Combining the CD79b-directed antibody-drug conjugate polatuzumab vedotin-piiq with rituximab, gemcitabine, and oxaliplatin (R-GemOx) significantly improved survival outcomes in patients with transplant-ineligible, relapsed or refractory diffuse large B-cell lymphoma (DLBCL), over standard rituximab plus gemcitabine/oxaliplatin alone, in the phase III POLARGO trial. For patients treated with the polatuzumab vedotin–based combination, deaths were significantly reduced by 40%, meeting POLARGO’s primary endpoint, reported Matthew J. Matasar, MD, Chief of the Division of Blood Disorders at Rutgers Cancer Institute and RWJBarnabas Health,
New Jersey, at the European Hematology Association (EHA) 2025 Congress.¹

Matthew J. Matasar, MD

“The POLARGO regimen did indeed lead to a statistically significant and clinically meaningful survival benefit compared with the standard of care, R-GemOx, with a stratified hazard ratio for death of 0.60 (P = .0017),” Dr. Matasar said. “The data reinforce the benefit of adding polatuzumab vedotin to chemoimmunotherapy regimens in a variety of clinical settings, giving clinicians potentially a new tool in the treatment of relapsed or refractory disease.”

Trial Details and Key Findings

The global trial enrolled 270 patients with relapsed or refractory DLBCL ineligible for autologous stem cell transplant who had not received polatuzumab vedotin. Patients were randomly assigned to receive polatuzumab vedotin plus R-GemOx or R-GemOx every 21 days for up to eight cycles. Two-thirds of patients were treated in the second-line setting. The primary endpoint was overall survival.

At a median follow-up of 24.6 months, median overall survival was 19.5 months with polatuzumab vedotin plus R-GemOx vs 12.5 months with R-GemOx (hazard ratio [HR] = 0.60; 95% confidence interval [CI] = 0.43–0.83; P = .0017). The 2-year overall survival rate was 44.0% vs 33.2%, respectively. Dr. Matasar emphasized that the overall survival benefit was robust, as those receiving R-GemOx had undergone more subsequent lines of therapy.

At a median follow-up of 18.7 months, progression-free survival was also significantly improved, increasing from 2.7 months to 7.4 months with the addition of polatuzumab vedotin (HR = 0.37; P < .0001). The 12-month progression-free survival rate was 36.6% vs 17.9%, respectively. Polatuzumab vedotin plus R-GemOx also nearly doubled the response rate, from 24.6% with standard therapy to 52.7%; thecomplete response rate was 19.0% vs 40.3%, respectively, representing an absolute difference of 21.3% (P < .0001), Dr. Matasar reported.

Dr. Matasar highlighted how the findings were consistent across the preplanned subgroup analyses, with overall survival favoring the polatuzumab vedotin–based combination therapy in essentially all cases. “This included our three stratification factors—age, number of prior lines of therapy, and response to the most recent line of therapy. This also included some interesting observations,” he said. “We saw that benefit accrued for both bulky and nonbulky disease, as well as for patients who were and were not primary-refractory. We saw no distinct geographic differences between Western and Eastern regions, or among nations, in terms of differential benefits from the addition of polatuzumab vedotin.”

Dr. Matasar continued: “There’s also been some interest in cell of origin, fueled in part by subset analyses of the POLARIX trial,² which seemed to suggest a preferential benefit in activated B-cell [ABC] biology, as opposed to germinal center biology [GCB]. However, POLARGO did not confirm this a priori hypothesis, as equal results were seen in both ABC and GCB determined by gene-expression profiling,” he said.

Safety Profile

The enhanced efficacy of polatuzumab vedotin plus R-GemOx, however, came with increased toxicity, which Dr. Matasar emphasized was not unexpected, given that patients received nearly twice as many treatment cycles (a median of 7.5 vs 4). The proportion of patients experiencing treatment-related adverse events was not notably greater in the arm given polatuzumab vedotin plus R-GemOx, but there were more treatment-related discontinuations in that arm. Those patients also developed more thrombocytopenia (grade ≥ 3, 34.4% vs 26.4%) and infections (21.9% vs 9.6%).

In addition, there were more deaths related to adverse events in the experimental arm (11.7% vs 4.0%), mostly from infections (primarily COVID-19). Seven patients died of COVID-19 infection during treatment, and three died after completing the study.

Peripheral neuropathy was observed in 57.0% of patients receiving polatuzumab vedotin plus R-GemOx vs 28.8% of those receiving R-GemOx, but the majority were grade 1; four patients in the experimental arm developed grade 3 neuropathy. The neuropathy was mostly low-grade and largely improved by study end. “In fact, one-third had complete resolution by study closure,” Dr. Matasar noted.

DISCLOSURE: Dr. Matasar reported personal financial relationships with AbbVie, Allogene Therapeutics, Arvinas, Bayer, BMS, Genentech, GenMab, Kite Pharma, Novartis, Pfizer, Roche, ADC Therapeutics, AstraZeneca, Ipsen, Johnson & Johnson, Regeneron, Pfizer, and Merck.

REFERENCES

1. Matasar M, et al: EHA 2025 Congress. Abstract S101. Presented June 14, 2025.

2. Salles G, et al: Blood 144(suppl 1):469, 2024.

EXPERT POINT OF VIEW

Michael D. Jain, MD, PhD, Associate Member and ICE-T Medical Director of the Moffitt Cancer Center Department of Blood and Marrow Transplant and Cellular Immunotherapy, shared his thoughts on the POLARGO trial results with The ASCO Post.

Michael D. Jain, MD, PhD

Dr. Jain pointed out that polatuzumab vedotin-piiq has been established as an active drug in diffuse large B-cell lymphoma (DLBCL), in both the first-line setting—in combination with R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone]—and in the relapsed setting—in combination with bendamustine and rituximab. Here, in POLARGO, it was combined with rituximab plus gemcitabine/oxaliplatin (R-GemOx), yielding an overall survival benefit over R-GemOx alone in transplant-ineligible, relapsed or refractory DLBCL.

As Dr. Jain pointed out, R-GemOx is a regimen that is fairly well tolerated by most patients, is convenient to use, and may produce some responses, although “it is not incredibly effective” and probably would not be the first choice for a relapsed patient today. POLARGO was designed before more effective treatments became available, such as the bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy, Dr. Jain acknowledged. R-GemOx has served as the control arm for several other DLBCL trials of novel agents, he added.

“With the advent of all the newer therapies, R-GemOx is more like a therapy we would use for bridging, and that’s the reason I like polatuzumab vedotin plus R-GemOx,” Dr. Jain explained. “The concern we had before, when we were giving polatuzumab vedotin plus bendamustine, was the potential for a negative effect of bendamustine on T-cell quality before CAR T-cell therapy.”

Bendamustine has been shown to have a toxic effect on circulating T cells that can be detrimental to CAR T-cell therapy and potentiate its failure, continued Dr. Jain. Studies have suggested that patients who have been exposed to bendamustine (regardless of the time to CAR T-cell therapy) have worse progression-free survival. “So, if you want to follow up your treatment with CAR T-cell therapy or a bispecific antibody, both of which leverage T cells, you may wonder whether you are going to have worse outcomes if you use bendamustine,” he said.

Dr. Jain continued: “We know that with something like the R-GemOx backbone, we won’t deplete the T cells. The backbone is nice, and the polatuzumab vedotin addition seems to increase its effectiveness. I treat a lot of patients with CAR T-cell therapy, and as we all know, this can take some time. Polatuzumab vedotin plus R-GemOx gives us a really great option for making sure the patient’s disease is well controlled while we take them through that process.”

DISCLOSURE: Dr. Jain has served as a consultant or advisor to Kite/Gilead and Novartis; has received research funding from Kite/Gilead, Incyte, and Loxo/Lilly; and has received reimbursement for travel expenses from Kite/Gilead.