Polivy (Polatuzumab Vedotin-piiq), Novel Antibody–Drug Conjugate, Approved for Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin lymphoma and the most common blood cancer.1,2 DLBCL accounts for approximately 33% of all lymphomas.3 DLBCL is an aggressive cancer that may start in the lymph nodes or outside the lymphatic system and may affect the bone, bone marrow, gastrointestinal tract, brain, breast, testes, liver, spleen, or other organs.2,4

According to 2016 data, nearly 18,000 new cases of DLBCL are diagnosed annually in the United States, most frequently in people aged 65 to 74 years.1 Approximately 63% of patients with DLBCL have a relative survival of 5 years.

Current treatments for DLBCL may be monotherapy or combination therapies, including chemotherapy regimens; monoclonal antibodies, chimeric antigen receptor T-cell therapy; CD79b-targeted therapies, radiation, and/or, in some cases, a stem-cell transplant.5 Treatment decisions are generally based on the patient’s disease stage and histology, age, performance status, and other risk factors, using the International Prognostic Index (IPI) score as a guide.5 Most patients with DLBCL respond to treatment; however, up to 40% of patients may have an inadequate response to treatment or disease relapse.6

Polatuzumab Vedotin Approved for Relapsed or Refractory DLBCL

On June 10, 2019, the US Food and Drug Administration (FDA) accelerated the approval of polatuzumab vedotin-piiq (Polivy; Genentech), a CD79b-directed antibody–drug conjugate, in combination with bendamustine chemotherapy and rituximab, a CD20-directed monoclonal antibody, for the treatment of adults with relapsed or refractory DLBCL after ≥2 therapies.7,8 The FDA granted polatuzumab vedotin breakthrough therapy and orphan drug designations.7

“Antibody–drug conjugates are an emerging class of targeted immunotherapies for cancer. This type of therapy, unlike traditional chemotherapy, is intended to target specific cells,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Today’s approval of Polivy provides an alternative option for patients in whom multiple treatments have not worked,”7 Dr Pazdur added.

Mechanism of Action

Polatuzumab vedotin is an antibody–drug conjugate that binds to CD79b, a B-cell specific surface protein expressed in most B-cells, including malignant B-cells.9,10 Polatuzumab vedotin is conjugated to monomethyl auristatin E (MMAE), an antimitotic agent attached to the antibody via a cleavable linker.9

On binding to the CD79b on B-cells, polatuzumab vedotin is internalized into the cell, where lysosomal proteases cleave the linker to activate intracellular delivery of MMAE. The MMAE then binds to microtubules and acts against the dividing B-cells by inhibiting cell division and inducing apoptosis.9

Dosing and Administration

Polatuzumab vedotin is available for injection as a lyophilized powder in a 140-mg single-dose vial. The recommended dose is 1.8 mg/kg as an intravenous infusion over 90 minutes, administered every 21 days for 6 cycles in combination with bendamustine plus rituximab. If the patient tolerates the previous infusion, subsequent infusions may be administered over 30 minutes.9

Before administering polatuzumab vedotin, premedication with an antihistamine and an antipyretic is recommended.9

Pivotal Clinical Trial: GO29365

The approval of polatuzumab vedotin was based on findings from GO29365, an open-label, multicenter, phase 1b/2 clinical trial of 80 patients (median age, 69 years) with relapsed or refractory DLBCL who received ≥1 previous treatments.9,10 Patients who were candidates for autologous hematopoietic stem-cell transplant at baseline were not eligible for this study.9,10

Eligible patients were randomized (1:1) to polatuzumab vedotin plus bendamustine-rituximab or bendamustine-rituximab alone for up to six 21-day cycles.9,10 The patients were premedicated with an antihistamine and an antipyretic before treatment.9 The polatuzumab-based combination cohort received a median of 5 cycles of treatment, with 49% of patients receiving 6 cycles. The bendamustine-rituximab cohort received a median of 3 cycles of treatment, with 23% of patients receiving 6 treatment cycles.

The efficacy was measured by complete responses and duration of the response. Overall, 40% of the patients who received the polatuzumab vedotin–based combination achieved complete responses versus 18% of patients who received chemoimmunotherapy with bendamustine-rituximab (Table).9,10 In addition, 64% of patients who achieved a complete or partial response with the polatuzumab vedotin regimen had a response lasting ≥6 months, and 48% had a response lasting ≥12 months.9

Table

Adverse Reactions

The most common (≥20%) adverse reactions associated with polatuzumab vedotin plus chemoimmunotherapy were diarrhea (45%), neutropenia (44%), peripheral neuropathy (40%), fatigue (40%), thrombocytopenia (31%), pyrexia (30%), decreased appetite (29%), anemia (28%), and pneumonia (13%).9,10

Serious events were reported in 64% of patients, most frequently from infections, including pneumonia (16%); febrile neutropenia (11%); pyrexia (9%); and sepsis (7%). In all, 7% of the patients died from adverse reactions within 90 days of the last treatment.9,10

Adverse reactions resulted in dose reduction in 18% of patients, dose interruption in 51%, and permanent treatment discontinuation in 31% of patients. Thrombocytopenia and/or neutropenia were the most common events leading to treatment discontinuation.9

Polatuzumab vedotin has no contraindications.9

Drug Interactions

The concomitant use of polatuzumab vedotin with a strong cytochrome (CY) P3A4 inhibitor may increase the concentration time and exposure of unconjugated MMAE, thereby increasing toxicities.9

The concomitant use of polatuzumab vedotin with a strong CYP3A4 inducer may decrease the concentration time and exposure of unconjugated MMAE.9

Use in Specific Populations

Polatuzumab vedotin should not be used in patients with moderate or severe hepatic impairment. No dose adjustments are required with mild hepatic impairment.9

The number of patients aged ≥65 years in the GO29365 study was insufficient to establish whether they respond to polatuzumab vedotin different from younger patients. Serious adverse events occurred in 64% of patients aged ≥65 years and 53% in patients aged <65 years.9

Data are not available on the presence of polatuzumab vedotin in human milk, its effect on milk production, or its effect on the breastfed child.9

Warnings and Precautions

Peripheral neuropathy, including severe cases, has occurred with pol­atuzumab vedotin as early as the first treatment cycle; the effects of peripheral neuropathy can be cumulative. Patients who have signs or symptoms of peripheral neuropathy may require a dose reduction, delay, or treatment discontinuation.9

Infusion-related reactions have been reported with polatuzumab vedotin. Patients should be premedicated with an antihistamine and an antipyretic before treatment. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management initiated.9

Serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia, have occurred with polatuzumab vedotin. The patient’s complete blood count should be monitored throughout treatment; dose delays or reductions and growth factor support may be required to manage myelosuppression.9

Fatal and/or serious infections, including opportunistic infections, have been reported with polatuzumab vedotin. Patients should be closely monitored for bacterial, fungal, or viral infections; prophylaxis should be administered for Pneumocystis jiroveci pneumonia and herpesvirus.9

Progressive multifocal leukoencephalopathy (PML) can occur after polatuzumab vedotin treatment. Patients should be monitored for new or worsening neurologic, cognitive, or behavioral changes indicative of PML.9

Patients with a high tumor burden and aggressive tumor activity may be at risk for tumor lysis syndrome. Tumor lysis syndrome prophylaxis is recommended.9

Serious hepatotoxicity can occur with polatuzumab vedotin. Monitor the patient’s liver enzyme and bilirubin levels.9

Polatuzumab vedotin can cause fetal harm. Pregnancy status should be confirmed before starting treatment. Women of reproductive potential should use contraception during treatment and for a minimum of 3 months after the last dose of polatuzumab vedotin. Male patients with female partners of reproductive potential should use contraception during treatment and for at least 5 months after the last dose of polatuzumab vedotin.9

Conclusion

The accelerated approval of polatuzumab vedotin, in combination with bendamustine-rituximab, provides the first chemoimmunotherapy option for patients with relapsed or refractory DLBCL. In a clinical trial, patients who received polatuzumab vedotin plus bendamustine-rituximab had a significantly greater complete response rate and objective response rate, more than twice the response rate than patients who received only bendamustine-rituximab. Of patients who received polatuzumab vedotin plus bendamustine-rituximab and had a complete or partial response, 64% sustained the response for ≥6 months and 48% sustained the response for ≥12 months.

References

  1. National Cancer Institute. SEER program cancer stat facts: NHL - diffuse large B-cell lymphoma (DLBCL). https://seer.cancer.gov/statfacts/html/dlbcl.html. Accessed September 25, 2019.
  2. National Institutes of Health. Diffuse large B-cell lymphoma. https://rarediseases.info.nih.gov/diseases/3178/diffuse-large-b-cell-lymphoma. Accessed September 25, 2019.
  3. American Cancer Society. Types of B-cell lymphoma. Revised January 29, 2019. www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html. Accessed September 25, 2019.
  4. National Cancer Institute. Diffuse large B-cell lymphoma definition. NCI Dictionary of Cancer Terms. www.cancer.gov/publications/dictionaries/cancer-terms/def/diffuse-large-b-cell-lymphoma. Accessed September 25, 2019.
  5. American Cancer Society. Treating B-cell non-Hodgkin lymphoma. Revised June 29, 2019. www.cancer.org/cancer/non-hodgkin-lymphoma/treating/b-cell-lymphoma.html. Accessed September 25, 2019.
  6. Maurer MJ, Ghesquières H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32:1066-1073.
  7. US Food and Drug Administration. FDA approves first chemoimmunotherapy regimen for patients with relapsed or refractory diffuse large B-cell lymphoma. June 10, 2019. www.fda.gov/news-events/press-announcements/fda-approves-first-chemoimmunotherapy-regimen-patients-relapsed-or-refractory-diffuse-large-b-cell. Accessed September 24, 2019.
  8. National Cancer Institute. Rituximab. NCI Drug Dictionary. www.cancer.gov/publications/dictionaries/cancer-drug/def/rituximab. Accessed September 25, 2019.
  9. Polivy (polatuzumab vedotin-piiq) for injection, for intravenous use [prescribing information]. South San Francisco, CA: Genentech; June 2019.
  10. 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.

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