In the treatment of diffuse large B-cell lymphoma (DLBCL), the R-CHOP regimen has been a cornerstone, but enhancing its efficacy remains a significant challenge in the medical community. At the 29th European Hematology Association (EHA) Annual Meeting, held from June 13-16, 2024, in Madrid, Spain, Professor Zhiming Li's team from Sun Yat-sen University Cancer Center presented research showing that zanubrutinib combined with CHOP offers superior treatment outcomes, garnering much attention. "Oncology Frontier - Hematology Frontier" invited Professor Zhiming Li to share insights from this study and discuss the future applications of zanubrutinib in B-cell lymphoma treatment.Oncology Frontier – Hematology Frontier: At this conference, you presented a study comparing zanubrutinib combined with CHOP versus rituximab combined with CHOP in treating CD20-positive newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. Could you briefly introduce the study design and main results?
Professor Zhiming Li: This study has been a decade-long effort, progressing from early phase I and II trials to the current phase III randomized controlled trial. So far, zanubrutinib has shown promising data and has received approval from the National Medical Products Administration, even being included in the health insurance directory, which significantly improves its accessibility for patients. The study design is relatively straightforward; it is a head-to-head comparison of the novel CD20 monoclonal antibody zanubrutinib combined with CHOP (Hi-CHOP) against the traditional rituximab combined with CHOP (R-CHOP) in a randomized controlled trial (RCT). The study population included newly diagnosed CD20-positive DLBCL patients, encompassing both germinal center B-cell-like (GCB) and non-GCB subtypes, with an International Prognostic Index (IPI) score of 0-3.
DLBCL is the most common type of B-cell lymphoma, with R-CHOP being the traditional treatment regimen. Recently, the Pola-CHP regimen has also been introduced. However, about 30-40% of patients treated with R-CHOP enter a refractory or relapsed stage, making it crucial to enhance the efficacy of R-CHOP. Previous attempts to add different drugs to R-CHOP (R-CHOP+x) have not significantly surpassed R-CHOP. Therefore, our study aimed to modify the CD20 monoclonal antibody (R), developing a simple and clinically accessible regimen. The primary endpoint was the objective response rate (ORR) after six cycles of treatment, with secondary endpoints including complete remission (CR) rate, 3-year event-free survival (EFS), overall survival (OS), and safety.
Preliminary results showed an ORR of 83.5% in the Hi-CHOP group versus 81.4% in the R-CHOP group at the end of the sixth cycle, with no significant statistical difference, though the zanubrutinib combination showed a slight advantage. In other domestic studies, CD20 monoclonal antibody combinations have shown ORRs slightly lower than R-CHOP, but the zanubrutinib combination increased the ORR by about 2%. Moreover, the Hi-CHOP group exhibited a higher CR rate [full analysis set (FAS) 75.2% vs. 67.9%, P=0.092; per protocol set (PPS) 85.7% vs. 77.3%, P=0.038]. Achieving CR is the first step towards curing DLBCL, and zanubrutinib showed good overall treatment data, albeit not reaching statistical significance.
Further subgroup analysis revealed a more pronounced efficacy advantage in the GCB subtype DLBCL in the Hi-CHOP group, including ORR (91.30% vs. 78.85%, P=0.0339), CR rate (79.35% vs. 63.46%, P=0.0377), 3-year EFS (79.25% vs. 63.39%, P=0.0457), and 3-year OS (94.49% vs. 84.18%, P=0.0143). Unlike the non-GCB subtype, which has more targeted treatment options, the GCB subtype lacks particularly effective treatments. This study is significant because it shows that the CR rate in GCB patients significantly increased, translating into a 15% improvement in 3-year EFS and a 10% improvement in OS, both with significant statistical differences. Other CD20 monoclonal antibodies have not achieved these results.
Overall, zanubrutinib combined with CHOP not only achieved non-inferiority compared to R-CHOP but also showed slightly better data. Notably, this study identified the GCB subtype, which constitutes a substantial proportion of DLBCL patients. Both CR rate and 3-year EFS and OS in the GCB group showed significant improvements. This provides new treatment options and rationale for GCB patients, making this study very interesting and valuable.
Oncology Frontier – Hematology Frontier: In the study, zanubrutinib combined with CHOP showed a higher CR rate compared to rituximab combined with CHOP, especially in GCB subtype patients. What do you think is the significance of this finding for DLBCL treatment strategies?
Professor Zhiming Li: In clinical practice, we primarily rely on clinical trials to guide treatment. The GCB subtype accounts for 20-30% of DLBCL. Although non-GCB subtype patients may be more prevalent in China, GCB subtype patients are relatively more common internationally, especially in Europe and the United States. Given the superior efficacy of zanubrutinib combined with CHOP in GCB subtype patients, I believe this combination has the potential to be promoted globally, offering hope to more GCB subtype patients. Currently, treating the GCB subtype remains challenging, with no drugs significantly improving efficacy over R-CHOP. The addition of zanubrutinib may change this situation, providing more treatment options worldwide. Additionally, zanubrutinib has been included in the national health insurance in China, making it more affordable and accessible for patients to choose this treatment.
Oncology Frontier – Hematology Frontier: In terms of safety, although the incidence of infusion-related reactions was slightly higher in the zanubrutinib group, the overall tolerability was good. How do you view these adverse reactions, and how should they be managed in clinical practice?
Professor Zhiming Li: Every drug in chemotherapy and targeted therapy has unique characteristics. For CD20 monoclonal antibodies, infusion reactions have been an issue for many years and cannot be entirely eliminated (as long as antibodies are present, this issue will exist). However, with extensive clinical experience, we have developed comprehensive strategies to manage these reactions, including timely pre-treatment, intervention, and monitoring. In our hospital, for example, we have pioneered a rapid titration method for rituximab, transitioning from long infusion times in each cycle to completing infusions within six hours in the second and subsequent cycles if no severe reactions occur in the first cycle. This method has been used for many years and is now standard practice, recommended in Chinese guidelines. Therefore, although zanubrutinib has a slightly higher incidence of infusion reactions in trials, I believe this is not a significant issue and will not impact its clinical use. With our accumulated experience, we can effectively prevent and manage these reactions.
Oncology Frontier – Hematology Frontier: Based on this study, what is your perspective on the future application of zanubrutinib in DLBCL treatment? Do you think zanubrutinib combined with CHOP has the potential to become a standard regimen for DLBCL treatment?
Professor Zhiming Li: Zanubrutinib, as a new CD20 monoclonal antibody, has shown superior efficacy in phase III randomized controlled trials. Our center, being one of the largest enrollment centers for this study in China, has accumulated rich experience from early phase I and II trials to the current phase III trials. The data have met or even exceeded our expectations, especially in the short- and long-term efficacy in the GCB subtype, showing statistically significant differences. Zanubrutinib has been approved in China for a year and included in the national health insurance directory, further improving its accessibility. Therefore, zanubrutinib combined with CHOP can be considered a first-line standard regimen for DLBCL treatment.
I believe there is still much room for future exploration. For instance, zanubrutinib could be a valuable direction for treating relapsed/refractory patients. Additionally, like the R-CHOP regimen, we can conduct clinical trials combining zanubrutinib with other treatments, offering more diverse treatment options and possibly achieving better outcomes for certain subtypes. Beyond DLBCL, other B-cell lymphoma subtypes are also worth investigating. While CD20 antibodies like rituximab have not obtained clear indications in some cases, they are widely used in practice. I suggest continuing collaboration with zanubrutinib developers to conduct more studies on other subtypes, providing more evidence-based medicine to support our clinical work.
