Combining polatuzumab vedotin-piiq with rituximab, gemcitabine, and oxaliplatin (Pola–R-GemOx) significantly improved survival outcomes in patients with transplant-ineligible, relapsed or refractory diffuse large B-cell lymphoma (DLBCL) over standard R-GemOx alone, in the phase III POLARGO trial. For patients treated with this investigational regimen, deaths were significantly reduced by 40%, meeting the study's primary endpoint, reported Matthew Matasar, MD, Chief of the Division of Blood Disorders at Rutgers Cancer Institute, New Brunswick, New Jersey, at the European Hematology Association (EHA) 2025 Congress (Abstract S101).
“The POLARGO regimen did indeed lead to a statistically significant and clinically meaningful survival benefit compared to the standard of care, R-GemOx, with a stratified hazard ratio for death of 0.60 (P = .0017), resulting in a 40% overall reduction in the risk of death with the use of polatuzumab plus R-GemOx,” Dr. Matasar said. “The data reinforce the benefit of adding polituzumab vedotin to chemoimmunotherapy programs in a variety of clinical settings, giving clinicians potentially a new tool in the treatment of relapsed/refractory disease.”
Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets and kills B cells. It is approved in a number of settings for the treatment of lymphoma.
Trial Details and Key Results
The global POLARGO trial enrolled 270 patients with relapsed or refractory DLBCL ineligible for autologous stem cell transplant and previously treated with at least one prior line of therapy (but not polatuzumab vedotin). Patients, most of whom had refractory disease, were randomly assigned to Pola–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 Pola–R-GemOx vs 12.5 months with R-GemOx (hazard ratio [HR] = 0.60; 95% confidence interval = 0.43–0.83; P = .0017). The 2-year overall survival rate was 44.0% vs 33.2%, respectively.
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), with the 12-month progression-free survival rate of 36.6% vs 17.9%, respectively. Pola–R-GemOx also nearly doubled the response rate, from 24.6% with standard therapy to 52.7%; the complete response rate was 19.0% vs 40.3%, respectively, representing an absolute difference of 21.3% (P < .0001), Dr. Matasar reported.
The overall survival benefit was consistent across subgroups, including those with and without bulky disease, and among both patients with primary refractory and nonrefractory disease. Of note, the survival benefit was seen in both activated B-cell (ABC) and germinal center B-cell subtypes—contrary to prior findings from the POLARIX trial, which had suggested preferential benefit in the ABC subtype.
Dr. Matasar emphasized that the overall survival benefit was robust, as patients receiving R-GemOx had undergone more subsequent lines of therapy. This ruled out the possibility that the results were confounded by postprogression treatment access, he noted.
Safety Profile
The enhanced efficacy of Pola–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 Pola–R-GemOx arm (57.0% vs 58.4%, grade ≥ 3), and that arm had more treatment-related discontinuations (23.3% vs 8.0%). Thrombocytopenia and infections were more frequent in this arm as well.
There were more deaths reported in the experimental arm, mostly related to infections and mostly from COVID. Ten deaths occurred during the study, which was conducted during the peak of the pandemic; seven patients died during treatment and three after completion of the study.
Peripheral neuropathy, which was not unexpected because of the overlapping neurotoxicity of polatuzumab vedotin and oxaliplatin, was observed in 57.0% of patients receiving Pola–R-GemOx vs 28.8% with R-GemOx, but the majority were grade 1; four patients (3.9%) in the experimental arm developed grade 3 neuropathy. The neuropathy was mostly reported to be low grade and largely improved by the study’s end. “In fact, one-third had complete resolution by study closure,” he noted.
Disclosure: Dr. Matasar reported personal relationships with AbbVie, Allogene, Arvinas, Bayer, BMS, Genentech, GenMab, Kite Pharma, Novartis, Pfizer, Roche, ADC Therapeutics, AstraZeneca, Ipsen, Johnson & Johnson, Regeneron, Pfizer, and Merck.
