Polatuzumab Vedotin Offers a New Option for Refractory DLBCL

Jeff P. Sharman, MD

Frontline therapy is able to cure approximately two-thirds of patients with diffuse large B-cell lymphoma (DLBCL), but that still leaves a large number of patients who experience relapse or refractory disease, according to Jeff Sharman, MD. Exploration of new options in this setting led to the FDA approval of polatuzumab vedotin-piiq (Polivy) in combination with bendamustine and a rituximab product in June 2019.

In an interview with OncologyLive^®, Sharman, director of research at Willamette Valley Cancer Institute in Eugene, Oregon, and medical director of hematology research for The US Oncology Network, discussed the current approval and potential future roles for the drug.

OncologyLive: Please provide an overview of the patient population eligible for this therapy.

Sharman: The original study [NCT02257567] included patients with both relapsed or refractory [R/R] DLBCL and a second cohort with relapsed follicular lymphoma [FL]. The drug was approved for those patients with R/R DLBCL. Interestingly, this was a randomized phase II study that was not originally designed as a pivotal study, but [investigators] were pleasantly surprised by the favorable outcomes and the FDA was willing to work with the data that they had.

In the study focusing exclusively on patients with relapsed DLBCL, these were patients who had at least 1 prior regimen therapy for their DLBCL—typically, anthracycline-based chemotherapy, such as R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone], which is capable of yielding a cure in about two-thirds of patients. A third of patients who relapsed would be potentially eligible for polatuzumab. The study design was a randomized phase II study of bendamustine in combination with rituximab plus or minus polatuzumab.

It’s worth noting that patients with relapsed large cell lymphoma can go down 2 pathways. Those pathways include patients who are suitable for autologous stem cell transplant; they would receive salvage chemotherapy followed by radiotherapy with stem cell rescue. Patients considered ineligible for autologous stem cell transplant [ASCT] would enroll in this type of study.

Could you describe the mechanism of action?

Polatuzumab is an antibody—drug conjugate, a monoclonal antibody directed against CD79. When there is signaling transmitted from the B-cell receptors, it goes through CD79 to cytoplasmic kinases. Upon binding to CD79, the antibody is internalized and from there forward, the mechanism of action is very similar to brentuximab vedotin [Adcetris], which is approved for the treatment of Hodgkin disease but is directed against CD30.

In fact, Genentech licensed the linker and payload technology from Seattle Genetics [which developed brentuximab vedotin] for the purpose of creating polatuzumab. It has the same linker and monomethyl auristatin E payload as brentuximab, which gets internalized from the cell and taken up into the lysosomes, where the linker is degraded, releasing the monomethyl auristatin E intracellularly. That intracellular drug then becomes a microtubular inhibitor and works in the same way as many of the other microtubular agents that are available.

How well is the drug tolerated?

In this study, polatuzumab was administered on a 3-week basis. The main [adverse events] of polatuzumab include neuropathy and some cytopenia. The neuropathy [events] were very similar to those that are experienced with brentuximab in part because the medications are really quite similar. It is a cumulative neuropathy that increases with successive doses and can be permanent, so it is something that needs to be carefully monitored, and as neuropathy gets worse, you need to consider dose reduction or interruption.

There is always the risk of myelosuppression, so individuals can see some cytopenia, but I would say it’s relatively mild. Infusion reactions are always possible but generally not dose limiting. And, since it is an effective drug, there is always the concern about tumor lysis syndrome; however, that’s not a supercommon problem with the drug but something that [oncologists] need to be aware of.

How does polatuzumab vedotin-piiq fit into the current treatment paradigm?

The drug was approved on the basis of an accelerated approval, and continued approval in this setting will require confirmatory studies. The biggest confirmatory study right now [POLARIX; NCT03274492] is a clinical trial of R-CHOP versus R-CHP [rituximab, cyclophosphamide, doxorubicin, and prednisone] plus polatuzumab in the frontline setting. That study is fully enrolled, and we are awaiting results that are anticipated either next year or early the following year.

The frontline setting in DLBCL has seen a very large number of negative phase III studies, probably almost 20, that have compared novel agents with R-CHOP. It’s a high bar to displace R-CHOP but that is what [POLARIX] is attempting.

Polatuzumab is currently indicated for any patient receiving a third line regimen that is not considered suitable for transplant. However, the other thing that is really evolving in this space is CAR [chimeric antigen receptor] T-cell therapy. Even if patients are not eligible for ASCT, they may be suitable for CAR T. Whereas polatuzumab is a palliative approach to minimize the disease or prolong palliative impact, with CAR T there is at least a hope that patients could be cured.

For the multiple-relapsed patient, after the first relapse, you would [consider] whether or not the patient is ASCT eligible. But as you move beyond that, the question is: Are they CAR T eligible or not? CAR T is challenged by availability and by distribution networks, so many patients are not able to access it. This sort of self-selects [patients] in terms of which patients are eligible [for polatuzumab vs CAR T]. But really, this is a diminishing group—those who are not cured by R-CHOP, who are not cured by ASCT or CAR T. It is not a huge number of patients currently.

What are the next steps for polatuzumab vedotin-piiq?

The biggest next step that will determine if this drug becomes broadly used or remains sort of niche will depend on the results of the frontline phase III study. If that is a positive study, it would likely change the standard of care for patients and if that’s the case, I think we will be using polatuzumab extensively.

Until we see the data, it will be difficult to estimate the likelihood that the trial will succeed. Our group has published combinations with R-CHP [rituximab-cyclophosphamide, doxorubicin, and prednisone] and polatuzumab with very impressive activity in the frontline setting so we’re optimistic, but until the data are available, it is purely speculative.