Polatuzumab Vedotin in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

The GO29365 Study

Christopher R. Flowers, MD, MD Anderson Cancer Center, Houston, TX discusses the results of the GO29365 study on polatuzumab vedotin in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). 

Polatuzumab vedotin combined with bendamustine and rituximab yielded a high complete response rate and reduced the risk of death by 58% in patients with transplantation-ineligible R/R DLBCL, according to results from the GO29365 trial. Based on the results of this trial, polatuzumab vedotin was approved from the FDA in combination with bendamustine and rituximab for adult patients with relapsed/refractory DLBCL, after ≥2 prior therapies in June 2019.

Transcript:

Hello, I'm Dr. Christopher Flowers, professor and chair of the department of Lymphoma Myeloma at the University of Texas MD Anderson Cancer Center. It’s my pleasure to talk about the GO29365 study, a study that looked at the combination of polatuzumab vedotin plus bendamustine rituximab. This was a phase 1b/2 study—really a phase 1b early phase clinical trial that had a long extension period to the trial. The exploratory nature of the trial was looking at the combination of polatuzumab vedotin with bendamustine and rituximab in a dose-finding component to understand what the best dose was to give for patients with follicular lymphoma and patients with diffuse large B-cell lymphoma.

Can you briefly describe polatuzumab vedotin and give us the background on the data that led to this trial?

Polatuzumab is an agent that is a CD79b directed antibody drug conjugate, meaning that it's CD79b tied to MMAE, which is a potent microtubular inhibitor. Essentially a drug that is about 10 times as potent as vincristine. And with CD79b gets targeted to the B-cells for diffuse large B-cell lymphoma. Essentially 95% of patients have expression of CD79b on their cell surface, and when that binding occurs, then that molecule is internalized to the mole to the cell.

This study looked at the combination of the polatuzumab vedotin plus bendamustine rituximab and had a first component that was randomized, randomizing patients who had, 40 who had polatuzumab, bendamustine, rituximab and 40 who received bendamustine rituximab alone. In that randomized portion of the trial, what we found was that there was a dramatic difference in progression-free survival and overall survival for the group that was randomized to bendamustine plus polatuzumab vedotin with a progression-free survival of 6 months in the group that had received bendamustine plus polatuzumab, versus 3.7 months for the group that received bendamustine alone.

What were the results of this study?

Importantly what was found in this study is that there was a dramatic difference in the progression-free survival and overall survival for patients who received polatuzumab plus bendamustine rituximab versus a group that received bendamustine rituximab alone in diffuse large B-cell patients. For the patients who received bendamustine rituximab alone, the progression-free survival was 3.7 months, and the group that received polatuzumab plus bendamustine rituximab, that was 9.2 months. Even more remarkable was the difference in overall survival where the group that received bendamustine rituximab alone had an overall survival of 4.7 months, whereas the group who received polatuzumab plus BR, that was 12 months. I think also importantly is that when you look at the extension cohort of patients, which is 106 patients who received polatuzumab plus BR, that their overall survival was also 12.4 months, really mirroring what was seen in the randomized portion of the trial.

Ultimately, this trial led to the approval of polatuzumab plus bendamustine rituximab for relapsed and refractory diffuse large B-cell lymphoma, and this outcome of overall survival of more than a year in this patient population at the median, really is quite meaningful for patients who have relapsed and refractory diffuse large B-cell lymphoma.

Is there anything else that is notable about the methods or results of this study?

The other thing to note with polatuzumab is that the most common adverse events that we saw were adverse events associated with cytopenias that we commonly see with combination regimens that were really not much different than what you see for bendamustine rituximab alone, with the exception of neutropenia and febrile neutropenia, which are all manageable with growth factors. And the other concern that we have of anytime MMAE is given is peripheral neuropathy. That peripheral neuropathy for most drugs appears to be cumulative and it appears to increase dramatically after six cycles of therapy. With this regimen and with other regimens, giving less than 6 cycles of therapy really limits the effect of peripheral neuropathy with that predominantly being time-limited. In this study, in the pooled cohort that received [polatuzumab, bendamustine and rituximab], the peripheral neuropathy was 31% of patients. And again, that was mostly time-limited.

There have been a few analyses since the initial publication of the study in 2020. Are there any results from those that you would like to highlight?

The main one was part of what I mentioned, and that was the extension cohort of the study. In the extension cohort, we saw nearly identical results that do what we're seeing in the randomized portion. So when we look at the overall response rate for the group that was randomized to polatuzumab plus BR, that overall response rate was 42.5%. When you look at the patients who were in the extension cohort, so another 106 patients, that overall response rate was 41.5%. The complete response rates were also quite similar, and as I mentioned, the progression-free survival and overall survival results were quite similar with the overall survival results being nearly identical with overall survival of 12.5 months on the median for the group that randomized polatuzumab BR and an median overall survival of 12.4 months in the group of the extension cohort.

What’s next for polatuzumab vedotin? Are we expecting more analyses from the GO29365?

This really was the final analysis of this trial that was presented and now published in Blood Advances at the end of 2022 with Laurie Sehn being the lead author of that manuscript. There will be other trial results that come out . A study that I participated in, a phase 1 setting looking at the combination of polatuzumab plus venetoclax plus anti-CD20 antibodies that should be coming out soon. And then there was the first line clinical trial, POLARIX, that used polatuzumab as a substitution for vincristine in the R-CHOP. Those first results were published last year in the New England Journal of Medicine as a first line trial. The other trial results that we are awaiting are the results from the POLARGO study that looks at polatuzumab in the relapse setting in a randomized fashion.

Sources:

1.     Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/jco.19.00172

2.     FDA Approves Polatuzumab Vedotin for Diffuse Large B-Cell Lymphoma. United States Food and Drug Administration. June 10, 2019. Accessed January 12, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma