Polatuzumab Vedotin-piiq

Polatuzumab vedotin-piiq (Polivy) is an antibody-drug conjugate approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have already received at least two prior therapies.¹ Polatuzumab vedotin is approved only for use in this indication in combination with two other cancer treatments—bendamustine and rituximab (BR)—this was the first chemoimmunotherapy regimen approved for patients with relapsed or refractory DLBCL.²

“This is a very effective combination that can be used for patients with relapsed/refractory DLBCL, and it can provide many patients with durable disease control,” noted Laurie Sehn, MD, MPH, Chair of the Lymphoma Tumour Group at the University of British Columbia Cancer Centre for Lymphoid Cancer, Clinical Professor of Medicine in the Division of Medical Oncology at the University of British Columbia, and Associate Editor of Blood. “Prior to the availability of [polatuzumab vedotin plus BR], there were limited treatment options for patients with transplant-ineligible DLBCL.

DLBCL is the most common type of non-Hodgkin lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for many years, offering potential cure for a high percentage of patients. However, historically, patients who relapse after R-CHOP have fared poorly, with limited treatment options.

In 2019, polatuzumab vedotin in combination with BR received accelerated approval from the FDA for patients with relapsed or refractory DLBCL who have experienced disease progression on at least two prior therapies, thus providing an alternative therapeutic option for individuals in whom multiple treatments have not worked. Although it is not yet approved as first-line therapy for previously untreated diffuse large B-cell lymphoma, data from a phase III trial point to its forthcoming approval for that indication.³

According to Justina Kiernan, PA, an oncology physician assistant at Memorial Sloan Kettering Cancer Center in New York City, “the benefit of this drug is the clear improved overall survival of patients with relapsed or refractory lymphoma. It is a very tolerable regimen with minimal secondary side effects, but if side effects such as neuropathy do become an issue, there is potential to dose-modify if needed.”

“Ultimately though,” she continued, “the benefit [of this regimen] lies in our ability to extend survival for people who may not otherwise have effective treatment options.”

Trial Data Led to Approval in Relapsed or Refractory DLBCL

The safety and efficacy of polatuzumab vedotin were evaluated in a study of 80 patients with relapsed or refractory DLBCL.⁴ The trial randomly assigned patients to polatuzumab vedotin combined with BR or BR alone, with efficacy based on complete response rate and duration of response.

Patients who received polatuzumab vedotin plus BR demonstrated higher rates of complete and partial responses. At the end of treatment, the complete response rate was 40% with the triplet regimen compared with 18% with BR alone. Of the 25 patients who achieved a partial or complete response to the triplet regimen, 16 (64%) had a duration of response of at least 6 months and almost half had a duration of response of 1 year or more.

Patients who received polatuzumab vedotin plus BR had higher rates of grade 3 or 4 neutropenia (46.2% vs. 33.3%), anemia (28.2% vs. 17.9%), and thrombocytopenia (41% vs. 23.1%), versus the BR group. However, the rate of grade 3 or 4 infections was similar between the two groups (23.1% vs. 20.5%).

According to Dr. Sehn, this drug combination was primarily tested in transplant-ineligible patients. Although it is generally used to achieve disease control and symptom relief for patients who otherwise don’t have curative options, it may also serve as a bridge to chimeric antigen receptor (CAR) T-cell therapy and other definitive therapies. However, if CAR T-cell therapy is considered, leukapheresis should be planned prior to the use of bendamustine, which can lead to significant lymphodepletion.

Polatuzumab vedotin plus BR may serve as a bridge to CAR T-cell therapy and other definitive therapies.

“Generally, the patients who are being treated with this regimen may not have further curative options, and the goal may be to achieve some level of durable disease control and symptom relief,” she told JNCCN 360. “We don’t know that this is a curative regimen, but a proportion of patients—approximately 15% in the pivotal trial—had prolonged disease control and had not relapsed after long follow-up.”

Polatuzumab vedotin works differently from traditional chemotherapies. The monoclonal antibody polatuzumab binds to CD79b B-cell surface markers expressed on both normal and malignant B cells and is internalized, releasing monomethyl auristatin E (MMAE), the cytotoxic compound. Because CD79b is expressed on both cancerous and healthy B cells, some adverse events are to be expected as a result of apoptosis or cell death.

Appropriate Patients and Side Effects

“Because polatuzumab vedotin is given as a package with bendamustine and rituximab, certain toxicities should be considered when trying to decide if it’s right for a given patient,” said Dr. Sehn.

Most physicians are familiar with the combination of bendamustine and rituximab, which is given routinely for patients with indolent lymphomas. “In my own clinic, when I use bendamustine and rituximab, I routinely give it to patients into their 80s,” commented Dr. Sehn. “Despite being chemotherapy-based, the backbone that it’s built on is really quite tolerable for most patients, regardless of age.”

However, the addition of polatuzumab vedotin to BR does increase toxicity somewhat, she acknowledged. Side effects are similar to those seen with other treatment regimens used in DLBCL. The most common side effects are low blood cell counts (platelets, red blood cells, white blood cells), peripheral neuropathy, fatigue, diarrhea, nausea, fever, decreased appetite, and infections.

“I’d say the biggest risks for patients are cytopenias, neutropenia, and increased risk of infection,” she said. “In my own clinic, there’s not really an age cutoff for this therapy, but if a patient is frail, it might not be suitable.”  

Although cytopenias are common, transfusion is rarely necessary in her practice, Dr. Sehn noted. “A transfusion requirement is rare, but essentially, patients can and will develop neutropenia and lymphopenia and can be at a higher risk of infection,” she said.

Peripheral Neuropathy

According to Dr. Sehn, peripheral neuropathy typically manifests as numbness and tingling of the extremities (similar to that seen with vincristine), although occasionally, patients may experience more painful peripheral neuropathy. In some cases, neurologic side effects may signal a need for dose reduction, treatment delays, or even treatment discontinuation. However, she pointed out, dose reductions and modifications are still fairly uncommon, and most patients are able to tolerate the full dose of treatment for the intended six cycles of therapy.

“As a combination treatment, part of the reason why it’s limited to six cycles is because the peripheral neuropathy is cumulative. Treating beyond six cycles would likely increase the risk of neurotoxicity,” Dr. Sehn observed. “But when limited to six cycles, if patients do develop peripheral neuropathy, it tends to be relatively mild.”

Ms. Kiernan agreed that neuropathy occurs over the course of treatment and tends to be delayed. “Most people push through the mild neuropathy to derive the maximum benefit of the drug, but it can become a dose-limiting toxicity. In rare situations, if neuropathy is beginning to interfere with daily life, affecting activities such as walking or grabbing a pen, then we do have to either dose-adjust or start looking at what alternatives are available,” she said. “It’s important for clinicians to make sure they’re assessing and grading peripheral neuropathy in patients.”

Patients who experience peripheral neuropathy do tend to report significant improvements after completion of six cycles of treatment. However, drugs such as gabapentin or pregabalin (as well as dose delays or reductions) may mitigate some of the side effects of peripheral neuropathy in the meantime, Ms. Kiernan added.

According to Ms. Kiernan, myelosuppression is uncommon with polatuzumab vedotin alone. However, it can become a dose-limiting or dose-modifying event when combined with bendamustine and rituximab, especially in the case of persistent neutropenia or thrombocytopenia, and may prompt dose adjustment or even elimination of bendamustine.

Treatment Administration and Infusion Reactions

Polatuzumab vedotin is typically given in an infusion unit. According to Ms. Kiernan, the initial monitoring and administration of the drug—as well as prophylactic medication and supplemental care in the case of a reaction—are, for the most part, handled by infusion nurses.

“The majority of infusion reactions are mild, because we are attentive to and cognizant of the reaction potential,” she said. “So, any reaction that does occur is usually addressed before it becomes severe.”

Ms. Kiernan and her attending physician assess any infusion reactions, as well as any secondary side effects (ie, peripheral neuropathy). Providers should monitor patients closely for serious side effects such as infusion-related reactions (fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of infusion); myelosuppression; fatal and/or serious bacterial, fungal, or viral infection; tumor-lysis syndrome; hepatotoxicity; and progressive multifocal leukoencephalopathy.

According to Ms. Kiernan, “some people don’t connect the dots that difficulty walking, such as not being able to lift and feel the foot move forward, is due to neuropathy. We make sure to do a comprehensive exam, and from there, we can formulate a plan as to what to do next.”

The recommended dose of polatuzumab vedotin is 1.8 mg/kg as an intravenous infusion over 90 minutes. The drug is administered with bendamustine and a rituximab product (in any order) on the first day of each treatment cycle, and bendamustine is given by itself on the second day of each cycle. The recommended dose of bendamustine is 90 mg/m²/day on days 1 and 2 when administered with polatuzumab vedotin and rituximab; the recommended dose of the rituximab product is 375 mg/m² intravenously on day 1 of each cycle.

“It’s given mainly in this combination, but on a patient-by-patient basis, different components of the combination could be dropped,” Dr. Sehn told JNCCN 360. “For example, in a patient who’s relapsed/refractory and a potential CAR T-cell candidate, there’s concern about giving bendamustine prior to the leukapheresis that is required for CAR T-cell therapies, so sometimes treaters will drop the bendamustine. But essentially, it is a package, and that package includes polatuzumab vedotin, bendamustine and rituximab right now; that’s the primary approval.”

If the first 90-minute infusion is well tolerated (patients should be monitored for infusion-related reactions during the infusion and for a minimum of 90 minutes following completion of the initial dose), subsequent infusions may be administered over 30 minutes. Treatment is repeated every 21 days for a total of six cycles.

“Once tolerability is established and the patient gets through the first dose, then we can titrate the rate of the next infusion accordingly,” Ms. Kiernan noted.

Most patients receiving polatuzumab vedotin plus BR should receive pretreatment prophylaxis with an antimicrobial, an antiviral, an antihistamine, and an antipyretic at least 30 minutes prior to administration, although patient needs may vary. According to Ms. Kiernan, some institutions also administer a steroid, although this is not standard. “Sometimes, we wait to give the steroid until after the reaction has presented,” she added.

Although contraindications to polatuzumab vedotin plus BR are not well established, Dr. Sehn emphasized the importance of working with a pharmacist to ensure the safety of the regimen on a case-by-case basis. Prophylactic granulocyte colony-stimulating factor is recommended and can help to reduce the risk of infection.

The importance of working with a pharmacist is to ensure the safety of the regimen on a case-by-case basis.

Usually, reactions only happen with the first dose,” said Ms. Kiernan. “If the patient ends up reacting to any degree, the infusion is stopped, and the patient is assessed.” Supplemental oxygen is given, as well as fluids, if the patient is hypotensive. Additional prophylactic drugs are then administered according to standard treatment protocols: an additional antipyretic if the patient is febrile, additional antihistamines, and steroids.

Ms. Kiernan pointed out that reactions to polatuzumab vedotin are similar to those seen with monoclonal antibodies. “I would say that 9 out of 10 patients will react in some capacity to a monoclonal antibody, even with the prophylactic regimen, but they typically get through it with a prolonged infusion with frequent pauses and supplemental medications,” she said. “Most patients can then go on to the second infusion with no subsequent reaction. Polatuzumab vedotin has been similar [to monoclonal antibodies] in terms of reporting of adverse reactions and frequency of those reactions.”

She added that because many patients on polatuzumab vedotin have already received rituximab, they’re likely well acquainted with some of the reactions that should be expected.

Optimizing Patient Outcomes

At Dr. Sehn’s institution, distribution of patient information handouts is standard protocol for all patients starting the polatuzumab vedotin plus BR regimen. These handouts detail topics such as potential side effects, what to look out for, and whom to contact in the event of these side effects. Although this regimen is typically well tolerated, she emphasized the importance of monitoring for infection (particularly because bendamustine causes lymphodepletion) and neuropathy.

“In my experience, this can be a very effective treatment for patients with relapsed/refractory DLBCL, and it’s particularly effective in patients who need rapid disease control,” she said. “The response rates are quite high, and if they’re going to benefit from it, patients will typically show evidence of benefit very early on, after as little as one cycle.”

Ms. Kiernan continued: “Providing open communication, good support, and information regarding possible side effects, and what we can do to alleviate them, is of utmost importance. If we can effectively relay our confidence in the drug, and our patients are confident in our abilities, I think we can extend the potential of this drug to many more people.”

Looking Ahead to Possible Approval in Newly Diagnosed Patients

The current standard of care for patients with newly diagnosed DLBCL is R-CHOP, but approximately 40% of patients who receive this regimen are not cured. However, findings from the phase III POLARIX trial may offer hope for more effective therapeutic options in newly diagnosed DLBCL. The study compared R-CHOP with polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, and prednisone in patients with previously untreated DLBCL.⁵

The POLARIX trial met its primary endpoint, with a 27% reduction in the relative risk of disease progression, relapse, or death associated with the polatuzumab vedotin combination regimen. The results also showed significant improvements with the combination in secondary endpoints such as event-free survival and disease-free survival, with a tolerable safety profile.

Disclosures

Laurie Sehn, MD, MPH, has served as a consultant and received honoraria from AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, Celgene, Chugai, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Roche/Genentech, Sandoz, Seattle Genetics, Servier, Teva, Takeda, TG Therapeutics, andVerastem; and has received research funding from Roche/Genentech and Teva.

Justina Kiernan, PA, reported no conflicts of interest.

References

1. U.S. Food and Drug Administration. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma#:~:text=The%20recommended%20dose%20of%20polatuzumab,the%20previous%20infusion%20is%20tolerated. Accessed April 11, 2022.
2. U.S. Food and Drug Administration. FDA approves first chemoimmunotherapy regimen for patients with relapsed or refractory diffuse large B-cell lymphoma. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-chemoimmunotherapy-regimen-patients-relapsed-or-refractory-diffuse-large-b-cell. Accessed April 11, 2022
3. Herve T, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell Llmphoma. N Engl J Med. 2022;386:351–363.
4. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38:155–165.
5. Polivy (polatuzumab vedotin) prescribing information. Available at https://www.gene.com/download/pdf/polivy_prescribing.pdf. Accessed April 11, 2022.