Dr John Burke: POLARIX Shows Marked Improvement in Patient Outcomes With Pola-R-CHP as First-line Treatment for DLBCL

Polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) is the only first-line therapy in over 2 decades to show an improvement on the previous standard of care in diffuse large B-cell lymphoma (DLBCL), said John Burke, MD, hematologist, Rocky Mountain Cancer Centers.

Dr Burke was the coauthor of the late-breaking abstract presented at ASH 2021, titled “The POLARIX Study: Polatuzumab Vedotin With Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients With Previously Untreated Diffuse Large B-Cell Lymphoma.”

Transcript

What are the mechanisms of action for pola-R-CHP? How does it compare with standard-of-care R-CHOP and what potential has it shown previously in the treatment of DLBCL?

So, polatuzumab vedotin is an antibody drug conjugate and what that means it's an antibody that binds to a protein called CD79b. CD79b is on the surface of B cells and it's on the surface of malignant B lymphocytes in DLBCL and other B-cell lymphomas. And the antibody is linked to a toxin that actually is a chemotherapy drug basically.

So, it binds to the surface of the cell and is internalized inside the cell, releases the toxin that can then kill the cell, and so it's a new mechanism of action. It was approved a couple of years ago for patients with relapsed DLBCL and so that's where it's been used to date. What was also known from an older study is that adding polatuzumab to existing agents—rituximab, cyclophosphamide, doxorubicin prednisone, called the R-CHP regimen—can be effective in DLBCL.

But we didn't know whether it was better than the currently existing R-CHOP—I can give you the names of the drugs, it’s rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and it's chemo that's administered intravenously once every 3 weeks. Usually, for a total of 6 cycles or 6 rounds of chemo, and so that's kind of the standard treatment and it achieves remissions in the majority of patients, and it cures about 60% of patients—60% to 70%—but about 30% to 40% will relapse after R-CHOP therapy.

Can you explain the design of the phase 3 POLARIX study and the efficacy/safety outcomes of pola-R-CHP vs R-CHOP reported at ASH?

So, as I said, we didn't really know whether polatuzumab plus R-CHP was better than R-CHOP, and so that was the question that was asked going into this study is if one of them is more effective or less effective than the other. And so that led to the design of this study, which was a randomized phase 3 trial, where more than 800 patients with advanced DLBCL participated.

They enrolled in the study and then they were randomly assigned to receive one regimen or the other. And as part of that design, there was a placebo so that patients who were assigned to get pola-R-CHP were given a placebo for vincristine, which is not in pola-R-CHP, so they were given fake vincristine.

Patients who were assigned to R-CHOP were given a placebo for the polatuzumab. So, they didn't know whether they were getting real polatuzumab or fake polatuzumab or real vincristine or fake vincristine, and neither did the treating physicians, and so it was it was called a double-blind study where the patients and the physicians didn't know what they were getting.

All patients were treated with 6 cycles of the chemotherapy followed by 2 additional cycles of rituximab and that was the design. Then the results that we've learned are that the polatuzumab R-CHP regimen led to better outcomes with a number of the end points. And those included the main end point, which was progression-free survival (PFS), meaning how long patients go before they have worsening of their cancer or a death event. And so, PFS was better, as was something called event-free survival.

So far, we've not seen any difference in overall survival, response rates were similar, and then the toxicity profile of the different regimens was really quite similar with not a lot of differences between the 2 regimens. So, what's really important about the trial is that it's the first in 2 decades to show an improvement on the previous standard.

A couple of decades ago, it was demonstrated that the addition of rituximab, the antibody targeting CD20, to CHOP improved outcomes. And this is really the first change since then, where we've shown that something can improve outcomes compared with R-CHOP. I failed to mention too another interesting finding was that because of the fewer progression events where the patient's cancer got worse, there was less need for additional things.

For example, patients did not need to go on and get second-line chemo as much, they didn't need to go on to get radiation as much, they didn't need to go on and get autologous stem cell transplant as much to sort of salvage a relapse situation. So, it significantly reduced the need for additional therapies because it lowered the risk of relapse.