Polivy Drug Information

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.

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.

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 . 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 . 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 6 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 6 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

Aspartate aminotransferase increased 26 0.7 23 1.1 Alanine aminotransferase increased 25 1.4

27

Alkaline phosphatase increased 23 0 22 0.5 Uric acid increased 19 18

17 16 Weight decreased 13 0.9 12

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

Altered taste 14 0 16 0 Headache 13 0.2 14 0.9 Gastrointestinal

Disorders Nausea 42 1.1 37

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

Abdominal pain Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric

discomfort, and related terms. 16 1.1 14

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

Infusion-related reaction Infusion related reaction is reflective of the combination regimen due

to same-day administration. 13 1.1 16

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

Infections Upper respiratory tract infection Upper respiratory tract infection incudes sinusitis, laryngitis

pharyngitis, nasopharyngitis, rhinitis, and specific infections. 17 0.5 16

Metabolism and Nutrition Disorders Decreased appetite 17 1.1 14 0.7 Respiratory Disorders

Cough 15 0 14 0 Dyspnea 13 0.9 10

Other clinically relevant adverse reactions in <10% of recipients of

POLIVY plus R-CHP included: Infections: pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection Metabolic disorders: tumor lysis syndrome Renal disorders: renal insufficiency Respiratory disorders: pneumonitis Relapsed or Refractory DLBCL, NOS GO29365 The data described in this section reflect exposure to POLIVY in Study GO29365, a multicenter clinical trial for adult patients with relapsed or refractory B-cell lymphomas . In patients with relapsed or refractory DLBCL, the trial included a single-arm safety evaluation of POLIVY in combination with bendamustine and a rituximab product (BR) (n = 6), followed by an open-label randomization to POLIVY in combination with BR versus BR alone (n = 39 treated per arm). Following premedication with an antihistamine and antipyretic, POLIVY 1.8 mg/kg was administered by intravenous infusion on Day 2 of Cycle 1 and on Day 1 of Cycles 2–6, with a cycle length of 21 days. Bendamustine 90 mg/m 2 daily was administered intravenously on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2–6. A rituximab product dosed at 375 mg/m 2 was administered intravenously on Day 1 of each cycle. Granulocyte colony-stimulating factor primary prophylaxis was optional and administered to 42% of recipients of POLIVY plus BR. In POLIVY-treated patients (n = 45), the median age was 67 years (range 33 – 86) with 58% being ≥age 65, 69% were male, 69% were White, and 87% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial required an absolute neutrophil count ≥1500/µL, platelet count ≥75/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times ULN, and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease.

Patients with Grade 2 or higher peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) were excluded. Patients treated with POLIVY plus BR received a median of 5 cycles, with 49% receiving 6 cycles. Patients treated with BR alone received a median of 3 cycles, with 23% receiving 6 cycles.

Fatal adverse reactions occurred in 7% of recipients of POLIVY plus BR within 90 days of last treatment. Serious adverse reactions occurred in 64%, most often from infection. Serious adverse reactions in ≥5% of recipients of POLIVY plus BR included pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%). In recipients of POLIVY plus BR, adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia.

Table 7 summarizes commonly reported adverse reactions. In recipients of POLIVY plus BR, adverse reactions in ≥20% of patients included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Table 7 Adverse Reactions Occurring in >10% of Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group in Study GO29365 Adverse Reactions by Body System POLIVY + BR n = 45 BR n = 39 All Grades, % Grade 3 or Higher, % All Grades, % Grade 3 or Higher, % The table includes a combination of grouped and ungrouped terms.

Events were graded using NCI CTCAE version 4. Blood and Lymphatic System Disorders Neutropenia 49 42 44 36 Thrombocytopenia 49 40 33 26 Anemia 47 24 28 18 Lymphopenia 13 13 8 8 Nervous System Disorders Peripheral neuropathy 40 0 8 0 Dizziness 13 0 8 0 Gastrointestinal Disorders Diarrhea 38 4.4 28 5 Vomiting 18 2.2 13 0 General Disorders Infusion-related reaction 18 2.2 8 0 Pyrexia 33 2.2 23 0 Decreased appetite 27 2.2 21 0 Infections Pneumonia 22 16 Includes 2 fatalities. 15

Includes 1 fatality. Upper respiratory tract infection 13 0 8 0 Investigations

Weight decreased 16 2.2 8

Metabolism and Nutrition Disorders Hypokalemia 16 9 10 2.6 Hypoalbuminemia 13 2.2

8 0 Hypocalcemia 11 2.2 5 0 Other clinically relevant adverse reactions (<10% or with a <5% difference) in recipients of POLIVY plus BR included: Blood and lymphatic system disorders: pancytopenia (7%) Musculoskeletal disorders: arthralgia (7%) Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increased (7%) Respiratory disorders: pneumonitis (4.4%) Selected treatment-emergent laboratory abnormalities are summarized in Table 8. In recipients of POLIVY plus BR, >20% of patients developed Grade 3 or 4 neutropenia, leukopenia, or thrombocytopenia, and >10% developed Grade 4 neutropenia (13%) or Grade 4 thrombocytopenia (11%). Table 8 Select Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group Laboratory Parameter Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown. POLIVY + BR n = 45 BR n = 39 All Grades, (%) Grade 3–4, (%) All Grades, (%) Grade 3–4, (%) Hematologic Lymphocyte count decreased 87 87 90 82 Neutrophil count decreased 78 61 56 33 Hemoglobin decreased 78 18 62 10 Platelet count decreased 76 31 64 26 Chemistry Creatinine increased 87 4.4 77 5 Calcium decreased 44 9 26 0 SGPT/ALT increased 38 0 8

SGOT/AST increased 36 0 26 2.6 Lipase increased 36 9 13 5

Phosphorus decreased 33 7 28 8 Amylase increased 24 0 18

Potassium decreased 24 11 28 5 Safety was also evaluated in 173

adult patients with relapsed or refractory lymphoma who received POLIVY, bendamustine, and either a rituximab product or obinutuzumab in Study GO29365, including the 45 patients with DLBCL described above. In the expanded safety population, the median age was 66 years (range 27 – 86), 57% were male, 91% had an ECOG performance status of 0-1, and 32% had a history of peripheral neuropathy at baseline. Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as a leading cause.

Serious adverse reactions occurred in 60%, most often from infection. Table 9 summarizes the most common adverse reactions in the expanded safety population. The overall safety profile was similar to that described above.

Adverse reactions in ≥20% of patients were diarrhea, neutropenia, peripheral neuropathy, fatigue, thrombocytopenia, pyrexia, decreased appetite, anemia, and vomiting. Infection-related adverse reactions in >10% of patients included upper respiratory tract infection, febrile neutropenia, pneumonia, and herpesvirus infection. Table 9 Most Common Adverse Reactions (≥20% Any Grade or ≥5% Grade 3 or Higher) in Recipients of POLIVY and Chemoimmunotherapy for Relapsed or Refractory Lymphoma Adverse Reaction by Body System POLIVY + Bendamustine + Rituximab Product or Obinutuzumab n = 173 All Grades, % Grade 3 or Higher, % The table includes a combination of grouped and ungrouped terms.

Blood and Lymphatic System Disorders Neutropenia 44 39 Thrombocytopenia 31 23 Anemia 28 14 Febrile neutropenia Primary prophylaxis with granulocyte colony-stimulating factor was given to 46% of all patients. 13 13 Leukopenia 13 8 Lymphopenia 12 12 Nervous System Disorders Peripheral neuropathy 40

Gastrointestinal Disorders Diarrhea 45 8 Vomiting 27 2.9 General Disorders Fatigue 40

5 Pyrexia 30

Decreased appetite 29 1.7 Infections Pneumonia 13 10 Includes 5 fatalities. Sepsis

6 6 Includes 4 fatalities. Metabolism and Nutrition Disorders Hypokalemia 18 6 Other clinically relevant adverse reactions (<20% any grade) included: General disorders: infusion-related reaction (7%) Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%) Respiratory: dyspnea (19%), pneumonitis (1.7%) Nervous system disorders: dizziness (10%) Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%) Musculoskeletal disorders: arthralgia (7%) Eye disorders: blurred vision (1.2%)

Effects of Other Drugs on

POLIVY Strong CYP3A Inhibitors Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC , 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 .

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , 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 at the recommended dose).

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