1.1 Previously Untreated DLBCL, NOS or HGBL

POLIVY in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater.

1.2 Relapsed or Refractory DLBCL, NOS

POLIVY in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.

2.1 Recommended Dosage

2.2 Management of Adverse Reactions

2.3 Recommended Prophylactic Medications

If not already premedicated for a rituximab product, administer an antihistamine and antipyretic at least 30 to 60 minutes prior to POLIVY for potential infusion-related reactions [see Warnings and Precautions (5.2)].

Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus throughout treatment with POLIVY.

Administer prophylactic granulocyte colony-stimulating factor (G-CSF) for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration for neutropenia in patients receiving POLIVY plus bendamustine and a rituximab product [see Warnings and Precautions (5.3)].

Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome [see Warnings and Precautions (5.6)].

2.4 Instructions for Preparation and Administration

Reconstitute and further dilute POLIVY prior to intravenous infusion.

POLIVY is a hazardous drug. Follow applicable special handling and disposal procedures.1

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

5.1 Peripheral Neuropathy

POLIVY can cause peripheral neuropathy, including severe cases. Peripheral neuropathy occurs as early as the first cycle of treatment and is a cumulative effect [see Adverse Reactions (6.1)]. POLIVY may exacerbate pre-existing peripheral neuropathy.

In POLARIX, of 435 patients treated with POLIVY plus R-CHP, 53% reported new or worsening peripheral neuropathy, with a median time to onset of 2.3 months. Peripheral neuropathy was Grade 1 in 39% of patients, Grade 2 in 12%, and Grade 3 in 1.6%. Peripheral neuropathy resulted in dose reduction in 4% of treated patients and treatment discontinuation in 0.7%. Among patients with peripheral neuropathy after POLIVY, 58% reported resolution after a median of 4 months.

In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with a median time to onset of 2.1 months. Peripheral neuropathy was Grade 1 in 26% of patients, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after a median of 1 month, and 48% reported complete resolution.

The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)].

5.2 Infusion-Related Reactions

POLIVY can cause infusion-related reactions, including severe cases. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred.

With premedication, 13% of patients (58/435) in POLARIX reported infusion-related reactions after the administration of POLIVY plus R-CHP. The reactions were Grade 1 in 4.4% of patients, Grade 2 in 8%, and Grade 3 in 1.1%.

With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 4.6% of patients, Grade 2 in 1.7%, and Grade 3 in 0.6%.

Symptoms occurring in ≥1% of patients included chills, dyspnea, pyrexia, pruritus, rash, and chest discomfort. Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management [see Dosage and Administration (2.2)].

5.3 Myelosuppression

Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia.

In POLARIX, 90% of patients treated with POLIVY plus R-CHP had primary prophylaxis with G-CSF. Grade 3–4 hematologic adverse reactions included lymphopenia (44%), neutropenia (39%), febrile neutropenia (15%), anemia (14%), and thrombocytopenia (8%) [see Adverse Reactions (6.1)].

In Study GO29365, in patients treated with POLIVY plus BR (n = 45), 42% received primary prophylaxis with G-CSF. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%) [see Adverse Reactions (6.1)]. Grade 4 hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients).

Monitor complete blood counts throughout treatment. Cytopenias may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)]. Administer prophylactic G-CSF for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration in patients receiving POLIVY plus bendamustine and a rituximab product.

5.4 Serious and Opportunistic Infections

Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY [see Adverse Reactions (6.1)].

In POLARIX, Grade 3–4 infections occurred in 14% (61/435) of patients treated with POLIVY plus R-CHP and infection-related deaths were reported in 1.1% of patients.

In Study GO29365, Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVYand infection-related deaths were reported in 2.9% of patients within 90 days of last treatment.

Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus. Administer prophylactic G-CSF for neutropenia as recommended [see Dosage and Administration (2.3)].

5.5 Progressive Multifocal Leukoencephalopathy (PML)

PML has been reported after treatment with POLIVY plus bendamustine and obinutuzumab in study GO29365 (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed.

5.6 Tumor Lysis Syndrome

POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis.

5.7 Hepatotoxicity

Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY.

In recipients of POLIVY plus R-CHP, Grade 3–4 elevation of ALT and AST developed in 1.4% and 0.7% of patients, respectively.

In Study GO29365, Grade 3 and Grade 4 transaminase elevations each developed in 1.9% of patients.

Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level.

5.8 Embryo-Fetal Toxicity

Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to a pregnant woman. The small molecule component of POLIVY, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure to POLIVY 1.8 mg/kg in 480 patients with large B-cell lymphoma (LBCL), including those with previously untreated LBCL (POLARIX) and relapsed or refractory DLBCL (GO29365).

7.1 Effects of Other Drugs on POLIVY

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

POLIVY can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

Safety and effectiveness of POLIVY have not been established in pediatric patients.

8.5 Geriatric Use

Among 435 patients treated with POLIVY plus R-CHP in POLARIX, 227 (52%) were ≥65 years of age. No overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients.

Among 173 patients treated with POLIVY plus BR in Study GO29365, 95 (55%) were ≥65 years of age. Patients aged ≥65 had a numerically higher incidence of serious adverse reactions (64%) than patients aged <65 (53%). This study did not include sufficient numbers of patients to determine whether efficacy differed in patients aged ≥65 and younger patients.

8.6 Hepatic Impairment

Avoid the administration of POLIVY in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 × ULN and any AST). Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions. POLIVY has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.7)].

No adjustment in the starting dose is required when administering POLIVY to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN or AST greater than ULN).

12.1 Mechanism of Action

Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with activity against dividing B cells. The small molecule, MMAE, is an anti-mitotic 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.

12.2 Pharmacodynamics

Over polatuzumab vedotin-piiq dosages of 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage), higher exposures (AUC and Cmax) of antibody-conjugated MMAE (acMMAE) and unconjugated MMAE were associated with higher incidence of some adverse reactions (including ≥Grade 3 thrombocytopenia and ≥Grade 3 anemia). Higher exposure (AUC and Cmax) of unconjugated MMAE was associated with higher incidence of ≥Grade 2 peripheral neuropathy. Lower acMMAE exposure (AUC) was associated with lower efficacy in patients with relapsed or refractory DLBCL.

12.3 Pharmacokinetics

The exposure parameters of acMMAE and unconjugated MMAE (the cytotoxic component of polatuzumab vedotin-piiq) are summarized in Table 10. The plasma exposure of acMMAE and unconjugated MMAE increased proportionally over a polatuzumab vedotin-piiq dose range from 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage). Cycle 3 acMMAE AUC were predicted to increase by approximately 30% over Cycle 1 AUC, and achieved more than 90% of the Cycle 6 AUC. Unconjugated MMAE plasma exposures were <3% of acMMAE exposures, and the AUC and Cmax were predicted to decrease after repeated every-3-week dosing.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of POLIVY or of other polatuzumab products.

In studies POLARIX and GO29365, 1.4% (6/427) and 6% (8/134) of patients tested positive for antibodies against polatuzumab vedotin-piiq, respectively, of which none were positive for neutralizing antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of polatuzumab products is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in animals have not been performed with polatuzumab vedotin-piiq or MMAE.

MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism. MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies in animals have not been performed with polatuzumab vedotin-piiq or MMAE. However, results of repeat-dose toxicity indicate the potential for polatuzumab vedotin-piiq to impair female and male fertility. In the 4-week repeat-dose toxicity study in rats with weekly dosing of 2, 6, and 10 mg/kg, dose-dependent testicular seminiferous tubule degeneration with abnormal lumen contents in the epididymis was observed. Findings in the testes and epididymis did not reverse and correlated with decreased testes weight and gross findings of small and/or soft testes at recovery necropsy in males given doses ≥2 mg/kg (below the exposure at the recommended dose based on unconjugated MMAE AUC).

MMAE-containing ADCs have been associated with adverse ovarian effects when administered to sexually immature animals. Adverse effects included decrease in, or absence of, secondary and tertiary ovarian follicles after weekly administration to cynomolgus monkeys in studies of 4-week duration. These effects showed a trend towards recovery 6 weeks after the end of dosing; no changes were observed in primordial follicles.

14.1 Previously Untreated DLBCL, NOS or HGBL

14.2 Relapsed or Refractory DLBCL, NOS

How Supplied

POLIVY (polatuzumab vedotin-piiq) for injection is a preservative-free, white to grayish-white lyophilized powder, which has a cake-like appearance. POLIVY is supplied as:

Storage and Handling

Store refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not use beyond the expiration date shown on the carton. Do not freeze. Do not shake.

POLIVY is a hazardous drug. Follow applicable special handling and disposal procedures.1

Peripheral Neuropathy

Advise patients that POLIVY can cause peripheral neuropathy. Advise patients to report to their healthcare provider any numbness or tingling of the hands or feet or any muscle weakness [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion reactions, including fever, chills, rash, or breathing problems, within 24 hours of infusion [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients to report signs or symptoms of bleeding or infection immediately. Advise patients of the need for periodic monitoring of blood counts [see Warnings and Precautions (5.3)].

Infections

Advise patients to contact their healthcare provider if a fever of 38°C (100.4°F) or greater or other evidence of potential infection such as chills, cough, or pain on urination develops. Advise patients of the need for periodic monitoring of blood counts [see Warnings and Precautions (5.4)].

Progressive Multifocal Leukoencephalopathy

Advise patients to seek immediate medical attention for new or changes in neurological symptoms such as confusion, dizziness, or loss of balance; difficulty talking or walking; or changes in vision [see Warnings and Precautions (5.5)].

Tumor Lysis Syndrome

Advise patients to seek immediate medical attention for symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.6)].

Hepatotoxicity

Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.7)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with POLIVY [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

Females and Males of Reproductive Potential

Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with POLIVY and for 3 months and 5 months after the last dose, respectively [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed while receiving POLIVY and for 2 months after the last dose [see Use in Specific Populations (8.2)].