted that the relatively short follow-up period of the study provided “limited data confirming the expected plateau in the progression-free survival curve.” It is still early to be able to detect overall survival differences given more effective treatments of relapsed disease.

Additionally, the researchers suggested that their findings may not generalize across patients who are older than 80, patients with lymphoma arising from previously diagnosed indolent lymphoma, or patients with a primary mediastinal lymphoma, given the study’s inclusion criteria. To address the study’s limitations, the researchers noted that a phase III trial is currently underway to evaluate an age-adapted regimen of pola-R-CHP with dose-attenuated chemotherapy in older patients.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363.


Perspectives

The recently published analysis of the randomized phase III POLARIX study reported that eligible patients with DLBCL receiving pola-R-CHP experienced a higher rate of progression free survival (PFS) as compared to those receiving R-CHOP. The reported hazard ratio of 0.73 exceeded the pre-specified hazard ratio of 0.77 for progression. Neither overall survival nor toxicity profiles differed significantly between treatment arms.

While patients receiving pola-R-CHP experienced a 27% reduction in the relative risk of progression as compared to those receiving R-CHOP, the number needed to treat with the former to avoid one progression event is approximately 15, which raises doubt that pola-R-CHP should become the new standard of care for all patients newly diagnosed with DLBCL. Forest plots included in the manuscript’s supplemental file suggest a PFS benefit in patients who are older than 60, are male, have an IPI score of 3-5, lack bulky disease, and have activated B-cell–like cell of origin when treated with pola-R-CHP. Still, clinicians should be highly cautious in offering pola-R-CHP to patients with these specific clinicopathologic characteristics based on this exploratory analysis.

Comprehensive genomic analysis of tumors in patients with newly diagnosed DLBCL has revealed significant molecular heterogeneity in DLBCL, with differing survival outcomes for patients treated with R-CHOP based on the cluster and classification of their individual tumors.1,2 Perhaps it is not surprising that a study investigating the incorporation of a therapy targeting a commonly expressed lymphoma cell surface marker in a heterogeneous group of patients newly diagnosed with DLBCL would show a modest improvement in PFS when compared to R-CHOP alone.

Although POLARIX did meet its defined primary endpoint, I believe that opportunities remain to improve survival rates for patients with newly diagnosed DLBCL, particularly through investigation of targeted therapies in those with high-risk disease as defined by molecular testing who are least likely to be cured by R-CHOP. The cumulative impact of this approach will hopefully result in avoidance of a progression event in more than just one out of every 15 patients with newly diagnosed DLBCL.

Daniel J. Landsburg, MD
University of Pennsylvania

References

  1. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679-690.
  2. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396-1407.

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