Editor's Note: A grand gathering of the world’s leading experts in hematologic oncology was recently held. This conference deeply explored the latest treatment advancements for malignant hematological diseases such as Diffuse Large B-cell Lymphoma (DLBCL). At the plenary session, Professor Juan M. Sancho Cia was invited to present a special report titled "Polatuzumab Vedotin, Rituximab, Gemcitabine, and Oxaliplatin (Pola-R-GemOx) in Relapsed/Refractory DLBCL: The Phase III POLARGO Study," elaborating on the significant breakthrough results of the POLARGO study, which brings new treatment options and survival hope for transplant-ineligible relapsed/refractory DLBCL patients. DLBCL is the most common subtype of non-Hodgkin lymphoma in adults. Although first-line treatment is highly effective, 30%-40% of patients still experience relapse or refractory disease, leading to poor prognosis. Especially for patients unsuitable for stem cell transplantation, treatment options are limited, representing a significant unmet clinical need. In this context, the success of the POLARGO Phase III clinical trial undoubtedly brings a ray of hope for this high-risk patient population.POLARGO Study Background and Design
Polatuzumab vedotin is an antibody-drug conjugate (ADC) targeting CD79b. CD79b is an important component of the B-cell receptor complex and is highly expressed on the surface of most malignant B-cell lymphomas. Polatuzumab vedotin specifically binds to CD79b, is internalized into tumor cells, and subsequently cleaves its linker to release the anti-microtubule drug monomethyl auristatin E (MMAE), thereby inhibiting cell division and inducing tumor cell apoptosis, demonstrating its potential for targeted B-cell killing. Currently, Polatuzumab vedotin has been approved in several regions for first-line treatment and relapsed/refractory DLBCL, and its efficacy has been confirmed in the POLARIS study (in combination with R-CHP for first-line treatment) and in combination with bendamustine and rituximab for relapsed/refractory treatment. The standard R-GEMOX (rituximab, gemcitabine, oxaliplatin) regimen is a commonly used chemotherapy regimen for relapsed/refractory DLBCL patients, particularly suitable for older patients or those with comorbidities who are not candidates for high-dose chemotherapy and autologous stem cell transplantation (ASCT). Given the potential neurotoxicity risk associated with polatuzumab vedotin and platinum-containing chemotherapy regimens, the POLARGO study aimed to evaluate the efficacy and safety of polatuzumab vedotin combined with R-GEMOX (Pola-R-GEMOX) compared to R-GEMOX alone in transplant-ineligible relapsed/refractory DLBCL patients. The POLARGO study was a global, multicenter, open-label, randomized Phase III clinical trial. Key inclusion criteria included: diagnosis of relapsed/refractory DLBCL (not otherwise specified or transformed from indolent lymphoma), having received at least one prior line of therapy, being transplant-ineligible, and having no prior exposure to polatuzumab vedotin. The study initially included a safety run-in phase with 15 patients to assess the tolerability and safety of the Pola-R-GEMOX regimen (administered every three weeks for 8 cycles). After confirming the safety and tolerability of the combination regimen, the study entered the randomization phase, enrolling a total of 255 patients, randomized 1:1 to either the Pola-R-GEMOX group or the R-GEMOX group, with both groups receiving the same number of treatment cycles. The primary endpoint of the trial was Overall Survival (OS), and key secondary endpoints included Progression-Free Survival (PFS), Overall Response Rate (ORR), and Complete Response Rate (CRR), with ORR and CRR assessed by an independent review committee. At baseline, patient characteristics were balanced between the two groups, with a median age of 67 and 64 years, respectively. Approximately half of the patients had a high International Prognostic Index (IPI), and over 60% had received only one prior line of therapy. Notably, more than half of the patients had primary refractory disease, and 65% were refractory to their last therapy, highlighting the treatment challenges in this patient population.
POLARGO Study Key Results: Significant Improvement in Survival and Response Rates
Professor Juan M. Sancho Cia reported that after a median follow-up of two years (24.6 months), the Pola-R-GEMOX regimen significantly improved patients’ overall survival compared to the R-GEMOX alone regimen. The median OS in the Pola-R-GEMOX group was 19.5 months, while in the R-GEMOX group it was 12.5 months, with a Hazard Ratio (HR) of 0.60 and a statistically significant P-value (p=0.0017). This indicates that the Pola-R-GEMOX regimen reduced the risk of death by 40%. The 24-month OS rate was 44.0% in the Pola-R-GEMOX group and 33.2% in the R-GEMOX group. Similarly, progression-free survival was also significantly improved in the Pola-R-GEMOX group, with median PFS increasing from 2.7 months in the R-GEMOX group to 7.4 months in the Pola-R-GEMOX group, with an HR of 0.37 and a statistically significant P-value (p<0.0001). The 12-month PFS rate was 36.6% in the Pola-R-GEMOX group and 17.9% in the R-GEMOX group. Regarding other efficacy endpoints, the Pola-R-GEMOX regimen also showed significant advantages. The Overall Response Rate in the Pola-R-GEMOX group reached 52%, and the Complete Response Rate reached 40%, almost twice that of the R-GEMOX group (ORR 24%, CRR 19%). Even when evaluating best response, the best ORR in the Pola-R-GEMOX group reached 65%, with nearly half of the patients achieving a complete response. Notably, a higher proportion of patients in the R-GEMOX group (65%) received subsequent therapies, compared to 45% in the Pola-R-GEMOX group. Despite R-GEMOX patients receiving more subsequent treatments, the two groups had similar or identical frequencies of highly effective subsequent therapies such as chimeric antigen receptor T-cell (CAR-T) therapy, bispecific antibodies, or stem cell transplantation. This suggests that the survival benefit observed in the POLARGO study primarily stemmed from the study treatment itself, rather than from subsequent therapies.
Subgroup Analysis: Broad Benefits of POLARGO Study
The OS subgroup analysis of the POLARGO study showed that the survival benefit of the Pola-R-GEMOX regimen was superior to the R-GEMOX regimen across most analyzed subgroups. This included patient populations considered “refractory,” such as primary refractory patients or those refractory to their last treatment. This finding is particularly important as it indicates that the Pola-R-GEMOX regimen is equally effective for these patients with poor prognoses. Furthermore, survival analysis based on Cell of Origin (COO) showed that patients in the Pola-R-GEMOX group had better survival than those in the R-GEMOX group, regardless of whether they had the Activated B-cell-like (ABC) or Germinal Center B-cell-like (GCB) subtype. This result differs from some findings in other Polatuzumab studies, suggesting that in relapsed/refractory DLBCL patients, Polatuzumab’s efficacy may not be influenced by cell-of-origin specificity.
Safety Profile and Risk Management
Regarding safety, patients in the Pola-R-GEMOX group received a higher median number of treatment cycles (7.5 cycles) than those in the R-GEMOX group (4 cycles), implying longer treatment exposure in the experimental arm. Although the incidence of adverse events was higher in the Pola-R-GEMOX group, the incidence of Grade 3/4 adverse events (57.0% and 58.4%, respectively) was very similar between the two groups. However, the Pola-R-GEMOX group had a higher proportion of serious adverse events, deaths due to adverse events, and discontinuations or dose reductions due to any drug. The main reasons for study discontinuation included thrombocytopenia and infection, while the main reasons for dose reduction included thrombocytopenia and peripheral neuropathy. Notably, the number of deaths in the R-GEMOX group (83 patients) was higher than in the Pola-R-GEMOX group (68 patients). The primary cause of death in both groups was disease progression, but in the R-GEMOX group, deaths due to disease progression were significantly higher than in the experimental group. The number of deaths due to adverse events was slightly higher in the Pola-R-GEMOX group, mainly caused by infections, especially COVID-19 infections. It is worth mentioning that the POLARGO trial was conducted between 2020 and 2024, coinciding with the peak of the global COVID-19 pandemic. Regarding hematologic toxicities, the incidence of thrombocytopenia and anemia was slightly higher in the Pola-R-GEMOX group, but the incidence of neutropenia or Grade ≥3 neutropenia, and even febrile neutropenia, was similar or identical between the two groups. This may be attributed to the mandatory infection prevention and granulocyte-colony stimulating factor (G-CSF) support measures included in the study protocol. The incidence of infections was higher in the Pola-R-GEMOX group, with many cases related to COVID-19 infection. The incidence of hepatic toxicity was also higher, but most hepatic toxicities were transient, manifesting as mild transaminase elevation, and rarely led to treatment discontinuation. Peripheral neuropathy, a known adverse event associated with polatuzumab vedotin and platinum-based drugs, had a higher incidence in the Pola-R-GEMOX group compared to the R-GEMOX group (57.0% vs 28.8%). However, most adverse events were low-grade 1-2, and rarely led to the discontinuation of polatuzumab vedotin. Only three patients discontinued polatuzumab vedotin due to peripheral neuropathy. At the time of this analysis, symptoms had resolved or improved in half of the patients, with complete resolution of peripheral neuropathy symptoms in one-third of these patients.
Expert Summary and Future Outlook
In his summary, Professor Juan M. Sancho Cia emphasized that the POLARGO study data demonstrated that for transplant-ineligible relapsed/refractory DLBCL patients, the Pola-R-GEMOX regimen, compared to the R-GEMOX regimen, reduced the relative risk of death by 40%, significantly improving patient prognosis. This survival benefit was consistent across all analyzed subgroups, including cell-of-origin subgroups and refractory patients. The safety profile of the Pola-R-GEMOX regimen was consistent with the known risks of each individual agent, including infection, peripheral neuropathy, and hematologic toxicities. The success of the POLARGO study further solidifies the benefits of polatuzumab vedotin in combination with chemotherapy for DLBCL treatment, aligning with conclusions from two previous randomized controlled trials. This breakthrough not only provides clinicians with a new therapeutic tool but also reaffirms the immense potential of innovative drugs in improving the quality of life for cancer patients.
Source of Contribution/Interview: Oncology Panorama – Oncology News
