Editor's Note: From June 12 to 15, 2025, the 30th Congress of the European Hematology Association (EHA) was held in Milan, Italy. As a premier event in the global hematology field, the congress brought together experts and scholars from around the world to discuss cutting-edge scientific advancements and transformative clinical practices. At the meeting, Professor Matthew Matasar from the Rutgers Cancer Institute of New Jersey, USA, unveiled for the first time the highly anticipated results of the POLARGO study. This study evaluated the efficacy and safety of polatuzumab vedotin combined with the R-GEMOX regimen in patients with relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) who are ineligible for transplant. Its findings are poised to change the current clinical practice landscape.Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma in adults. For patients who are relapsed or refractory after first-line therapy and are not candidates for autologous stem cell transplantation, treatment options are limited, and their prognosis urgently needs improvement. Against this backdrop, the global, randomized, controlled Phase III POLARGO clinical trial was initiated to evaluate the value of adding the anti-CD79b antibody-drug conjugate (ADC), polatuzumab vedotin, to the R-GEMOX (rituximab, gemcitabine, oxaliplatin) regimen.
POLARGO Study Design: Forging a New Path for Transplant-Ineligible R/R DLBCL Patients
Professor Matthew Matasar began by introducing the rigorous design of the POLARGO study. It is a global, multicenter, open-label, randomized Phase III trial. Following an initial safety run-in phase, a total of 255 patients with histologically confirmed DLBCL (including transformations from indolent lymphoma) who had failed or relapsed after at least one prior line of therapy were enrolled. A key inclusion criterion was that patients were deemed ineligible for transplant by the investigator and had not previously received polatuzumab vedotin.
Enrolled patients were randomly assigned in a 1:1 ratio to either the Pola-R-GEMOX experimental arm or the R-GEMOX standard-of-care control arm, for a maximum of 8 cycles of treatment. The primary endpoint was Overall Survival (OS), with key secondary endpoints including Progression-Free Survival (PFS), Complete Response (CR) rate, and Overall Response Rate (ORR). Baseline characteristics were well-balanced between the two arms. Approximately two-thirds of the patients were in the second-line setting, and the majority (about two-thirds) were refractory to their most recent line of therapy.
Dual Survival Benefits: Historic Breakthroughs in Both Overall and Progression-Free Survival
Professor Matasar excitedly announced that the POLARGO study had successfully met its primary endpoint. The data showed that, compared to the standard R-GEMOX regimen, the Pola-R-GEMOX regimen significantly improved patients’ overall survival. The median OS in the experimental arm reached 19.5 months, compared to only 12.5 months in the control arm, representing a 40% relative reduction in the risk of death (stratified HR=0.60, P=0.0017). Furthermore, the two-year survival rate increased from 33% to 44%.
The improvement in the key secondary endpoint of PFS was equally impressive. The median PFS in the experimental arm was substantially extended from 2.7 months to 7.4 months, reducing the risk of disease progression by 63% (stratified HR=0.37, P<0.0001). The one-year progression-free survival rate doubled from 18% to 36%. Concurrently, both the complete response rate and overall response rate nearly doubled in the experimental arm, as assessed by both central imaging review and investigators. Professor Matasar emphasized, “These data clearly confirm that adding polatuzumab vedotin to the R-GEMOX regimen provides clinically meaningful survival benefits for patients.”
Consistent Benefits Across Subgroups, Cell of Origin No Longer a Key Predictor of Efficacy
In the prespecified subgroup analyses, the Pola-R-GEMOX regimen demonstrated a consistent OS benefit regardless of age (cutoff at 70 years), number of prior lines of therapy (1 vs. >1), or response status to the last therapy (relapsed vs. refractory). Interestingly, the study found no correlation between efficacy and tumor burden (Bulky/Non-bulky) or primary refractory status.
Of particular note were the results from the Cell of Origin (COO) subgroup. Subgroup analysis from the previous POLARIX study had suggested that polatuzumab vedotin might offer greater benefits to patients with the Activated B-Cell-like (ABC) subtype. However, the POLARGO study, using Gene Expression Profiling (GEP), found that the Pola-R-GEMOX regimen delivered equivalent improvements in OS and PFS in both the ABC and Germinal Center B-cell-like (GCB) subtypes, a finding that challenges previous assumptions. Professor Matasar commented on this, stating, “I believe the cell of origin story is not the whole story. As our understanding of the molecular classification of lymphoma deepens, we recognize there is significant heterogeneity within the GCB subtype. It seems that higher-risk biological features, regardless of their COO classification, can benefit from intensified therapies, including those with polatuzumab vedotin.”
Manageable Safety: Risks Correlated with Longer Treatment Exposure
Regarding safety, as patients in the experimental arm received treatment for a longer duration (median cycles 7.5 vs. 4), the incidence of adverse events was correspondingly higher. The rates of drug discontinuation or dose reduction due to adverse events were higher in the experimental arm. Notably, the rate of Grade 5 adverse events (resulting in death) was 11.7% in the experimental arm, compared to 4% in the control arm. Professor Matasar explained that the primary cause of death in both arms was disease progression, but the experimental arm had more deaths attributed to adverse events, with infection being the main cause, and COVID-19 being the most common fatal infection. He reminded the audience that the study was conducted during the peak of the COVID-19 global pandemic.
Other common adverse events included cytopenias (especially thrombocytopenia) and peripheral neuropathy. As both polatuzumab vedotin and oxaliplatin have neurotoxicity, special attention was paid to peripheral neuropathy. In the experimental arm, 57% of patients reported neuropathy of any grade, but the vast majority were Grade 1. By the end of the study, symptoms had improved in about half of the patients, and had completely resolved in nearly one-third.
Expert Opinion and Clinical Application Outlook
During the discussion session, Professor Matasar addressed questions about the study’s future clinical application. He noted that while a direct head-to-head comparison is not possible, the data from POLARGO are comparable to the efficacy of the Pola-BR regimen in the previous GO29365 study, although patients in the POLARGO study were generally in an earlier line of therapy.
What is the significance of POLARGO today, when polatuzumab vedotin has become a first-line standard of care (Pola-R-CHP)? Professor Matasar stated unequivocally, “The data from this study are not applicable to patients who have already received polatuzumab vedotin in the first line. However, for the large population of patients who relapse after first-line treatment with R-CHOP or similar regimens, these data are highly relevant.”
Furthermore, the study provides clinicians with a potent, non-bendamustine-based chemotherapy backbone. This is particularly important for patients who may subsequently receive T-cell engaging therapies like CAR-T, as it helps to avoid the negative impact of bendamustine on T-cell function.
Conclusion
The results of the POLARGO study are undoubtedly a major step forward in the treatment of R/R DLBCL. By significantly improving OS and PFS while maintaining a manageable safety profile, the Pola-R-GEMOX regimen offers a new, highly effective treatment option for transplant-ineligible R/R DLBCL patients. The release of this landmark data not only reinforces the cornerstone role of polatuzumab vedotin in the comprehensive management of DLBCL but also sets a potential new standard of care in the field, bringing the hope of life to more patients through innovative ADC combination therapies.
