Polatuzumab Vedotin

POLIVY is a CD79b-directed antibody and microtubule inhibitor conjugate indicated: in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) 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. ( 1.1 ) in combination with bendamustine and a rituximab product for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies. ( 1.2 )

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.

For injection: 30 mg/vial or 140 mg/vial of polatuzumab vedotin-piiq as a white to grayish-white lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 30 mg or 140 mg of polatuzumab vedotin-piiq as a lyophilized powder in a single-dose vial. ( 3 )

None. None. ( 4 )

Peripheral Neuropathy: Monitor patients for peripheral neuropathy and modify or discontinue dose accordingly. ( 5.1 ) Infusion-Related Reactions: Premedicate with an antihistamine and antipyretic. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions. ( 5.2 ) Myelosuppression: Monitor complete blood counts. Manage using dose delays or reductions and growth factor support. Monitor for signs of infection. ( 5.3 ) Serious and Opportunistic Infections: Closely monitor patients for signs of bacterial, fungal, or viral infections. ( 5.4 ) Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML. ( 5.5 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden or rapidly proliferative tumors. ( 5.6 ) Hepatotoxicity: Monitor liver enzymes and bilirubin. ( 5.7 ) Infusion Site Extravasation Injury: Ensure patent venous access prior to initiating the infusion and closely monitor the infusion site throughout administration for any signs of extravasation. Stop the infusion immediately if extravasation occurs. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 3 months after the last dose. ( 5.9 )

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 Infusion Site Extravasation Injury Cases of tissue damage following infusion site extravasation, including severe events, have been reported in clinical studies and in the postmarketing setting in patients treated with POLIVY. […]

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Peripheral Neuropathy [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Myelosuppression [see Warnings and Precautions (5.3) ] Serious and Opportunistic Infections [see Warnings and Precautions (5.4) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.5) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Infusion Site Extravasation Injury [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥20%) in patients with large B-cell lymphoma treated with POLIVY in combination with R-CHP, excluding laboratory abnormalities, are peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3 to 4 laboratory abnormalities (≥10%) are lymphopenia, neutropenia, hyperuricemia, and anemia. ( 6.1 ) The most common adverse reaction (≥20%) in patients with relapsed or refractory DLBCL treated with POLIVY in combination with BR are neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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). Previously Untreated DLBCL, NOS or HGBL GO39942 (POLARIX) The safety of POLIVY in combination with R-CHP chemoimmunotherapy was evaluated in POLARIX, a randomized double-blind, placebo-controlled, multicenter study of 873 patients with previously untreated large B-cell lymphoma, 435 of whom received POLIVY plus R-CHP [see Clinical Studies (14.1) ] . Patients were randomized 1:1 to receive POLIVY plus R-CHP or to receive R-CHOP for six 21-day cycles followed by two additional cycles of rituximab alone in both arms. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 90% of patients in the POLIVY plus R-CHP arm and 93% of patients in the R-CHOP arm. Following premedication with an antihistamine and antipyretic, POLIVY was administered intravenously at 1.8 mg/kg on Day 1 of Cycles 1–6. R-CHP was administered starting on Day 1 of Cycles 1–6. Rituximab monotherapy was administered on Day 1 of Cycles 7–8 [see Clinical Studies (14.1) ] . The trial required an absolute neutrophil count ≥1,000/µL, platelet count ≥75,000/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. The trial excluded patients having age >80, ECOG performance status above 2, known central nervous system (CNS) lymphoma, and Grade 2 or higher peripheral neuropathy. The median age was 65 years overall (range: 19 to 80 years); 54% of patients were male; 53% were White, 19% were Asian, 2%, Black or African American, and 5% were Hispanic or Latino. In the POLIVY plus R-CHP group, 92% of patients received 6 cycles of POLIVY, and 94% completed 6 cycles of combination therapy. Serious adverse reactions occurred in 34% of patients who received POLIVY plus R-CHP, including febrile neutropenia and pneumonia in ≥5% of recipients. Fatal adverse reactions occurred in 3% of recipients of POLIVY plus R-CHP within 90 days of last treatment, primarily from infection including pneumonia (0.9%) and sepsis (0.2%). Adverse reactions led to dose reduction of POLIVY in 6% of patients, mainly from peripheral neuropathy. Adverse reactions lead to dose interruption of POLIVY in 18% of patients, most commonly from pneumonia and neutropenia, and permanent discontinuation of POLIVY in 4.4% of patients. Table 7 summarizes adverse reactions in POLARIX. In recipients of POLIVY plus R-CHP, adverse reactions in ≥20% of patients, excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. New or worsening Grade 3 to 4 laboratory abnormalities in ≥10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia. Table 7 Select Adverse Reactions Occurring in ≥10% of Patients Treated with POLIVY Plus R-CHP in POLARIX Adverse Reactions by Body System POLIVY + R-CHP n = 435 R-CHOP n = 438 All Grades, % Grade 3–4, % All Grades, % Grade 3–4, % The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0. Blood and Lymphatic System Disorders Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes. Lymphopenia 80 44 77 44 Anemia 68 14 67 11 Neutropenia 60 39 60 42 Thrombocytopenia 32 8 33 6 Febrile neutropenia Febrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis. 15 15 9 9 Investigations Creatinine increased 66 0.7 64

0.9 Aspartate aminotransferase increased 26 0.7 23

1.1 Alanine aminotransferase increased 25 1.4 27

0.5 Alkaline phosphatase increased 23 0 22

0.5 Uric acid increased 19 18 17 16 Weight decreased 13 0.9 12

0.2 Nervous System Disorders Peripheral neuropathy At last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY + R-CHP arm and in 33% in the R-CHOP arm. , Peripheral neuropathy includes all terms containing "neuropathy", neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia. 53 1.6 54

1.1 Altered taste 14 0 16 0 Headache 13 0.2 14

0.9 Gastrointestinal Disorders Nausea 42 1.1 37

0.5 Diarrhea 31 3.9 20

1.8 Constipation 29 1.1 29

0.2 Mucositis Mucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration. 22 1.4 19

0.5 Abdominal pain Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms. 16 1.1 14

1.6 Vomiting 15 1.1 14

0.7 General Disorders Fatigue 37 2.5 38

3.0 Pyrexia 16 1.4 13 0 Edema Edema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling. 14 0.5 11

0.2 Infusion-related reaction Infusion related reaction is reflective of the combination regimen due to same-day administration. 13 1.1 16

1.6 Skin and Subcutaneous Tissue Disorders Alopecia 24 0 24

0.2 Rash Rash includes rash, dermatitis, and related terms. 13 0.7 11 0 Musculoskeletal Disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain. 19 0.5 21

1.8 Infections Upper respiratory tract infection Upper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections. […]

Concomitant use of strong CYP3A inhibitors or inducers has the potential to affect the exposure to unconjugated monomethyl auristatin E (MMAE). ( 7.1 )

7.1 Effects of Other Drugs on POLIVY Strong CYP3A Inhibitors Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC [see Clinical Pharmacology (12.3) ] , which may increase POLIVY toxicities. Monitor patients for signs of toxicity. Strong CYP3A Inducers Concomitant use with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC [see Clinical Pharmacology (12.3) ] .

Hepatic impairment has the potential to increase exposure to MMAE. Monitor patients for adverse reactions. ( 8.6 ) Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , POLIVY can cause fetal harm. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of the small molecule component of POLIVY, MMAE, to pregnant rats during organogenesis at exposures below the clinical exposure at the recommended dose of 1.8 mg/kg POLIVY every 21 days resulted in embryo-fetal mortality and structural abnormalities (see Data ) . Advise a pregnant woman of the potential risks to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data No embryo-fetal development studies in animals have been performed with polatuzumab vedotin-piiq. In an embryo-fetal developmental study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of POLIVY, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

8.2 Lactation Risk Summary There is no information regarding the presence of polatuzumab vedotin-piiq in human milk, the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with POLIVY and for 2 months after the last dose.

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) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating POLIVY [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the final dose [see Nonclinical Toxicity (13.1) ] . Infertility Females Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), POLIVY may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1) ] . Males Based on findings from animal studies, POLIVY may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1) ] .

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).

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.