On June 10, 2019, the CD79b-directed antibody-drug conjugate polatuzumab vedotin-piiq was granted accelerated approval for use in combination with bendamustine and a rituximab product for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least two prior therapies.1,2
Supporting Efficacy Data
Approval was based on findings in the open-label Study GO29365 (ClinicalTrials.gov identifier NCT02257567).2 In the trial, a cohort of 80 patients with relapsed or refractory DLBCL after at least one prior regimen were randomly assigned to receive polatuzumab vedotin-piiq in combination with bendamustine and a rituximab product (triplet therapy; n = 40) or bendamustine plus a rituximab product (doublet therapy; n = 40) for six 21-day cycles. Polatuzumab vedotin-piiq (1.8 mg/kg) was given via intravenous infusion on day 2 of cycle 1 and on day 1 of subsequent cycles. Bendamustine (90 mg/m2) was administered on days 2 and 3 of cycle 1 and on days 1 and 2 of subsequent cycles. A rituximab product (375 mg/m2) was administered on day 1 of each cycle.
The prescribing information for polatuzumab vedotin-piiq includes warnings and precautions for peripheral neuropathy, infusion-related reactions, myelosuppression, infections, progressive multifocal leukoencephalopathy, tumor-lysis syndrome, hepatotoxicity, and embryofetal toxicity.
The median age of patients was 69 years (range = 30–86 years); 66% were male; 71% were white; 98% had DLBCL not otherwise specified; the median number of prior therapies was two (range = 1–7), with 29% receiving one, 25% receiving two, and 46% receiving at least three prior therapies; and 80% of patients had refractory disease to their last therapy. Patients with at least grade 2 peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation were excluded from the study.
Efficacy was based on the complete response rate and the response duration, as determined by an independent review committee. At the end of therapy, the complete response rate was 40% in the triplet-therapy group vs 18% in the doublet-therapy group. The best overall response rate (complete plus partial responses) was 63% with the triplet therapy compared with 25% with the doublet therapy. Of the 25 patients who achieved a partial or complete response to the triplet therapy, 16 (64%) had response durations of at least 6 months, and 12 (48%) had response durations of at least 12 months.
How It Works
Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with activity against dividing B cells. The small molecule, monomethyl auristatin E (MMAE), is an antimitotic agent covalently attached to the antibody via a cleavable linker. The monoclonal antibody binds to CD79b, a B-cell–specific surface protein, which is a component of the B-cell receptor. Upon binding CD79b, polatuzumab vedotin-piiq is internalized, and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.
How It Is Used
The recommended dose of polatuzumab vedotin-piiq is 1.8 mg/kg administered as an intravenous infusion over 90 minutes every 21 days for 6 cycles in combination with bendamustine and a rituximab product. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated. The recommended dose of bendamustine is 90 mg/m2 daily on days 1 and 2, and the recommended dose of a rituximab product is 375 mg/m2 on day 1 of each cycle.
If the patient is not already premedicated for a rituximab product, an antihistamine and antipyretic must be given at least 30 to 60 minutes
prior to polatuzumab vedotin-piiq for potential infusion-related reactions. Prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus must be administered throughout treatment. Prophylactic granulocyte colony-stimulating factor administration should be considered for neutropenia. Tumor-lysis syndrome prophylaxis should be given to patients at increased risk for tumor-lysis syndrome.
Product labeling provides instructions on management, including dose reduction, withholding, and discontinuation, for grade 2 or 3 peripheral neuropathy; grade 4 peripheral neuropathy; grade 1 to 3 infusion-related reactions; grade 4 infusion-related reactions; grade 3 or 4 neutropenia; and grade 3 or 4 thrombocytopenia.
Concomitant use of strong CYP3A inhibitors/inducers has the potential to increase/decrease exposure to unconjugated MMAE. Hepatic impairment has the potential to increase exposure to MMAE.
Safety data are from 45 patients receiving polatuzumab vedotin-piiq in the randomized portion of Study GO29365 and a single-arm safety evaluation. The most common adverse events of any grade in the triplet-therapy group (incidence at least 20%) included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. The most common grade 3 or 4 adverse events included neutropenia (42% vs 36%), thrombocytopenia (40% vs 26%), anemia (24% vs 18%), and pneumonia (16% vs 2.6%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (87%), decreased neutrophils (61%), decreased platelets (31%), decreased hemoglobin (18%), and decreased potassium (11%).
Serious adverse events occurred in 64% of the triplet-therapy group, most often from infection, with the most common being pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%). Adverse events led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%; the most common causes of discontinuation were cytopenias (18%). Fatal adverse reactions occurred in 7% of the recipients of the triple therapy within 90 days of the last treatment.
The prescribing information for polatuzumab vedotin-piiq includes warnings and precautions for peripheral neuropathy, infusion-related reactions, myelosuppression, infections, progressive multifocal leukoencephalopathy, tumor-lysis syndrome, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for peripheral neuropathy, complete blood cell counts, liver enzymes and bilirubin, as well as signs of infection. Patients should be advised not to breastfeed while receiving polatuzumab vedotin-piiq. ■
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. Accessed on July 24, 2019.
2. Polatuzumab vedotin-piiq (Polivy) prescribing information. Genentech. June 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761121s000lbl.pdf. Accessed on July 24, 2019.