Shots:
- In the five-year follow-up data from the randomized POLARIX study, where participants received R-CHOP with a placebo for polatuzumab (control arm) and Pola-R-CHP with a placebo for vincristine
- The primary endpoint of the study was progression free survival, and the secondary endpoint was overall survival
- PharmaShots welcomes Dr. John Burke from Rocky Mountain Cancer Centers, in an enlightening dialogue exchange focusing on standard care for DLBCL.
Saurabh: Establishing a standard treatment for DLBCL remains a major challenge in non-Hodgkin lymphoma care. Let’s talk about the five-year POLARIX study and what were the noteworthy insights of this real-world study.
John: Yes, so POLARIX was actually not what’s typically described as a real-world study, but it was a clinical trial conducted internationally throughout the US, Europe, Asia and Australia. It was a randomized trial in which patients with previously untreated diffuse large B cell lymphoma, with an IPI score between two and five, were randomly assigned to receive the control arm of R-CHOP with a placebo for polatuzumab or the investigational arm of Pola-R-CHP with a placebo for vincristine. Patients were treated with six cycles of that therapy, followed by two cycles of rituximab.
The primary endpoint of the study was progression free survival; overall survival was a secondary endpoint. We previously reported outcomes of this trial with shorter durations of follow-up, and what we showed at the ASH meeting in 2024 was the five-year follow up for the first time.
What had previously been shown was that the Pola-R-CHP regimen improved progression free, but not overall, survival compared with R-CHOP. We had shown that it reduced the requirement for patients to get salvage therapies, which includes radiation therapy, other systemic chemo regimens, stem cell transplant CAR T cell therapies. All of those were reduced in the Pola-R-CHP arm. The toxicities of the Pola-R-CHP regimen were quite similar to those of the R-CHOP regimen. There was very little in the way of different rates of toxicity.
With this five year follow up, what we showed is that the progression free survival benefit continues to be maintained, that there was about a 6% absolute difference in progression free survival or a 27% reduction in the risk of progression or death in the Pola-R-CHP arm compared with the R-CHOP arm.
We showed a similar disease-free survival benefit. We showed that the rates of salvage therapies continued to be less in those who received Pola-R-CHP, so that by preventing relapses, Pola-R-CHP is preventing need for CAR-T, stem cell transplant and other salvage therapies.
Finally, with overall survival, at this point there is not a statistically significant difference between the two groups; however, within the last two years, we are starting to see some difference emerge that is not statistically significant. The curve does appear to be showing a modest separation over the last couple of years. The plan then is to continue follow patients for an additional couple of years to see if a significant overall survival benefit starts to emerge with Pola-R-CHP.
Another key finding on the subgroup analysis is that the ABC subgroup, as determined by the NanoString assay, clearly is demonstrating both progression-free and an overall survival benefit with receipt of Pola-R-CHP as compared with R-CHOP, whereas there were no differences in the GCB subgroup. So the regimen appears to have more predominant activity in NanoString-determined ABC subtype of DLBCL. However, the study was not powered to detect differences in any particular subgroup.
Saurabh: Pola-R-CHP shows promising results and confirms it as a standard of care for patients with previously untreated or high-risk DLBCL. How is this revelation going to impact the DLBCL management globally and the pharma industry in general?
John: The Pola-R-CHP regimen has been approved by regulatory authorities in the US and in Europe. It is not available in all countries so I would say globally it sort of remains to be determined whether this finding would lead some of those other countries to provide regulatory approval for polatuzumab. That would be one potential implication of this study globally. In the US, I don’t know that too much will change other than that it’s conceivable that providers might be perhaps a little bit more inclined to use Pola-R-CHP than they have been in the past based on the subtle separation in the overall survival curve that may be emerging, although again we don’t have enough statistical power to state that there is an overall survival benefit here.
In the ABC subtype of patients, once again as determined by NanoString, Pola-R-CHP remains the clearly superior regimen.
Will this trial lead more people to start using NanoString? I think probably not. Most likely this update will not have a major impact on practice in the United States, other than to confirm that Pola-R-CHP remains a reasonable standard of care for patients with previously untreated DLBCL.
Saurabh: Mortality remains an important parameter while securing a treatment for standardization. What role did it play in comparing Pola-R-CHP and R-CHOP?
John: Overall survival was a secondary endpoint and while at this time there is not a statistically significant difference, there may be an emerging difference in number of deaths from lymphoma within the last couple of years, and the cumulative number of lymphoma-related deaths was lower in the Pola-R-CHP group compared with the R-CHOP group.
Mortality and overall survival are really important endpoints to continue to look at, and that’s why we’re going to continue to follow patients for those endpoints over the next couple of years to see if a more statistically significant difference does emerge with long follow-up.
Saurabh: What other combination therapies may enter the race for establishing standard care in DLBCL?
John: There have been a couple of trials that have been completed that we are waiting on results of that could enter the space. The first one that comes to mind is called the FRONTMIND trial, which compares R-CHOP with or without the combination of the CD19 antibody tafasitamab plus lenalidomide and we hope to get a readout on the results of that study sometime soon.
Another trial that has been completed and is waiting a readout on events and outcomes is the ESCALADE study, which looked at adding acalibrutinib to R-CHOP in the activated B cell subtype of diffuse large B cell lymphoma.
Important ongoing studies that are enrolling patients are looking at the addition of bispecific antibodies to conventional chemo immunotherapy; I’m aware of ongoing trials with glofitamab and epcoritamab in that space.
Finally, I’m aware of other newer molecules – golcadomide and zilovertamab vedotin – are entering trials in treatment-naive DLBCL. Those trials are just getting kind of rolled out. There’s a number of products entering the space and testing themselves against frontline standard therapies.
Saurabh: What are the next steps for Pola-R-CHP in terms of regulatory approvals across geographies?
John: It’s not likely that anything would change in the US or Europe where polatuzumab is already approved though other countries could perhaps give regulatory approval if they haven’t already.
About the Author:
Dr. John Burke
Dr. John Burke is a board-certified hematologist and medical oncologist who joined Rocky Mountain Cancer Centers in 2003. He specializes in blood cancers, with an emphasis on lymphoid disorders, including lymphomas, chronic lymphocytic leukemia (CLL), and multiple myeloma. Dr. Burke is considered a national and international expert in blood cancers, lecturing primarily on lymphoid malignancies. He is very active in clinical research, helping to develop new therapies for lymphoid malignancies, and has published numerous articles in peer-reviewed medical journals, including the New England Journal of Medicine, Blood, and the Journal of Clinical Oncology.
Dr. Burke contributes to maximizing the quality of medical publications, serving as Editor-in-Chief for Targeted Therapies in Oncology and as an Associate Editor for JCO Oncology Practice. He is active in hematology and oncology professional societies, having recently served a term on the Ethics Committee of the American Society of Clinical Oncology (ASCO) and currently serving a term on the Committee on Practice of the American Society of Hematology (ASH).
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